Turmeric and Curcumin for Neurodegenerative Diseases 0128224487, 9780128224489

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TURMERIC AND CURCUMIN FOR NEURODEGENERATIVE DISEASES

TURMERIC AND CURCUMIN FOR NEURODEGENERATIVE DISEASES

MAGISETTY OBULESU Regional Agricultural Research Station, Acharya N.G. Ranga Agricultural University, Tirupati, India

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-822448-9 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

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Author biography

M. Obulesu is a Research Associate at the Regional Agricultural Research Station, Acharya N.G. Ranga Agricultural University, Tirupati, India. He worked as a Research Associate for 4 years at the University of Tsukuba, Japan. He has 20 years of research and teaching experience. His research areas are multifarious and include food science, the pathology of neurodegenerative diseases, and designing polymer-based biomaterials such as hydrogels. He carried out Alzheimer’s disease research and developed an aluminum-induced neurotoxicity rabbit model. Mr. Obulesu’s present research focuses on the development of redox-active injectable hydrogels of polyion complexes. His research area also includes the development of metal chelators to overcome metal-induced toxicity. This is his third monograph with Elsevier following his other titles Alzheimer’s Disease Theranostics and Parkinson’s Disease Therapeutics: Emphasis on Nanotechnological Advances Diseases. He is also the editor in Phytomedicine and Alzheimer’s Disease and Nutraceuticals in Cancer Therapy, both printed by other major publishers. Mr. Obulesu received a senior research fellowship from the Indian Council of Medical Research (ICMR) in India and the Tsukuba Scholarship and Nikki Saneyoshi Fellowship from Japan. He was also awarded a certificate from Stanford University for their Scientific Writing course. He is the first and corresponding author for the majority of his articles. He is on the editorial boards of a few pathology journals including Journal of Medical Laboratory and Diagnosis and Journal of Medical and Surgical Pathology. He is also on the editorial board of nanotechnology journals including Journal of Nanotechnology and Materials Science. He also serves as a reviewer for Elsevier’s journal Neurobiology of Diseases.

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CHAPTER ONE

Health benefits of turmeric: Emphasis on anticancer activity Contents Introduction Gun puffing Curcumin Anticancer efficacy of curcumin Colorectal cancer Renal, bone, and lung cancer Blood and other cancers Antioxidant and antiinflammatory activity Noncurcuminoids Turmerones Elemenes β-Elemene Furanodiene, furanodienone, curcumol, and calebin A Conclusions and future perspectives References Further reading

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Introduction Curcuma longa L. (turmeric), which belongs to the family Zingiberaceae is usually grown in Asia (Choi et al., 2019; Jung et al., 2004). Although it is mostly used as a culinary spice, it is also extensively used in traditional medicine in India (Choi et al., 2019). It has vital ingredients such as 4%–6% curcuminoids, 2%–4% essential oils, and 2%–3% fixed oils (Hwang et al., 2016; Choi et al., 2019). Curcuminoids are the pivotal pigments and bioactive components in turmeric, which include curcumin (1,7-bis-(4-hydroxy-3methoxyphenyl-1,6-heptadiene-3,5-dione) and its derivatives, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), which are known for antioxidant, antimutagenic, anticancer, and antibacterial functions Turmeric and Curcumin for Neurodegenerative Diseases https://doi.org/10.1016/B978-0-12-822448-9.00006-6

© 2021 Elsevier Inc. All rights reserved.

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(Kang et al., 1996; Sharma et al., 2005, Park et al., 2007; Choi et al., 2019). The principal ingredient, curcumin is a polyphenolic compound considered safe by the United States (US) Food and Drug Administration (FDA) (Huang et al., 1998; Chainani-Wu, 2003; Choi et al., 2019).

Gun puffing In order to ameliorate antioxidant and antiinflammatory activities turmeric has been gun puffed at different pressures (Choi et al., 2019). Puffed turmeric showed an enhanced brown color, porous structure exhibiting the involvement of Maillard reaction, and vaporization during the process (Choi et al., 2019). Interestingly, puffing did not change vital ingredients despite a little reduction in crude fat extraction during certain circumstances (Choi et al., 2019). In addition, total phenolic compounds and antioxidant efficacy has been profoundly ameliorated in a puffing pressure dependent manner (Choi et al., 2019). Puffed turmeric extracts also inhibited proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-treated macrophages (Choi et al., 2019). In line with this, it can be concluded that puffing is a reliable and feasible method to enhance the antioxidant and antiinflammatory effects of turmeric (Choi et al., 2019).

Curcumin Curcumin, an essential ingredient extracted from turmeric (Curcuma longa L.), offers ample of health benefits. It has been measured as the basic component in the ground turmeric rhizome (Ahmad et al., 2020). However, its low bioavailability and increased biotransformation impede its success (Stohs et al., 2019). A plethora of curcumin pharmacokinetic studies in humans has evaluated total (free plus conjugated) curcumin (Stohs et al., 2019). A wealth of studies has shown the health benefits of curcumin in animal and in vitro studies by its antiinflammatory, antioxidant, immunomodulating, cytoprotective, antibacterial, metabolism mediating, antifungal, antineoplastic, antiviral, and antidepressant actions (Stohs et al., 2019). Nevertheless, free curcumin without any formulation and processing shows low water solubility, bioavailability, and gastrointestinal absorption. To overcome these issues a plethora of formulations has been studied (Douglass and Clouatre, 2015; Stohs et al., 2018, 2019).

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Anticancer efficacy of curcumin Since ages Curcuma longa has been used in the treatment of manifold illnesses (Singh, 2007; Farjam et al., 2014). Turmeric and its constituents can be regarded as multitargeted phytochemicals in cancer treatment as they show potential impact on apoptosis, autophagy, and cell cycle (Zhu and Bu, 2017). Multiple signaling pathways (e.g., p53, Ras, phosphoinositide 3- kinase, AKT, Wnt/β-catenin, and mammalian target of rapamycin) are considered as anticancer targets of curcumin (Kasi et al., 2016; Song et al., 2019). In addition, control of microRNAs network expression is altered by turmeric (Mirzaei et al., 2018). It should also be understood that histone deacetylases activity is attenuated by curcumin, based on in vitro and in vivo studies (Soflaei et al., 2018; Ahmad et al., 2020).

Colorectal cancer Colorectal cancer (CRC) is a startling universal health care issue currently. Studies have proven that obesity and related metabolic troubles are associated with colorectal cancer (Gunter and Leitzmann, 2006; Huang and Chen, 2009). Curcumin is probably a practical medication in the avoidance of CRC in obese individuals. Indeed, it initiates AMP-activated kinase by reducing the emergence of COX-2 protein and suppressing the nuclear factor-κB (NF-κB) action on the mucosa of the colon. Curcumin also curtails the leptin concentration in the serum, which on the contrary enhances the adiponectin level (Chuengsamarn et al., 2012). In another study, poloxamer 407 can be employed as a polymer for the extension of the colorectal medication liberation system for curcuminoids in CRC treatment (Chen et al., 2012). Turmeric offers antitumor and anticancer functions by attenuating NF-κB organization and downregulation of NF-κB-related gene products linked to persistence, propagation, and metastasis of cancer cells. Turmeric ameliorates the production of reactive oxygen species (ROS) and reduces the growth of tumor cell lines. Moreover, turmeric enhances the sensitivity of the tumor cells to capecitabine and taxol (chemotherapeutic drugs). It also controls NF-κB activation stimulated by receptor activator of nuclear factor-kappa B ligand (RANKL), which probably is linked to the suppression of osteoclastogenesis. Therefore, turmeric can effectively hinder the proliferation of tumor cells by the attenuation of NF-κB and STAT3 pathways (Kim et al., 2012; Troselj and Kujundzic, 2014; Jimenez-Flores et al., 2014). In addition, turmeric can substantially counter the challenge

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of P-glycoprotein-mediated multidrug resistance of CRC, as demonstrated in in vitro and in vivo studies (Lee et al., 2018).

Renal, bone, and lung cancer Chronic introduction of a human kidney cell line to 10 μM curcumin alters the swelling-initiated chloride current in a dose-dependent manner. Curcumin provokes apoptosis in the human kidney cells and initiates the appearance of a subpopulation of the cells with enlarged volume at a concentration of 5.0–10 μM. Similarly, 50 μM curcumin promotes apoptosis and enhances the size of colorectal adenocarcinoma cells. The cell cycle arrest might be the cause that augments the size of the cell line after treating with curcumin (Kossler et al., 2012). Dennis and coworkers showed an innovative amalgamation treatment by utilizing a synthetic analog of natural compound pancratistatin with curcumin for the treatment of osteosarcoma (Ma et al., 2011). Despite the robust antiproliferative and antiinflammatory properties of curcumin, its low water solubility impedes its success. A study has explained the preparation and characterization of nanocurcumin using poly-lactic-coglycolic acid. This preparation remarkably enhanced water solubility and antitumor activity of curcumin (Nair et al., 2012). Curcuma longa is currently found to possess tumor attenuating properties in both in vitro and in vivo. It has been shown that curcumin can advance the tumor hampering efficacy of docetaxel in lung cancer. Similarly, the synchronized introduction of curcumin and docetaxel lead to a little toxicity to normal tissues and the bone marrow and liver (Yin et al., 2011).

Blood and other cancers Curcumin is capable to suppress the development of a range of malignant cell types along with the lymphoma cells. The treatment of Burkitt’s lymphoma cell lines with curcumin in association with ionizing radiation (IR) showed that curcumin treatment enhances the sensitivity of lymphoma cells to IR-initiated apoptosis and ameliorates G2/M phase arrest in the cell cycle (Qiao et al., 2012). Curcumin and L-asparaginase (L-ASP) combination treatment instigates the apoptosis by initiating a variety of members of cysteine proteases (caspase-8 and caspase-9/3) together with initiating phase-I detoxification system. Curcumin acts collaboratively with L-ASP in blood and bone marrow cancer patients (Shah et al., 2012; Wang et al., 2012; Jiang et al., 2015). Furthermore, curcumin considerably reduces

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the castrate-resistant disease and human leiomyosarcoma cell lines proliferation and disrupts the cell growth of uterine leiomyosarcoma by targeting the serine/threonine protein kinase (AKT)-mammalian target of rapamycin pathway for discretion (Wong et al., 2011; Shah et al., 2012). Curcumin in an adequate quantity reduces the T cells, whereas a little quantity of curcumin improves the T cells isolated from mice harboring Lewis lung cancer cell lines (3LL) tumor. Therefore, improved CD8+ T cells demonstrated amelioration in the cytokine IFN-γ release and proliferation principally against 3LL tumor cells; all of these lead to the success of tumor attenuating efficacy (Luo et al., 2011; Han et al., 2014). The study about antiproliferative activities of turmeric constituents on human cancer cell lines such as MDAMB-231, MCF-7, and HepG2 and immunomodulatory actions of turmerones on mononuclear cells of human blood showed that the alpha-turmerone and curcuminoids noticeably inhibit the generation of cancer cells. Amelioration in the proliferation of peripheral blood mononuclear cells and the framework of cytokine has been found after the treatment of alpha-turmerone and aromatic-turmerone (Yue et al., 2010). Encapsulation of curcumin into nanocarrier systems has been shown to overcome solubility issues and facilitate its diffusion into the tissues. Accordingly, curcumin encapsulated nanocapsules remarkably reduce the tumor volume (Mazzarino et al., 2011).

Antioxidant and antiinflammatory activity Turmeric has been of utmost importance in recent times because of its antioxidant activities, which are rendered via direct scavenging of oxygen radicals and initiating antioxidant responses by nuclear factor erythroid 2-related factor 2 (Nrf2) activation. In addition to the amenable results on the endothelial function and the inflammatory state of the tissue and plasma, it was found useful for the treatment of diabetic microangiopathy substantially (Mazzarino et al., 2011). The bioactive constituents available in turmeric volatile oil involve turmerone that is found to be effective against carcinogenesis. The earlier study showed that turmeric had characteristic antioxidant efficacy (Chinedum et al., 2015). In a recent study, different fractions and turmeric oil showed extensive antimutagenic and antioxidant efficacy ( Jayaprakasha et al., 2002). Curcumin at a concentration of 200 mg/kg body weight of female Wistar rats considerably mitigated the oxidative damage in the hippocampus of rats when treated with the organophosphate pesticides parathion;

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therefore, it is a substitute to avert neurodegenerative damage after pesticide exposure (Canales-Aguirre et al., 2012). Moreover, turmeric extract has been found to have robust antioxidant activity as indicated by 2,20 -azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) tests. The antioxidant efficacy of turmeric leads to reduced levels of prostaglandin E2 (as a marker of oxidative stress) in HepG2 cells (Menghini et al., 2010). Curcumin is also supportive in enhancing the lifespan of Caenorhabditis elegans by mitigating the intracellular ROS and lipofuscin during aging (Liao et al., 2011). Earlier studies carried out to evaluate the efficacy of turmeric against lead-induced injury to the hippocampal cells of male Wistar rats showed that it broadly averted lipid peroxidation. The reaction between curcumin and metals (cadmium and lead) led to the formation of complex compounds that proved the ability of curcumin to bind to metals (Daniel et al., 2004). Turmeric harbors marked antiinflammatory activities, chiefly through Wnt/β-catenin, nuclear factor-kappa B (NF-κB) probably by blockage of myeloid differentiation primary response 88 and toll-like receptor 4/NF-κB signal (Zhang and Zeng, 2019), downregulating mRNA expression of NF-κ B-p65 (Suresh et al., 2018) and mitogen-activated protein kinases pathways, and also by epigenetic modulatory role and redox regulation (Li et al., 2019). Studies have shown that curcumin can render antiinflammatory effects by altering numerous proinflammatory cytokines (e.g., TNF-α, interleukin-6 (IL-6), and interleukin-8 (IL-8)) in a physically active cohort (FernandezLazaro et al., 2020). The similar activity was also noticed in an in vitro model of intestinal inflammation. In addition, the protective efficacy of turmeric on the intestinal epithelium may be successful in patients with inflammatory bowel disease (Governa et al., 2018). Further, it has been demonstrated that turmeric remarkably subsides the level of high-sensitivity C-reactive protein (as an acute-phase protein) in several clinical trials (Samadian et al., 2017; Saraf-Bank et al., 2019). Moreover, the efficacy of curcumin in human ectopic endometriotic stromal cells isolated from women with endometriosis has been examined. It was observed that the treatment of endometriotic stromal cells with curcumin offered substantial suppression of mRNA expression of ICAM-1 and VCAM-1. Curcumin also considerably curtailed the TNF-αinitiated cell surface and appearance of ICAM-1 and VCAM-1. In addition, the introduction of curcumin into the endometriotic stromal cells potentially decreased the TNF-α-stimulated release of IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1). Additionally, curcumin controls the initiation of transcription factor NF-κB in human endometriotic stromal cells

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(Huang and Chen, 2009). Studies have also shown that curcumin severely decreased the pancreatic injury and remarkably ameliorated the expression of peroxisome proliferator-activated receptor-γ (PPARγ). Curcumin introduction leads to modulation of cytokine TNF-α discharge that could be a probable explanation for its efficacy to inhibit the pancreatic injury. These effects together result in the upregulation of PPARγ and downregulation of NF-κB (Yu et al., 2011; Liu et al., 2014). Turmeric can attenuate the NF-κB, and epidural introduction of curcumin leads to enhanced revival from spinal cord injury (SCI) without any adverse effects. Therefore, curcumin may act as a promising treatment for humans with SCI (Ormond et al., 2012; Ahmad et al., 2020). Based on these findings, it can be concluded that a diet supplemented with turmeric can keep manifold ailments away.

Noncurcuminoids Mounting evidence has shown that the therapeutic efficacy of noncurcuminoids is on par with the curcuminoids but there is no significant amount of studies focused on them (Nair et al., 2019). Noncurcuminoids include turmerones, elemene, furanodiene (FN), bisacurone, germacrone, calebin A (CA), curdione, and cyclocurcumin. Similar to curcuminoids, therapeutic applications of noncurcuminoids were also impeded by low solubility and bioavailability. Therefore, the encapsulation of noncurcuminoid constituents in multifarious drug delivery systems like co-crystals, solid lipid nanoparticles, liposomes, microspheres, and polar-nonpolar sandwich (PNS) technology has been extensively studied to overcome their shortcomings and exhibit their potential benefits such as anticancer activities. Primarily, its volatile oil and nonvolatile oleoresins comprise bioactive constituents that are categorized as diphenylheptanoids (nonvolatile), diphenylpentanoids (nonvolatile), phenylpropene (cinnamic acid type) derivatives (nonvolatile), and turmeric oil comprising terpenoids (volatile) ( Jacob, 2016). Important diphenylheptanoids are curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which are named as curcuminoids (Srinivasan, 1952; Anand et al., 2008). On the other hand, noncurcuminoids can be described as all the biologically active ingredients other than curcuminoids, specifically, curcumin-free bioactive constituents of turmeric (Aggarwal et al., 2013). Noncurcuminoids like turmerones, elemene, bisacurone, curdione, cyclocurcumin, germacrone, furanodiene, curcumol, and calebin A were focused substantially due to their pharmacological activities like antiinflammatory, antioxidant, and anticancer activities. Studies have particularly

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shown that noncurcuminoids have a wide-range of anticancer activities on various cell lines together with complex and drug-resistant malignancies. Despite the demonstration of similar efficacy of noncurcuminoids with that of curcuminoids, their anticancer studies are obscure (Aggarwal et al., 2013; Li et al., 2014).

Turmerones Turmerones are the principal sesquiterpenes obtained from turmeric. They are categorized as α-turmerone, ar-turmerone, and β-turmerone, and among them ar-turmerone has been found to be more effective against cancer. However, Yue et al. elucidated the immunomodulatory and chemopreventive activities of α-turmerone and unraveled its efficiency to be on par with curcuminoids. Turmerones control the propagation of cancer cells in a dose-dependent manner with half-maximal inhibitory concentration (IC50) values ranging from 11.0 to 41.81 g/mL (Yue et al., 2010). The bioavailability of curcumin could be remarkably enhanced by (α, ar) turmerones as described by Yue et al. in human intestinal epithelial colorectal adenocarcinoma Caco-2 cells. The protective efficacy of curcumin was increased in association with turmerones in human colonic cancer cells (HCT-116 and HT-29) and human umbilical vein endothelial cells (HUVEC) (Yue et al., 2016; Nair et al., 2019). It was observed that α-turmerone remarkably decreased the p-glycoprotein (p-gp) with the upregulated level of multiresistance protein gene 1 (MDR1), multiresistance protein gene 2 (MDR2), and breast cancer resistance protein (BCRP). This was analyzed by the levels of messenger ribonucleic acid (mRNA) expression, rhodamine-123 aggregation, and efflux transport studies. They showed that α-turmerone and ar-turmerone have substantial efficacy as anticancer drugs in multiresistant cancer cells and colorectal cancer (Yue et al., 2012).

Elemenes Elemenes, (1-methyl-1-vinyl-2, 4-diisopropenyl-cyclohexane) are constituents of the 109 sesquiterpenes available in turmeric (Li et al., 2011a,b). The efficacy of elemenes, extracted from turmeric has been previously reported in China’s food and drug administration and is widely utilized in the chemotherapy of the cancer patients in China. A wealth of studies has proven that elemenes can attenuate the tumor growth of a wide-range of cells like ovarian, laryngeal, nonsmall cell lung, prostate, melanoma, leukemia,

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breast, brain, hepatoma, colorectal adenocarcinoma, glioblastoma, and human cervix epithelioid carcinoma cells because of its apoptotic behavior (Mukunthan et al., 2017). Hua et al. showed the antitumor activity of elemenes by investigating the attenuation characteristic of it on myeloid cell line (HL-60) cell proliferation. This activity is linked to cell cycle arrest between phase transitions from S to G2M phase, thus initiating apoptosis (Hua et al., 1997). Elemenes showed the potential to span the blood-brain barrier and protect against the carcinomas of the brain because of its small size and lipophilic nature (Wu et al., 2009).

β-Elemene β-elemene, (1S,2S,4R)-1-ethenyl-1-methyl-2-4-bis(prop-1-en-2yl) cyclohexane, a sesquiterpene investigated for its anticancer activity in multifarious cancer cells via its antiproliferative activity and consequent apoptosis initiation showed significant success (Nair et al., 2019). Li et al. stated that β-elemene enhances the sensitization of human nonsmall-cell lung cancer cell (NSCLC) lines (Aa549 and H460) to cisplatin because of the mitochondria-mediated intrinsic apoptosis pathway, which includes IAPs (inhibitor of apoptosis proteins) and Bcl-2 family proteins in a time and dose-dependent manner. Therefore, β-elemene and cisplatin combination has been found to be effective in the treatment of lung cancer and cisplatin-resistant tumors (Li et al., 2009). Metformin enhances the efficacy of β-elemene by blocking AKT signaling and attenuating DNA (cytosine5)-methyltransferase 1 (DNMT1) protein expression. Moreover, the correlation of AMP-activated protein kinase (AMPKa) and extracellular regulated kinase (ERK1/2) signaling pathways is accountable for β-elemene responses (Zhao et al., 2015). It was also observed that β-elemene, extracted from Curcuma aromatica and associated with etoposide, enhances the protection against lung cancer (Zhang et al., 2011).

Furanodiene, furanodienone, curcumol, and calebin A Furanodiene, (5E,9E)-3,6,10-trimethyl-4,7,8,11-tetrahydrocyclodeca[b] furan, is an additional sesquiterpene isolated from the volatile oil fraction of turmeric by using the CO2 supercritical fluid technique. Furanodiene showed a repressive effect on different cells like HL-60 (promyelocytic leukemia), HeLa (cervical carcinoma), SGC-7901 (gastric cancer) HeLa, K562 (leukemia), A549 (lung adenocarcinoma), MDA-MB-435s (breast cancer)

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HT-1080 (fleshy tumor), Hep-2 (laryngocarcinoma), SMMC-7721 (hepatoma), and PC3 (prostatic carcinoma), exhibiting its munificent efficacy with diverse mechanisms of action. In hepatoma cells (Hep G2), the efficacy of furanodiene was exhibited by DNA fragmentation assay. The attenuation of cell proliferation induced cell cycle arrest at the G2/ Mphase and apoptosis via the mitochondria-caspase apoptotic pathway, which stimulated p38 and attenuated the ERK/mitogen-activated protein kinase (MAPK) signaling pathway (Xiao et al., 2007). Furanodienone is a sesquiterpene with a structure differentiated by a cyclodecane ring, substituted with two methyl groups and an isopropyl group. It is also a substantial anticancer agent. The impact of furanodienone on human breast (MCF-7, MDA-MBA-231, and T47D) cells was examined by Li et al. This study demonstrated a remarkable reduction in cell growth in a dose-dependent manner, by attenuating estrogen receptor α signals and mRNA expression levels. It also blocked 17β-estradiol (E2)-initiated MCF-7 cell proliferation and E2-initiated estrogen response element motivated plasmid activity and eliminated E2 targeted gene expression (Cyclin D1, Bcl-2, and c-myelocytomatosis (MYC)), which attenuated cell proliferation with the induction of apoptosis (Li et al., 2011a,b). Curcumol, (1S,2S,5S,9S)-9-isopropyl-2-methyl-6-methylene-11oxatricyclo (6.2.1.01,5) undecan-8-ol, is a robust anticancer sesquiterpenoid, which attenuates proliferation of Hela, OV-UL-2, MCF-7, and MM231 cancer cells by RNA synthesis in a concentration-dependent manner. The anticancer effects on colorectal cancer LOVO cells were augmented by curcumol. Curcumol treatment in these cells reduced Bcl-2 and enhanced Bax to provoke apoptosis. Additionally, the inhibition of insulin-like factor-1 receptor increased the phosphorylation of p38MAPK and reduced the camp-response element binding protein (CREB) expression to initiate apoptosis (Wang et al., 2015). Calebin A(CA),(3E)-4-(4-hydroxy-3-methoxyphenyl)-2-oxobut-3en-1-yl(2E)-3-(4 hydroxy-3-methoxyphenyl) prop-2-enoate), extracted from Curcuma longa, has a ferulic acid ester bond, which is devoid of 1, 3-diketonic structure of curcuminoid compounds. Several lines of evidence have demonstrated that calebin A is effective against manifold cancerous cells like colon, gastric, multiple myeloma, breast cells, and multiresistant cancer cells. A study of calebin A recommended that it is a robust ingredient in chemotherapy for multidrug resistant cancers, as it attenuates the growth of the cell and caused apoptosis in SGC7901/vincristine cells, a multidrug resistant (MDR) human gastric adenocarcinoma cell line, A549/DDP

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(cisplatin)-MDR pulmonary carcinoma cell line, and HepG2/ADM (Adriamycin)-MDR hepatoma cell line. This study unraveled that the drug efflux function of p-glycoprotein was suppressed with their treatment, but the expression level of P-glycoprotein continued. Calebin A was also identified to alter the activities of MAPK, which involved enhanced protein kinase of p38, 38kda activity. They also reduced c Jun N terminal kinase (JNK) and ERK. These observations indicated that this is a valid compound for the treatment of human gastric and other MDR cancers (Li et al., 2008).

Conclusions and future perspectives Turmeric comprises manifold ingredients, which are categorized as curcuminoids and noncurcuminoids. Both curcuminoids and noncurcuminoids exhibit a plethora of health benefits due to the significant anticancer and antiinflammatory properties of these essential ingredients. However, both curcuminoids and noncurcuminoids show low bioavailability and short systemic circulation. Therefore, to overcome these challenges associated with these bioactive agents numerous drug delivery systems have been extensively studied (Chapters 4, 7, and 10). Despite the remarkably enhanced solubility of curcumin after encapsulation into drug delivery system (DDS), a few demerits such as nontargeted delivery still persist. To overcome these challenges and enhance the therapeutic efficacy of turmeric products or curcumin, numerous further studies are required. A potential therapeutic arsenal designed by amalgamating expertise of several fields such as biochemistry, nanotechnology, and medicine to enhance the bioavailability of bioactive agents such as curcumin will become a holy grail in the field of science as it becomes a potential tool to overcome numerous diseases.

References Aggarwal, B.B., Yuan, W., Li, S., Gupta, S.C., 2013. Curcumin-free turmeric exhibits antiinflammatory and anticancer activities: identification of novel components of turmeric. Mol. Nutr. Food Res. 57, 1529–1542. Ahmad, R.S., Hussain, M.B., Sultan, M.T., Arshad, M.S., Waheed, M., Shariati, M.A., et al., 2020. Biochemistry, safety, pharmacological activities, and clinical applications of turmeric: a mechanistic review. Evid. Based Complement. Alternat. Med. 2020, 7656919. Anand, P., Thomas, S.G., Kunnumakkara, A.B., Sundaram, C., Harikumar, K.B., Sung, B., et al., 2008. Curcumin and cancer: an “old-age” disease with an “age-old” solution. Biochem. Pharmacol. 76, 1590–1611. Canales-Aguirre, A.A., Gomez-Pinedo, U.A., Luquin, S., Ramirez-Herrera, M.A., Mendoza-Magana, M.L., Feria-Velasco, A., 2012. Curcumin protects against the

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oxidative damage induced by the pesticide parathion in the hippocampus of the rat brain. Nutr. Neurosci. 15, 62–69. Chainani-Wu, N., 2003. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J. Altern. Complement. Med. 9, 161–168. Chen, M.J., Cheng, Y.M., Lai, P.H., Wu, J.F., Hsu, Y.C., 2012. In vitro biocompatibility of thermally gelling liquid mucoadhesive loaded curcuminoids in colorectal cancer chemoprevention. Int. J. Color. Dis. 27, 869–878. Chinedum, E., Kate, E., Sonia, C., Ironkwe, A., Andrew, I., 2015. Polyphenolic composition and antioxidant activities of 6 new turmeric (Curcuma longa L.) accessions. Recent Pat. Food Nutr. Agric. 7, 22–27. Choi, Y., Ban, I., Lee, H., Baik, M.Y., Kim, W., 2019. Puffing as a novel process to enhance the antioxidant and anti-inflammatory properties of Curcuma longa L. (turmeric). Antioxidants 8, 506. Chuengsamarn, S., Rattanamongkolgul, S., Luechapudiporn, R., Phisalaphong, C., Jirawatnotai, S., 2012. Curcumin extract for prevention of type 2 diabetes. Diabetes Care 35, 2121–2127. Daniel, S., Limson, J.L., Dairam, A., Watkins, G.M., Daya, S., 2004. Through metal binding, curcumin protects against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-induced tissue damage in rat brain. J. Inorg. Biochem. 98 (2), 266–275. Douglass, B.J., Clouatre, D.L., 2015. Beyond yellow curry: assessing commercial curcumin absorption techniques. J. Am. Coll. Nutr. 34, 347–358. Farjam, M., Mehrabani, D., Abbassnia, F., Tanideh, N., Imanieh, M.H., Pakbaz, S., et al., 2014. The healing effect of Curcuma longa on liver in experimental acute hepatic encephalopathy of rat. Comp. Clin. Pathol. 23, 1669–1673. Fernandez-Lazaro, D., Mielgo-Ayuso, J., Seco Calvo, J., Cordova Martinez, A., Caballero Garcia, A., Fernandez-Lazaro, C.I., 2020. Modulation of exercise-induced muscle damage, inflammation, and oxidative markers by curcumin supplementation in a physically active population: a systematic review. Nutrients 12, 501. Governa, P., Marchi, M., Cocetta, V., De Leo, B., Saunders, P.T.K., Catanzaro, D., et al., 2018. Effects of Boswellia Serrata Roxb. and Curcuma longa L. in an in vitro intestinal inflammation model using immune cells and Caco-2. Pharmaceuticals 11, 126. Gunter, M.J., Leitzmann, M.F., 2006. Obesity and colorectal cancer: epidemiology, mechanisms and candidate genes. J. Nutr. Biochem. 17, 145–156. Han, F., Luo, B., Shi, R., Han, C., Zhang, Z., Xiong, J., et al., 2014. Curcumin ameliorates rat experimental autoimmune neuritis. J. Neurosci. Res. 92, 743–750. Hua, Y., Xianping, W., Linlin, Y., Shu, Z., 1997. The antitumor activity of elemene is associated with apoptosis. Chin. J. Cancer Res. 9, 83–88. Huang, X.F., Chen, J.Z., 2009. Obesity, the PI3K/Akt signal pathway and colon cancer. Obes. Rev. 10, 610–616. Huang, M., Lou, Y.R., Xie, J.G., Ma, W., Lu, Y.P., Yen, P., et al., 1998. Effect of dietary curcumin and dibenzoylmethane on formation of 7, 12-dimethylbenz [a] anthraceneinduced mammary tumors and lymphomas/leukemias in Sencar mice. Carcinogenesis 19, 1697–1700. Hwang, K.W., Son, D., Jo, H.W., Kim, C.H., Seong, K.C., Moon, J.K., 2016. Levels of curcuminoid and essential oil compositions in turmerics (Curcuma longa L.) grown in Korea. Appl. Biol. Chem. 59, 209–215. Jacob, J.N., 2016. Comparative studies in relation to the structure and biochemical properties of the active compounds in the volatile and nonvolatile fractions of turmeric (C. longa) and ginger (Z. officinale). Stud. Nat. Prod. Chem. 48, 101–135. Jayaprakasha, G.K., Jena, B.S., Negi, P.S., Sakariah, K.K., 2002. Evaluation of antioxidant activities and antimutagenicity of turmeric oil: a byproduct from curcumin production. Z. Naturforsch. C J. Biosci. 57, 828–835.

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Ma, D., Tremblay, P., Mahngar, K., Collins, J., Hudlicky, T., Pandey, S., 2011. Selective cytotoxicity against human osteosarcoma cells by a novel synthetic C-1 analogue of 7-deoxypancratistatin is potentiated by curcumin. PLoS One 6, e28780. Mazzarino, L., Silva, L.F.C., Curta, J.C., Licinio, M.A., Costa, A., Pacheco, L.K., et al., 2011. Curcumin loaded lipid and polymeric nanocapsules stabilized by nonionic surfactants: an in vitro and in vivo antitumor activity on B16-F10 melanoma and macrophage uptake comparative study. J. Biomed. Nanotechnol. 7, 406–414. Menghini, L., Genovese, S., Epifano, F., Tirillini, B., Ferrante, C., Leporini, L., 2010. Antiproliferative, protective and antioxidant effects of artichoke, dandelion, turmeric and rosemary extracts and their formulation. Int. J. Immunopathol. Pharmacol. 23, 601–610. Mirzaei, H., Masoudifar, A., Sahebkar, A., Zare, N., Nahand, J.S., Rashidi, B., et al., 2018. MicroRNA: a novel target of curcumin in cancer therapy. J. Cell. Physiol. 233, 3004–3015. Mukunthan, K.S., Satyan, R.S., Patel, T.N., 2017. Pharmacological evaluation of phytochemicals from south Indian black turmeric (Curcuma caesia Roxb.) to target cancer apoptosis. J. Ethnopharmacol. 209, 82–90. Nair, K.L., Thulasidasan, A.K.T., Deepa, G., Anto, R.J., Kumar, G.V., 2012. Purely aqueous PLGA nanoparticulate formulations of curcumin exhibit enhanced anticancer activity with dependence on the combination of the carrier. Int. J. Pharm. 425, 44–52. Nair, A., Amalraj, A., Jacob, J., Kunnumakkara, A.B., Gopi, S., 2019. Non-curcuminoids from turmeric and their potential in cancer therapy and anticancer drug delivery formulations. Biomol. Ther. 9, 13. Ormond, D.R., Peng, H., Zeman, R., Das, K., Murali, R., Jhanwar-Uniyal, M., 2012. Recovery from spinal cord injury using naturally occurring antiinflammatory compound curcumin. J. Neurosurg. Spine 16, 497–503. Park, K.N., Park, L.Y., Kim, D.G., Park, G.S., Lee, S.H., 2007. Effect of turmeric (Curcuma aromatica Salab.) on shelf life of tofu. Korean J. Food Preserv. 14, 136–141. Qiao, Q., Jiang, Y., Li, G., 2012. Curcumin improves the antitumor effect of X-ray irradiation by blocking the NF-κB pathway. Anti-Cancer Drugs 23, 597–605. Samadian, F., Dalili, N., Poor-reza Gholi, F., Fattah, M., Malih, N., Nafar, M., et al., 2017. Evaluation of Curcumin’s effect on inflammation in hemodialysis patients. Clin. Nutr. ESPEN 22, 19–23. Saraf-Bank, S., Ahmadi, A., Paknahad, Z., Maracy, M., Nourian, M., 2019. Effects of curcumin supplementation on markers of inflammation and oxidative stress among healthy overweight and obese girl adolescents: a randomized placebo-controlled clinical trial. Phytother. Res. 33, 2015–2022. Shah, S.A., Prasad, S., Knudsen, K.E., 2012. Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression. Cancer Res. 72, 1248–1259. Sharma, R.A., Gescher, A.J., Steward, W.P., 2005. Curcumin: the story so far. Eur. J. Cancer 41, 1955–1968. Singh, S., 2007. From exotic spice to modern drug? Cell 130 (5), 765–768. Soflaei, S.S., Momtazi-Borojeni, A.A., Majeed, M., Derosa, G., Maffioli, P., Sahebkar, A., 2018. Curcumin: a natural pan-HDAC inhibitor in cancer. Curr. Pharm. Des. 24, 123–129. Song, X., Zhang, M., Dai, E., Luo, Y., 2019. Molecular targets of curcumin in breast cancer. Mol. Med. Rep. 19, 23–29. Srinivasan, K.R., 1952. The coloring matter in turmeric. Curr. Sci. 21, 311–312. Stohs, S.J., Ji, J., Bucci, L.R., Preus, R.G., 2018. A comparative pharmacokinetic assessment of a novel highly bioavailable curcumin formulation with 95% curcumin: a randomized, double-blind, cross-over study. J. Am. Coll. Nutr. 37, 51–59.

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Stohs, S.J., Chen, C.Y.O., Preuss, H.G., Ray, S.D., Bucci, L.R., Ji, J., et al., 2019. The fallacy of enzymatic hydrolysis for the determination of bioactive curcumin in plasma samples as an indication of bioavailability. BMC Complement. Altern. Med. 19, 293. Suresh, S., Sankar, P., Telang, A.G., Kesavan, M., Sarkar, S.N., 2018. Nanocurcumin ameliorates Staphylococcus aureus-induced mastitis in mouse by suppressing NF-κB signaling and inflammation. Int. Immunopharmacol. 65, 408–412. Troselj, K., Kujundzic, R., 2014. Curcumin in combined cancer therapy. Curr. Pharm. Des. 20 (42), 6682–6696. Wang, H., Geng, Q.R., Wang, L., Lu, Y., 2012. Curcumin potentiates antitumor activity of L-asparaginase via inhibition of the AKT signaling pathway in acute lymphoblastic leukemia. Leuk. Lymphoma 53, 1376–1382. Wang, J., Huang, F., Bai, Z., Chi, B., Wu, J., Chen, X., 2015. Curcumol inhibits growth and induces apoptosis of colorectal cancer LoVo cell line via IGF-1R and p38 MAPK pathway. Int. J. Mol. Sci. 16, 19851–19867. Wong, T.F., Takeda, T., Li, B., Tsuiji, K., Kitamura, M., Kondo, A., et al., 2011. Curcumin disrupts uterine leiomyosarcoma cells through AKT-mTOR pathway inhibition. Gynecol. Oncol. 122, 141–148. Wu, X.S., Xiea, T., Lina, J., Fana, H.Z., Huang-Fua, H.J., Nia, L.F., et al., 2009. An investigation of the ability of elemene to pass through the blood-brain barrier and its effect on brain carcinomas. J. Pharm. Pharmacol. 61, 1653–1656. Xiao, Y., Yang, F.Q., Li, S.P., Gao, J.L., Hu, G., Lao, S.C., et al., 2007. Furanodiene induces G2/M cell cycle arrest and apoptosis through MAPK signaling and mitochondria-caspase pathway in human hepatocellular carcinoma cells. Cancer Biol. Ther. 6, 1044–1050. Yin, H., Guo, R., Xu, Y., Zheng, Y., Hou, Z., Dai, X., et al., 2011. Synergistic antitumor efficiency of docetaxel and curcumin against lung cancer. Acta Biochim. Biophys. Sin. 44, 147–153. Yu, W.G., Xu, G., Ren, G.J., Xu, X., Yuan, H., Qi, H., et al., 2011. Preventive action of curcumin in experimental acute pancreatitis in mouse. Indian J. Med. Res. 134, 717–724. Yue, G.G.L., Ben, C.L., Chan, B.C.L., Hon, P.M., Mavis, Y.H., Lee, M.Y.H., et al., 2010. Evaluation of in vitro antiproliferative and immunomodulatory activities of compounds isolated from Curcuma longa. Food Chem. Toxicol. 48, 2011–2020. Yue, G.G.L., Cheng, S.W., Yu, H., Xu, Z.S., Lee, J.K.M., Hon, P.M., et al., 2012. The role of turmerones on curcumin transportation and P-glycoprotein activities in intestinal Caco-2 cells. J. Med. Food 15, 242–252. Yue, G.G.L., Jiang, L., Kwok, H.F., Lee, J.K.M., Chan, K.M., Fung, K.P., et al., 2016. Turmeric ethanolic extract possesses stronger inhibitory activities on colon tumor growth than curcumin—the importance of turmerones. J. Funct. Foods 22, 565–577. Zhang, Y., Zeng, Y., 2019. Curcumin reduces inflammation in knee osteoarthritis rats through blocking TLR4/MyD88/NF-κB signal pathway. Drug Dev. Res. 80, 353–359. Zhang, F., Xu, L., Qu, X., Zhao, M., Jin, B., Kang, J., et al., 2011. Synergistic antitumor effect of β-elemene and etoposide is mediated via induction of cell apoptosis and cell cycle arresting non-small cell lung carcinoma cells. Mol. Med. Rep. 4, 1189–1193. Zhao, S.Y., Wu, J., Zheng, F., Tang, Q., Yang, L.J., Li, L., et al., 2015. β-Elemene inhibited expression of DNA methyltransferase 1 through activation of ERK1/2 and AMPKa signalling pathways in human lung cancer cells: the role of Sp1. J. Cell. Mol. Med. 19, 630–641. Zhu, Y., Bu, S., 2017. Curcumin induces autophagy, apoptosis, and cell cycle arrest in human pancreatic cancer cells. Evid. Based Complement. Alternat. Med. 2017, 5787218.

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Further reading Ak, T., Gulcin, I., 2008. Antioxidant and radical scavenging properties of curcumin. Chem. Biol. Interact. 174, 27–37. Amalraj, A., Pius, A., Gopi, S., Gopi, S., 2017. Biological activities of curcuminoids, other molecules from turmeric and their derivatives—a review. J. Tradit. Complement. Med. 7, 205–233. Fan, X., Zhang, C., Liu, D.B., Yan, J., Liang, H.P., 2013. The clinical applications of curcumin: current state and the future. Curr. Pharm. Des. 19, 2011–2031. Huminiecki, L., Horbanczzuk, J., Alanasov, A.G., 2017. The functional genome studies of curcumin. Semin. Cancer Biol. 46, 107–118. Jurenka, J.S., 2009. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Alt. Med. Rev. 14, 141–153. Kocaadam, B., Sanlier, N., 2017. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit. Rev. Food Sci. Nutr. 57, 2889–2895. Kotecha, R., Takami, A., Espinoza, J.L., 2016. Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence. Oncotarget 7, 52517–52529. Prasad, S., Tyagi, A.K., Aggarwal, B.B., 2014. Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from the golden spice. Cancer Res. Treat. 46, 2–18. Pulido-Moran, M., Moreno-Fernandez, J., Ramirez-Tortosa, C., Ramirez-Tortosa, C.M., 2016. Curcumin and health. Molecules 21, 264. Rahmani, A.H., Alsahli, M.A., Aly, S.M., Khan, M.A., Aldebasi, Y.H., 2018. Role of curcumin in disease prevention and treatment. Adv. Biomed. Res. 7, 38.

CHAPTER TWO

Turmeric products in Alzheimer’s disease Contents Introduction Alzheimer’s disease pathology Natural compounds Curcumin Volatile essential oils of curcumin Studies on human subjects Metal-chelation by curcumin Antiamyloidogenic activity Amyloid beta Signaling Curcumin analogs Theracurmin Shortcomings in therapeutic efficacy of curcumin In vitro studies In vivo studies Conclusions and future perspectives References Further reading

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Introduction Alzheimer’s disease pathology Alzheimer’s disease (AD), explained for the first time in 1906 by, the German psychiatrist, Alois Alzheimer (Obulesu, 2019; Small and Cappai, 2006) is the most common neurodegenerative disease, which affects memory, thinking, and behavior (Cole and Frautschy, 2006; da Costa et al., 2019). World Alzheimer’s report 2019 stated that more than 50 million citizens currently suffer from dementia, and this number is estimated to enhance to more than 152 million by 2050 (World Alzheimer Report, 2019; Chainoglou and

Turmeric and Curcumin for Neurodegenerative Diseases https://doi.org/10.1016/B978-0-12-822448-9.00001-7

© 2021 Elsevier Inc. All rights reserved.

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Hadjipavlou-Litina, 2020). Therefore, it has also been described as “plague of the twenty-first century” (Sharma and Kumar, 2019). Significant brain volume deterioration because of neuronal degeneration leads to a synaptic loss in AD (Mattson, 2004; Heneka and O’Banion, 2007; da Costa et al., 2019). The free radical production by Aβ enhances lipid peroxidation, protein oxidation (Xiao et al., 2000; da Costa et al., 2019), and DNA damage (Canevari et al., 2004; da Costa et al., 2019) but reduces the activity of antioxidant enzymes like superoxide oxidase and catalase (Ban et al., 2006; da Costa et al., 2019). Accordingly, tissues of postmortem AD patients corroborated oxidative damage instigated by Aβ (Fu et al., 2006; da Costa et al., 2019). Although the etiology of AD has been found to be multifactorial, yet research is in progress to unravel molecular underpinnings (Potter, 2013; Chainoglou and Hadjipavlou-Litina, 2020).

Natural compounds Manifold natural products with adequate therapeutic efficacy specifically against AD include curcumin, Gingko biloba, vitamin C, green tea, vitamin E, beta carotene, ginseng, sage, and rosemary (Mohd Sairazi et al., 2015; Solanki et al., 2015; van de Rest et al., 2015; Sharma and Kumar, 2019). Therefore, the use of natural products has tremendously increased with the advent of herbal medicines (Sachan et al., 2015; da Costa et al., 2019). Nevertheless, multiple hitherto available therapies reduce clinical symptoms of AD but fail to curb neuronal death (da Costa et al., 2019). A plethora of plant bioactive molecules like curcumin, resveratrol (nonflavonoids), and flavonoids significantly curtail cellular stress (Mattson et al., 2007; Bisht et al., 2010; da Costa et al., 2019). In line with this, curcumin has been one among the novel therapeutics that show protection against degenerative changes in neurodegenerative diseases (NDs) (da Costa et al., 2019). Epidemiological studies have shown that daily consumption of 80–200 mg of curcumin in the Indian population is the probable reason for the reduced incidence and prevalence of AD in this country (Chandra et al., 2001; da Costa et al., 2019).

Curcumin Curcumin was extracted in 1815 for the first time as a yellow colored-matter from the rhizomes of Curcuma longa (turmeric) (Kunnumakkara et al., 2017) and was termed as curcumin (Reddy et al., 2018). It has been used in Indian Ayurveda and named as Haldi in India (Reddy et al., 2018). The chemical name of curcumin is diferuloylmethane, the molecular formula is C21H20O6

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and molecular mass is 368.37% g/mol (Reddy et al., 2018). Curcuma L. species plays a pivotal role in the treatment of gastrointestinal disorders, pain, inflammation, wounds, and cancer since ages (Dosoky and Setzer, 2018). Curcuma is enriched with polyphenols and flavonoids (Hossen et al., 2017; da Costa et al., 2019). Phenylalanine, a vital precursor in flavonoid biosynthesis, is also a precursor for it (Kita et al., 2008, Sandhu et al., 2011; da Costa et al., 2019). Curcuma species used in the treatment of pneumonia, bronchial ailments, leucorrhea, diarrhea, dysentery, infectious wounds, and insect bites in countries like India, Bangladesh, Malaysia, Nepal, and Thailand (Akarchariya et al., 2017; Chuakul and Boonpleng, 2003; Basaka et al., 2010; Dosoky and Setzer, 2018). Additionally, it offers protection against pathological events of AD such as cognitive decline, mood disorders, and dementia (Zhang et al., 2015a,b; da Costa et al., 2019). The therapeutic properties of curcumin include attenuation of amyloid pathology, defense against oxidative stress and inflammation, suppression of amyloid aggregation, and tau hyperphosphorylation (Lim et al., 2001; Garcia-Alloza et al., 2007; da Costa et al., 2019). It also suppresses phospholipase A2 and cyclooxygenase (COX-2) enzymes linked to metabolic activities of neural membrane phospholipids to prostaglandins thus mitigating neuroinflammation (Wang et al., 2013; Sharma and Kumar, 2019). It also effectively reduces cholesterol, attenuates acetylcholinesterase, regulates insulin signaling pathway, metal-chelation (binds copper), and averts cerebral dysregulation induced by bio-metal toxicity and mitigates microglia formation (Mishra and Palanivelu, 2008; Tang and Taghibiglou, 2017; Sharma and Kumar, 2019). The vital constituents of rhizome include nonvolatile curcuminoids and the volatile oil (Mau et al., 2003; Jayaprakasha et al., 2005; Lobo et al., 2009; Dosoky and Setzer, 2018). Curcuminoids such as curcumin, demethoxycurcumin, bisdemethoxycurcumin are polyphenolic derivatives without toxicity and with numerous biological activities (Itokawa et al., 2008; Dosoky and Setzer, 2018). Curcuminoids contribute to 3%–5% of turmeric, and curcumin is the vital bioactive ingredient (Agrawal and Mishra, 2010; Chainoglou and Hadjipavlou-Litina, 2020). Although multiple therapeutic properties of curcumin were observed, yet increased intake induces diarrhea, nausea, dizziness, and stomach irritability (Sharma and Kumar, 2019).

Volatile essential oils of curcumin Although numerous nonvolatile curcuminoids show biological activities, yet there are a few volatile chemicals in it (Dosoky and Setzer, 2018). These are

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essential oils specifically from Curcuma L., which showed ample of health benefits (Dosoky and Setzer, 2018). The essential oil of Curcuma species exerts pharmacological activities such as antioxidant, anticancerous, antiinflammatory, antiproliferative, antidiabetic, hypocholesterolemic, antihepatotoxic, diuretic, antidiarrheal, carminative, hypotensive, antirheumatic, antiviral, antimicrobial, antivenomous, insecticidal, larvicidal, antithrombotic, antityrosinase, and cyclooxygenase-1 (COX-1) inhibitory activities (Mau et al., 2003; Wilson et al., 2005; Reanmongkol et al., 2006; Chen et al., 2008; Afzal et al., 2013; Krup et al., 2013; Angel et al., 2014; Sikha et al., 2015; Herath et al., 2017; Dosoky and Setzer, 2018).

Studies on human subjects In a randomized double-blind, controlled study carried out on 60 elderly people aged between 60 and 85 by treating with curcumin (400 mg/day) for 1 month showed amelioration of attention and working memory and working memory and mood after acute and chronic administration, respectively (Baum et al., 2008; da Costa et al., 2019). Curcumin also suppresses peroxidase and controls the cytopathologies in AD patients (Atamna and Boyle, 2006; Reddy et al., 2018).

Metal-chelation by curcumin It binds to redox-active metals such as iron and copper and attenuates inflammatory damage by avoiding metal-mediated activation of nuclear factor kappa beta (Nf-κB) (Baum and Ng, 2004; Reddy et al., 2018). Curcumin analogs aid in metal chelation (Ferrari et al., 2014; Peng et al., 2015; Hareram et al., 2020, Chainoglou and Hadjipavlou-Litina, 2020) and also act as robust antioxidants in mitochondria (Singulani et al., 2020; Chainoglou and Hadjipavlou-Litina, 2020). Ferrari et al., (2014) studied the molecular links between curcuminoids and metal chelation that can be explored in AD treatment (Reddy et al., 2018).

Antiamyloidogenic activity Amyloid beta Amyloid plaques, which are also named as “senile plaques” arise from amyloid beta-peptide due to its abnormal cleavage of amyloid precursor protein (APP) by β-secretase (Mazzanti and Giacomo, 2016). Aβ monomers

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accumulate into soluble oligomers and merge to form insoluble fibrils aggregated outside neurons and often in the walls of small blood vessels in the brain. Small oligomers with 40–42 amino-acids are specifically toxic to neurons inducing membrane perturbance, Ca2+ efflux, oxidative damage, impairment in insulin signaling pathways and synaptic function and mitochondria (Reddy et al., 2012; Goozee et al., 2016; Mazzanti and Giacomo, 2016). Curcumin, an essential ingredient of Curcuma longa species can ferry blood-brain barrier (BBB) and bind to Aβ both in vitro and in vivo (Yang et al., 2005; Sharma and Kumar, 2019). Mounting evidence from in vivo studies has also shown that curcumin provokes disaggregation of amyloid, averts accumulation of new Aβ, and curtails the size of residual amyloid deposits (Yang et al., 2005; Garcia-Alloza et al., 2007; Reddy et al., 2018). Curcumin significantly affects the stability of Aβ40 and Aβ42 (Ono et al., 2004; Reddy et al., 2018). In addition, curcumin analogs like isoxazoles and pyrazoles bind to the Aβ and impede AβPP metabolism (Narlawar et al., 2008; Reddy et al., 2018). Curcuminoids attenuate the production of huge toxic Aβ oligomers (Bisceglia et al., 2019; Chainoglou and Hadjipavlou-Litina, 2020). The antiamyloidonegic activity has been attributed to the presence of the phenolic hydroxyl group in curcumin (Chainoglou and Hadjipavlou-Litina, 2020). Phenyl methoxy group involves in the inhibition of Aβ42 and amyloid precursor protein (APP) (Chainoglou and Hadjipavlou-Litina, 2020).

Signaling Curcumin mediates multifarious TNF-activating cell signaling pathways, including c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase (PI3K) family of protein kinase) (AKT). Therefore, curcumin can curb tumor necrosis factor (TNF) generation and involve in proinflammatory pathways associated with several chronic diseases (Bertram and Tanzi, 2008; da Costa et al., 2019). Mounting evidence has shown that polyphenols such as CUR can control cellular signaling pathways entailed in cognitive processes like cAMPresponse element-binding protein (CREB) signaling and brain-derived neurotrophic factor (BDNF) initiation (Williams et al., 2008; Gomez-Pinilla and Nguyen, 2012; Salehi et al., 2020). This is important for both neurons’ growth and existence and synaptic plasticity. Polyphenols primarily protect brain health (Salehi et al., 2019, 2020).

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Curcumin analogs Several lines of evidence within the past 10 years have shown the enhanced pharmacokinetic profile and robust theranostic efficacy of multifarious curcumin analogs (Orteca et al., 2018; Zhang et al., 2013, 2015a,b; Chainoglou and Hadjipavlou-Litina, 2020). Manifold hydroxyl substituents were introduced on curcumin to make curcumin analogs that overcome solubility and bioavailability (Chainoglou and Hadjipavlou-Litina, 2020). Lakey-Beitia et al. (2017) studied nine curcumin derivatives prepared by etherification and esterification of the aromatic region, which showed anti-Aβ accumulation and antiinflammatory activities in AD (Reddy et al., 2018) (Fig. 1). Cui et al., (2019) synthesized two curcumin analogs AB1 and AB2 using Boc-L-isoleucine, which showed increased water solubility and attenuated amyloid fibril formation (Chainoglou and Hadjipavlou-Litina, 2020). While both AB1 and AB2 showed better binding with hen egg-white lysozyme (HEWL) close to the tryptophan amino acid residue area, AB2 significantly prevented fibril formation (Chainoglou and Hadjipavlou-Litina, 2020).

Fig. 1 Shows multifarious AD theranostic tools designed using curcumin.

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Additionally, Wang et al. (2018), synthesized AB4 at 20.139 mM and AB5 at 49.622 mM profoundly attenuated the amyloid fibrillation of HEWL (Chainoglou and Hadjipavlou-Litina, 2020). Polysubstituted hydroxyl curcuminoids substantially upregulated neprilysin, a vital Aβ degrading enzyme (Chen et al., 2016; Chainoglou and Hadjipavlou-Litina, 2020). Another sugar derivative of curcumin synthesized by “click chemistry” augmented bioactivity and attenuated around 1000 times Aβ peptide aggregation compared to curcumin (Dolai et al., 2011; Chainoglou and Hadjipavlou-Litina, 2020). AB7, a metabolite of curcumin exhibited protective efficacy against Aβ instigated toxicity in rat primary hippocampal cultures (Shilpa Mishra et al., 2011; Chainoglou and Hadjipavlou-Litina, 2020). Moreover, AB9 and AB12 analogs were evaluated for their protective efficacy against Aβ42, APP, and BACE1 in swAPP HEK293 cells (human HEK293 cell lines overexpressing APP). They confirmed that phenyl methoxy groups aid the process of Aβ42, APP. AB12 inhibited BACE1 mRNA levels and AB9 inhibited both BACE1 and mRNA levels (Liu et al., 2010; Chainoglou and Hadjipavlou-Litina, 2020).

Theracurmin Theracurmin was derived by employing the submicron colloidal dispersion technique, by which its bioavailability was enhanced to nearly 27 times that of curcumin (Kim et al., 2019; Sasaki et al., 2011). Theracurmin, an augmented bioavailable form of curcumin, potentially ameliorated recognition and spatial memories in 5xFAD mice (Kim et al., 2019). In addition, the antioxidant activity of Theracurmin, as measured by superoxide dismutase (SOD) activity and levels of decreased glutathione (GSH) and malondialdehyde (MDA), exhibited remarkable improvements (Kim et al., 2019a). Extensive lines of evidence have shown that intake of Theracurmin on a regular basis for 18 months ameliorated memory and attention in adults without dementia (Kim et al., 2019; Small et al., 2018).

Shortcomings in therapeutic efficacy of curcumin Despite the significant therapeutic efficacy of curcumin in manifold pathways, a few limitations such as poor water solubility and low bioavailability impede its success. Low bioavailability is because of hepatic and intestinal glucuronidation (da Costa et al., 2019). Co-administration of curcumin (2 g) along with

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piperine (20 mg) has been found to enhance the bioavailability by 2000% (Shoba et al., 1998; Suresh and Srinivasan, 2010; da Costa et al., 2019).

In vitro studies Of the 19 studies conducted in vitro, 3 studies showed that curcumin inhibited Aβ initiated cytotoxicity in pheochromocytoma (PC12) cells by attenuating oxidative stress, intracellular calcium levels, and tau hyperphosphorylation, apoptosis, and reactive oxygen species (ROS) (Huang et al., 2012; Park et al., 2008; da Costa et al., 2019). Seven studies conducted on SH-SY5Y cells showed that curcumin mitigates Aβ fixation in the membrane by inhibiting toxic interactions and decreasing its breakdown (Thapa et al., 2013; da Costa et al., 2019). Additionally, it has been understood that curcumin suppresses glycogen synthase kinase (GSK)-3 mediated initiation of presenilin 1 (PS1) and mitigates Aβ generation (Xiong et al., 2011; da Costa et al., 2019). In line with this, curcumin has also been found to mediate total expression of GSK-3β and phospho-Ser9 thus attenuating Aβ depolarization, inhibiting mitochondrial apoptotic proteins like cytochrome c, caspase-3, and bax, and regulating the cellular antioxidant enzymes superoxide dismutase (SOD) and catalase (Huang et al., 2012b; da Costa et al., 2019). In accordance with the study of Park et al. (2008), Huang et al., (2015) also showed that curcumin works by curtailing the intracellular calcium levels (da Costa et al., 2019). It has also been found that curcumin can curtail mitochondrial impairment by mediating biogenesis and synaptic activity (da Costa et al., 2019). Studies have also shown that curcumin offers cytoprotection in APPs we transfected SH-SY5Y cells by mediating the balance between heme oxygenase 1 and 2 in turn protecting the cells against H2O2 induced cytotoxicity (Yin et al., 2012).

In vivo studies Studies have shown the remarkable protective efficacy of curcumin on cortical neurons against Aβ induced cytotoxicity (Qin et al., 2010; Zhang et al., 2010; Sun et al., 2014; da Costa et al., 2019). It protected neurons from the toxicity process, ameliorated membrane potential and reduced ROS levels, attenuated apoptotic cell death and activated sirtuin1 (SIRT1) expression, and deteriorated Bax expression (da Costa et al., 2019). Two studies have evaluated the action of curcumin on hippocampal cells and

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showed that it decreases ROS levels in cells of Sprague-Dawley rats (Ye et al., 2012; da Costa et al., 2019), mediates the expression of caspase-3, and attenuates the levels of protein cyclin D1 with irregular activation in Wistar rat cells (Wang et al., 2012; da Costa et al., 2019). Curcumin also averted the expansion of microglial inflammatory response by eliminating interleukins IL-1 and IL-6 and TNF-α in cells of neonatal rats (Shi et al., 2015; da Costa et al., 2019). Three studies conducted in vivo evaluated transgenic mice transfected with the APPswe/PS1dE9 gene, demonstrated that curcumin can avoid and decrease amyloid accumulation and moderately yields dendritic deviations (Garcia-Alloza et al., 2007), also declining insulin receptor and insulin receptor substrate-1 expression in the CA1 area of the hippocampus (Feng et al., 2016; da Costa et al., 2019). Intragastric introduction of curcumin in 5XFAD transgenic mice for 2 months inhibited learning and memory deficit by averting structural perturbance in synapses and attenuation of Aβ accumulation specifically Aβ1-42 in the brain by mediating the expression of Beta-secretase 1 (BACE1) (Zheng et al., 2017; da Costa et al., 2019). Curcumin decreased the levels of oxidized proteins and IL1B in the brain tissues of APP mice (Lim et al., 2001; Reddy et al., 2018).

Conclusions and future perspectives Although curcumin has been found to stop disease progression in experimental models, yet there are more studies required to corroborate these findings. Additionally, a few studies showed no remarkable protective efficacy of curcumin in animal models of AD (Begum et al., 2008; Ringman et al., 2012; da Costa et al., 2019). The most important reasons for the poor efficacy of curcumin were low bioavailability and poor concentration in brain tissue (Hishikawa et al., 2012; da Costa et al., 2019). Curcumin primarily exerts its protective efficacy by curbing Aβ accumulation, tau hyperphosphorylation, ROS production, apoptosis, and inflammation (da Costa et al., 2019). Although curcumin and its analogs have shown their robust theranostic efficacy in both in vitro and in vivo, yet a significant number of further studies are required to overcome AD. To accomplish this expertise from multifarious specialities such as medicine, biochemistry, and nanotechnology need to be gathered to lay a cornerstone in the development of potential armamentarium.

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Yang, F., Lim, G.P., Begum, A.N., Ubeda, O.J., Simmons, M.R., Ambegaokar, S.S., et al., 2005. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 280, 5892–5901. Ye, M.X., Li, Y., Yin, H., Zhang, J., 2012. Curcumin: updated molecular mechanisms and intervention targets in human lung cancer. Int. J. Mol. Sci. 13, 3959–3978. Yin, W., Zhang, X., Shi, X., Li, Y., 2012. Curcumin protects SH-SY5Y cells from oxidative stress by up-regulating HO-1 via phosphatidylinositol 3 kinase/Akt/Nrf-2 and downregulating HO-2. Mol. Neurodegener. 7, S14. Zhang, C., Browne, A., Child, D., Tanzi, R.E., 2010. Curcumin decreases amyloid-beta peptide levels by attenuating the maturation of amyloid-beta precursor protein. J. Biol. Chem. 285, 28472–28480. Zhang, X., Tian, Y., Li, Z., Tian, X., Sun, H., Liu, H., et al., 2013. Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer’s disease. J. Am. Chem. Soc. 135, 16397–16409. Zhang, L., Fang, Y., Xu, Y., Lian, Y., Xie, N., Wu, T., et al., 2015a. Curcumin improves amyloid β-peptide (1-42) induced spatial memory deficits through BDNFERK signaling pathway. PLoS One 10, e0131525. Zhang, X., Tian, Y., Zhang, C., Tian, X., Ross, A.W., Moir, R.D., et al., 2015b. Nearinfrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 112, 9734–9739. Zheng, K., Dai, X., Xiao, N., Wu, X., Wei, Z., Fang, W., et al., 2017. Curcumin ameliorates memory decline via inhibiting BACE1 expression and β-amyloid pathology in 5FAD transgenic mice. Mol. Neurobiol. 54, 1967–1977.

Further reading Orteca, G., Tavanti, F., Bednarikova, Z., Gazova, Z., Rigillo, G., Imbriano, C., et al., 2008. Curcumin protected PC12 cells against betaamyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Food Chem. Toxicol. 46, 2881–2887. Reddy, P.H., Manczak, M., Yin, X., Grady, M.C., Mitchell, A., Kandimalla, R., et al., 2016. Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer’s disease. J. Investig. Med. 64, 1220–1234. Rigamonti, L., Saladini, M., Bednarikova, Z., Gazova, Z., Rigillo, G., Imbriano, C., et al., 2018. Curcumin derivatives and Aβ-fibrillar aggregates: an interactions’ study for diagnostic/therapeutic purposes in neurodegenerative diseases. Bioorgan. Med. Chem. 26, 4288–4300.

CHAPTER THREE

Curcumin in Alzheimer’s disease diagnosis and treatment Contents Introduction Curcumin Curcumin’s influence on enzymes Curcumin and resveratrol Oxidative damage Chemistry and metabolism Inflammation Curcumin in Alzheimer’s disease diagnosis Studies on humans Amyloid interaction Conclusions and future perspectives References

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Introduction Curcumin Alzheimer’s disease (AD) is the most common deleterious neurodegenerative disorder with incompletely understood etiology. Since the first diagnosis of AD, tremendous research has been done but the etiology has not been completely understood (Hampel et al., 2018). Therefore, there has been a growing need to discover the appropriate biomarkers to identify the symptoms and progression of AD (Hampel et al., 2018). Manifold drugs and therapeutic bioactive compounds showed limited success until now. Among them curcumin, an ingredient of turmeric, showed a significant therapeutic effect against neurodegenerative disorders. A few constituents of turmeric, such as turmerin, turmerone, elemene, furanodiene, curdione, bisacurone, cyclocurcumin, calebin A, and germacrone show biological activity that can substantiate the therapeutic effects of curcumin (Aggarwal et al., 2013;

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Mazzanti and Giacomo, 2016). Turmeric has three curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin), sugars, proteins, volatile oils (natlantone, tumerone, and zingiberone), and resins (Gupta et al., 2013; Kim and Clifton, 2018). Among the three curcuminoids, curcumin is the vital and lipophilic polyphenol compound that shows adequate stability in the acidic pH of the stomach (Wang et al., 1997; Jurenka, 2009; Kim and Clifton, 2018). Curcumin intake of
3.6 g/day in manifold studies showed the measurable concentrations of curcumin and its metabolites in both blood and urine (Cheng et al., 2001; Sharma et al., 2004; Garcea et al., 2004, 2005; Kim and Clifton, 2018; Vareed et al., 2008). Curcumin controls related molecular target pathways to progress glucose and lipid metabolism, inhibit inflammation, initiate antioxidant enzymes, simplify insulin signaling, and lessen gut absorptivity. It also attenuates Aβ and tau aggregation in animal models and improves mitochondria and synaptic function (Kim and Clifton, 2018). Overarching evidence has also shown that curcumin exhibits pharmacological functions, thus improving cognitive functions, attenuating cerebral edema (Zhu et al., 2014; Li et al., 2019), and augmenting cell proliferation in embryonic cortical neural stem cells (Kim et al., 2008; Tiwari et al., 2014; Li et al., 2019; Obulesu, 2020). The beneficial effects exerted by curcumin include regulation of the normal structure and function of cerebral vessels, mitochondria, and synapses (Chen et al., 2018). Commercial curcumin with the name curcumin complex includes curcumin (77%), demethoxycurcumin (17%), and bisdemethoxycurcumin (3%) (Goel et al., 2008; Chen et al., 2018). Studies have shown that curcumin, curcuminoids, curcumin conjugates, and its bioavailable formulations substantially attach to amyloid fibrils in primordial/condensed plaques in AD brain tissue (Haan et al., 2018). Similarly, curcumin isoforms and conjugates specifically bind to neurofibrillary tangles (NFTs) in AD brain tissue (Haan et al., 2018). Interestingly, curcumin has been found to effectively bind to amyloid aggregates with condensed amyloid structure (Haan et al., 2018). Additionally, curcumin can overcome the amyloid pathology already present and ameliorates neurotoxicity in a mouse model (Yang et al., 2005; Garcia-Alloza et al., 2007; Haan et al., 2018). A recent study has shown the ability of curcumin to identify retinal amyloid in vivo (Koronyo et al., 2017; Haan et al., 2018). Manifold studies have shown that curcumin plays a vital role in the diagnosis and management of AD (Belkacemi et al., 2011; Goozee et al., 2016; Chen et al., 2018).

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Curcumin’s influence on enzymes Curcumin has also been known to substantially suppress enzymes such as histone acetyltransferases (HAT) (Boyanapalli and Tony Kong, 2015) and DNA methyltransferase (DNMT1) (Hardy and Tollefsbol, 2011; Mazzanti and Giacomo, 2016). These enzymes mediate the expression of genes entailed in AD pathogenesis (Feng et al., 2010; Mazzanti and Giacomo, 2016). Curcumin attenuates cytochrome P450 monooxygenases (drugmetabolizing enzymes) and p-glycoprotein (an efflux pump) from the ATP-binding cassette (ABC) family, which propels an array of xenobiotics (e.g., drugs) out of the cell. Only one clinical trial showed profound interaction between curcumin and drugs (Bahramsoltani et al., 2017; Kim and Clifton, 2018).

Curcumin and resveratrol Curcumin and resveratrol were found to show similar biological properties such as anticancer and exhibit synergistic effects (Du et al., 2013; Masuelli et al., 2014; Mazzanti and Giacomo, 2016). Both compounds exert antiamyloidogenic effect (Mazzanti and Giacomo, 2016). Curcumin attenuates the formation of Aβ and dissociates preformed fibrils (Lim et al., 2001; Ono et al., 2004; Mazzanti and Giacomo, 2016). Similarly, resveratrol remarkably curtails the levels of secreted or intracellular Aβ peptides by controlling proteasome (Marambaud et al., 2005; Mazzanti and Giacomo, 2016). It probably shows effect indirectly by specifically provoking proteasomal destabilization of vital mediators of Aβ scavenging (Mazzanti and Giacomo, 2016). The neuroprotective effect of resveratrol was also connected with the initiation of protein kinase C, which initiates α-secretase enzyme and accordingly the nonamyloidogenic pathway, leading to the deterioration of Aβ generation (Bastianetto et al., 2015; Mazzanti and Giacomo, 2016). While a few studies showed that resveratrol attenuates and degrades the formation of Aβ1-42 fibrils (Richard et al., 2011), a few studies showed that it failed to impede Aβ fibril formation in human neuroblastoma cells treated with Aβ (Granzotto and Zatta, 2011; Mazzanti and Giacomo, 2016). The substantial antioxidant activity of both curcumin and resveratrol plays an essential role in overcoming neurodegeneration in AD (Kim et al., 2010; Mazzanti and Giacomo, 2016). Resveratrol eliminates free radicals and defends neurons and microglia (Zhuang et al., 2003; Candelario-Jalil et al., 2007), and inhibits Aβ triggered

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intracellular reactive oxygen species (ROS) formation ( Jang and Surh, 2003; Koukoulitsa et al., 2016; Mazzanti and Giacomo, 2016). Kwon et al. (2010) showed that the resveratrol treatment inhibited ROS generation, mitochondrial membrane potential dysregulation, and repleted the normal levels of GSH decreased by Aβ1-42 in a murine HT22 hippocampal cell line (Mazzanti and Giacomo, 2016). It also upregulates cellular antioxidants (i.e., glutathione) and the gene expression of phase 2 enzymes and curbs oxidative and electrophilic damage (Cao and Li, 2004) and similar to curcumin substantiates the HO-1 pathway (Kwon et al., 2011). Clinical trials conducted using curcumin and resveratrol showed adequate tolerance (Mazzanti and Giacomo, 2016). Of the three curcumin trials conducted on adult or old patients with varying severity of AD symptoms, only one study showed promising results (Hishikawa et al., 2012; Mazzanti and Giacomo, 2016). Curcumin and resveratrol exert multitargeting biological effects, both in vitro and in vivo, which include attenuation of Aβ accumulation, decrease of oxidative stress, instigation of cell growth, suppression of cholinesterase activity and brain pro-inflammatory responses, inhibition of neuronal cell death, improvement of neuroprotective sirtuin-1 activity, etc., (Goozee et al., 2016; Ahmed et al., 2017) that make them model candidates in the treatment of neurodegenerative diseases (Mazzanti and Giacomo, 2016). Moreover, curcumin and resveratrol were found to influence epigenetic mechanisms that alter gene expression patterns without perturbing the DNA sequence. Gene expression can either be stimulated or silenced through epigenetic regulations as epigenetic changes probably exhibit risk variation for a few diseases (Fig. 1) (Sezgin and Dincer, 2014; Mazzanti and Giacomo, 2016).

Curcumin and Resveratrol

Antioxidant Activity

Antiamyloidogenic Activity

Anticancer Activity

HO-1 pathway

Fig. 1 Describes the common pathways of curcumin and resveratrol in inducing neuroprotection.

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Oxidative damage Cognitive dysfunction was found to be linked to enhanced levels of ROS and reactive nitrogen species (RNS), and oxidative stress is the initial event followed by plaque formation in AD (Wahlster et al., 2013; Mazzanti and Giacomo, 2016). In vitro studies have shown that curcumin eliminates nitric oxide radicals and defends the brain from lipid peroxidation (Wei et al., 2006; Mazzanti and Giacomo, 2016). It also averts the DNA-oxidative damage by eliminating the hydroxyl radicals (Agnihotri and Mishra, 2011; Mazzanti and Giacomo, 2016). It also binds to Cu2+ and Fe2+, which play a key role in Aβ accumulation and oxidative damage in the brain (Baum and Ng, 2004; Mazzanti and Giacomo, 2016). These studies were corroborated by Banerjee (2014), which showed the curcumin’s potential to bind Cu2+ and/or Zn2+ and subsequently attenuate the formation of β-sheet rich Aβ protofibrils (Mazzanti and Giacomo, 2016). It also initiates glutathione Stransferase (Nishinaka et al., 2007) and moderately repletes glutathione levels (Ishrat et al., 2009) in the brain and provokes the antioxidant enzyme heme oxygenase-1 (HO-1), which is involved in the enhancement of stress tolerance in the brain (Motterlini et al., 2000; Mazzanti and Giacomo, 2016). Pretreatment of cerebellar granule neurons of rats with curcumin substantially enhanced the HO-1 expression and GSH levels by initiating nuclear factor (erythroid-derived 2)-like 2 (Nrf2) movement into the nucleus (Gonzalez-Reyes et al., 2013; Mazzanti and Giacomo, 2016). In line with this, in vivo studies showed the efficacy of curcumin in decreasing the brain levels of oxidized proteins with carbonyl groups (Lim et al., 2001; Mazzanti and Giacomo, 2016). Begum (2008) found decreased protein oxidation in the curcumintreated Tg2576 mice and recommended that the dienone bridge in the chemical structure of curcumin is essential for this (Mazzanti and Giacomo, 2016). In another in vivo study, curtailed malondialdehyde (MDA) levels were found in brain tissue after curcumin intake (Belviranl et al., 2013; Mazzanti and Giacomo, 2016). Hyperglycemia induces autooxidation of glucose, glycation of protein, and increased polyol pathways resulting in the augmented ROS (Giacco and Brownlee, 2010; Kim and Clifton, 2018). Continuous oxidative stress can provoke chronic inflammation, which probably leads to chronic diseases like type-2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and AD (Reuter et al., 2010; Akash et al., 2013; Kim and Clifton, 2018; Lontchi-Yimagou et al., 2013; Rehman and Akash, 2016). The robust antioxidant activity of curcumin as a free radical scavenger is potentially

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connected to its phenolic O-H and C-H groups (Kim and Clifton, 2018; Priyadarsini et al., 2003).

Chemistry and metabolism Approximately 35%–89% of the orally introduced curcumin has been detected in the feces (Holder et al., 1978; Ravindranath and Chandrasekhara, 1981; Haan et al., 2018). Additionally, it undergoes phase 1 (reduction) and phase 2 (conjugation) metabolism in the liver. Its reduction leads to the generation of dihydrocurcumin, tetrahydrocurcumin, and hexahydrocurcumin (Pan et al., 1999; Marczylo et al., 2007, 2009; Haan et al., 2018). Curcumin gets conjugated to sulfates and glucuronides and is mostly circulated in the conjugated form (Ireson et al., 2002; Dhillon et al., 2008; Marczylo et al., 2007, 2009). Curcumin has two phenols conjugated by a linear β-diketone linker, which initiates keto-enol tautomerism. It offers crucial photophysical and photochemical properties due to its special structure (Priyadarsini, 2009; Chen et al., 2018). The low bioavailability of curcumin curbs its efficacy as a potential diagnostic agent.

Inflammation Curcumin has been found to mediate inflammatory responses by inhibiting the activity of the transcription factors, nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), and activator protein-1 (Nanji et al., 2003; Bengmark, 2006; Sandur et al., 2007; Mazzanti and Giacomo, 2016). In addition, curcumin curbs the initiation inducible nitric oxide synthase (iNOS) and attenuates lipoxygenase and cyclooxygenase-2 (COX-2) (Nanji et al., 2003; Bengmark, 2006; Sandur et al., 2007; Mazzanti and Giacomo, 2016). Both in vitro and in vivo studies also have proven that it attenuates tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), -2, -6, -8, and -12 (Millington et al., 2014; Karunaweera et al., 2015; Mazzanti and Giacomo, 2016).

Curcumin in Alzheimer’s disease diagnosis There is no appropriate diagnostic test at the asymptomatic stage available until now (Chen et al., 2018). A wealth of studies has shown that curcumin analogs can bind to Aβ plaques, aggregates, dimers, and monomers, but fail to bind to other amyloid peptides such as amylin (Chen et al., 2017;

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Chainoglou and Hadjipavlou-Litina, 2020). It has also been shown that curcumin and its analogs can bind to soluble and insoluble forms of Aβ (Lee et al., 2013; Chainoglou and Hadjipavlou-Litina, 2020). Although there are scant reports regarding the scaffolds and their binding to the soluble Aβs, yet the curcumin scaffold has been reported as a vital structure for second-generation Aβ positron emission tomography (PET) tracer design (Yang et al., 2019; Chainoglou and Hadjipavlou-Litina, 2020). Nearinfrared imaging (NIR) is a vital tool for primary AD recognition due to its reasonable depth diffusion, noninvasive procedure, and low-cost instrumentation. Despite the demonstration of NIR imaging only in animal studies, a few NIR probes could be simply improved to PET imaging probes (Ran et al., 2009; Chainoglou and Hadjipavlou-Litina, 2020). A new curcumin analog Me-CUR was designed, which binds, identifies, and shows high sensitivity to Aβ fibrils and exerts appreciable fluorescence (Sato et al., 2018; Chainoglou and Hadjipavlou-Litina, 2020). Gan et al. (2017) showed that curcumin analogs recognize Aβ plaques in the brain (Chainoglou and Hadjipavlou-Litina, 2020). According to them, fluorescent staining was obtained by 1,5-diphenyl-1,4-pentadien-3-one derivative. The radioiodinated ligand [125I] 1,5-diphenyl-1,4-pentadien-3-one showed increased brain uptake and feasible elimination from there (Chainoglou and Hadjipavlou-Litina, 2020). Rubagotti et al. (2016) synthesized the first gallium-68 labeled curcuminoid compounds and substantially utilized in the diagnosis of AD. They demonstrated that the curcuminoid complexes 68Ga(CUR)2+ and 68Ga (DAC)2+ are significantly bound to both amyloid fibrils and plaques in vitro, whereas 68Ga(bDHC)2+ has a modest effect (Chainoglou and Hadjipavlou-Litina, 2020). However, these complexes failed to show their efficacy in in vivo (Chainoglou and Hadjipavlou-Litina, 2020). Similarly, Asti et al. (2014) studied Ga-curcuminoid complexes 68Ga(CUR)2+, 68Ga(DAC)2+, and 68Ga(bDHC)2+, which showed increased stability in saline human serum when tested with diethylenetriaminepentaacetic acid (DTPA) or with Fe3+, Zn2+, and Cu2+ for transchelation or transmetalation studies (Chainoglou and Hadjipavlou-Litina, 2020). As both compounds showed better affinity and fluorescent emission, there is a probability to design a radioactive/fluorescent pharmacophore that can aid as a dual-mode imaging tool (Chainoglou and Hadjipavlou-Litina, 2020). Yi et al. (2016) studied antiamyloid activities. They immobilized capture oligomeric and fibril related antibodies in fluidic channels and developed an innovative surface plasmon resonance biosensor (Reddy et al., 2016a,b).

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AD diagnosis has been accomplished using Aβ1-42 and tau -181 quantitative measurement in cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), cortical atrophy measurement on magnetic resonance imaging (MRI), or hypometabolism by fluorodeoxyglucose-PET (FDGPET) (McKhann et al., 2011; Haan et al., 2018). A wealth of studies has shown that difluoroboron complexes of fluorine-substituted curcumin derivatives conjugate strongly to amyloid plaques in APP/PS1 transgenic mouse brain sections (Kim et al., 2019b). A few radiolabeled forms of curcumin derivatives, such as 40 -O-18F-fluoropropyl curcumin and other 18F-labeled curcumins, exhibited low brain-spanning ability, in spite of their capability to conjugate to Aβ plaques (Ryu et al., 2006; Lee et al., 2011; Rokka et al., 2014; Kim et al., 2019b). Consequently, difluoroboron complexes of fluorine-substituted curcumin derivatives, with sufficient lipophilicity, demonstrated improved blood-brain barrier (BBB) spanning ability, in turn, binding to the Aβ plaques (Kung et al., 2010; Kim et al., 2019b). Imaging the Aβ plaques with curcumin, has long been in progress (Cole et al., 2004; Garcia-Alloza et al., 2007; den Haan et al., 2018; Lichtenegger et al., 2019). Research studies have also used fluorescence of curcumin to identify amyloid plaques in brain slices, using the multimodal visible-light optical coherence microscopy technique (Lichtenegger et al., 2019).

Studies on humans Curcumin, its isoforms and bioavailable forms preferably bind to Aβ fibrillar forms and cerebral amyloid angiopathy (CAA) in post mortem AD brain (Yang et al., 2005; Koronyo-Hamaoui et al., 2011; Mutsuga et al., 2012; Veldman et al., 2016; Haan et al., 2018). Therefore, curcumin with its potential fluorescent ability and Aβ binding is a robust AD noninvasive diagnostic tool (Hun Bong, 2000; Mondal et al., 2016; Mutsuga et al., 2012; Haan et al., 2018).

Amyloid interaction Curcumin specifically interacts with the N-terminus of Aβ1-42 monomers and avoids the expansion of oligomers from 1–2 to 3–5 nm (Fu et al., 2014; Mazzanti and Giacomo, 2016). Growing evidence has also shown that it initiates robust conformational changes Asp-23-Lys-28 salt bridge region and near the Aβ1-42 C terminus (Mazzanti and Giacomo, 2016). Electron microscopy studies have shown to disturb Aβ1-42 structure (Mithu et al., 2014;

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Mazzanti and Giacomo, 2016). Studies on Sprague-Dawley rats showed that curcumin reversed Aβ40 and Aβ42 induced neurodegeneration and ameliorated memory (Frautschy et al., 2001; Mazzanti and Giacomo, 2016). Further, these results were corroborated by Ahmed et al. (2010) who showed that curcumin enhanced the expression of genes responsible for synaptic plasticity, such as synaptophysin (Mazzanti and Giacomo, 2016).

Conclusions and future perspectives The etiology of AD is unclear despite the voluminous studies since its discovery in 1906. Curcumin substantially inhibits manifold pathological events as described in this chapter. It also has the potential to ferry blood-brain barrier and bind to the Aβ plaques and exhibit adequate fluorescence. Accordingly, it can be described that curcumin is a robust theranostic agent. While the antioxidant activity of curcumin is the prominent event that plays an important role in inhibiting AD symptoms by eliminating a plethora of free radicals like ROS and RNS, the other activities such as antiamyloidogenic activity and antiinflammatory activities show an additive therapeutic effect. However, limitations such as low water solubility and poor bioavailability impede its success. To overcome these challenges several drug delivery systems were designed, which showed appreciable enhancement in the therapeutic properties of curcumin (Chapter 4).

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CHAPTER FOUR

Curcumin loaded drug delivery systems in the treatment of Alzheimer’s disease Contents Introduction Curcumin Tau inhibition Challenges Curcumin delivery systems Polymeric nanoparticles Poly(lactic-co-glycolic acid) Surface modification Chitosan Micelles Phytosomes Lipid-based nanocarriers Liposomes Liquid crystalline nanocarriers Solid lipid nanoparticles Nanostructured lipid carriers Magnetic nanoparticles Theranostic approach of curcumin Conclusions and future perspectives References

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Introduction The brain being the principal control organ of the body, its health significantly influences the overall body health. Accordingly, a disease in the brain leads to severe damage to the body as well (Salehi et al., 2020). Neurodegenerative diseases (NDs) such as AD, Parkinson’s disease, and multiple sclerosis raise the number of deaths remarkably worldwide (Salehi et al., 2020). Turmeric and Curcumin for Neurodegenerative Diseases https://doi.org/10.1016/B978-0-12-822448-9.00008-X

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World Health Organization (WHO) stated in 2015 that around 12% of the global death rate was triggered by neurological disorders. Of them, Alzheimer’s disease (AD) and other dementias account for a high percentage of the whole deaths compared to others, comprising a 2.84% of death rate in developed countries in 2005 (WHO, 2006; Salehi et al., 2020).

Curcumin Curcumin’s plethora of therapeutic applications has been explored for almost 2000 years (Farooqui and Farooqui, 2019; Hatcher et al., 2008; Salehi et al., 2020). Curcumin was first explained in 1815 by Vogel and Pelletier (Vogel and Pelletier, 1815; Salehi et al., 2020) as a mixture of resin and turmeric oil. Further, in 1842; Vogel Jr. attained the pure form of curcumin, and after 68 years, Milobedzka and Lampe discovered its structure as (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (Gupta et al., 2012; Salehi et al., 2020). An array of therapeutic benefits shown by curcumin include antioxidant, amyloid β-binding, antiinflammatory, tau attenuation, metal chelation, neurogenesis activity, and synaptogenesis initiation (Salehi et al., 2020). Polyphenols play a key role in improving memory, attention, and concentration, which probably ameliorate cerebral blood flow (Salehi et al., 2019). As curcumin is less expensive and shows less or no side effects (Carroll et al., 2011), it has been considered a robust neuroprotective agent (Salehi et al., 2020). Primarily, neuroprotective effects of curcumin are due to its antioxidant, antiamyloidogenic, antiinflammatory, antidepressant, antidiabetic, and antiaging properties (Aggarwal, 2010; Acar et al., 2012; Babu et al., 2019; Salehi et al., 2020). The potential correlation between curcumin intake in India and reduced AD incidence paved the way to explore its remarkable neuroprotective properties (Chandra et al., 2001; Vas et al., 2001; Salehi et al., 2020). Fan et al., (2018) evaluated the role of various antioxidants in food such as curcumin in AD and found that due to the potential metal chelating ability, it averts heavy metal aggregation in the brain (Salehi et al., 2020).

Tau inhibition AD has been characterized primarily by protein deposits of Aβ and Tau neurofibrillary tangles (NFTs) (Cai et al., 2018). Tau proteins or aggregates transmit through nerve fibers and extend the disease to the entire brain tissue

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(Guillozet-Bongaarts et al., 2005). Several lines of evidence have shown that curcumin inhibits tau hyperphosphorylation into NFTs (Patil et al., 2013; Salehi et al., 2020).

Challenges Despite the worth commending therapeutic and diagnostic potential of curcumin, a few demerits such as low absorption, swift metabolism, systemic circulation, hydrophobicity, reduced blood-brain barrier (BBB) ferrying, low water solubility (0.4 μg/mL at normal gastric (pH: 1.5–4) and less cellular uptake (Wang et al., 1997) impede its success as a substantial neurotheranostic agent (Sharma et al., 2007; Wahlang et al., 2011; Ullah et al., 2017; Jakubek et al., 2019; Salehi et al., 2020).

Curcumin delivery systems To overcome the above mentioned challenges associated with curcumin, manifold formulations have been designed (Ghalandarlaki and Alizadeh, 2014; Maiti and Dunbar, 2018; Salehi et al., 2020). Nanotechnological methods used in designing DDS provide a few merits such as enhanced systemic circulation, water solubility, bioavailability, and potential to span physiological barriers (Li and Sabliov, 2013; Fonseca-Santos et al., 2015; Bhatia, 2016; Maria et al., 2019). The nanocarrier-based delivery systems increase the drug colloidal stability and potential to span biological barriers, thus facilitating the targeting of specific tissue (Lombardo et al., 2019; Sadegh Malvajerd et al., 2019; Salehi et al., 2020). They specifically enhance bioavailability by augmenting its chemical stability and solubility, permeability, and tissue distribution (Aqil et al., 2013; Schiborr et al., 2014). A wide range of hitherto developed curcumin nanocarriers includes liposomes, solid-lipid nanoparticles (SLNs), micelles, polymer nanoparticles, and polymeric conjugates. They were used in the treatment of neurodegenerative disorders (Salehi et al., 2020). Numerous novel nanotechnological methods have been detected to design curcumin loaded nanoparticles (NPs), which substantially increased bioavailability of curcumin (Bhawana et al., 2011; Salehi et al., 2020). Microspheres and microcapsules with loaded curcumin or distributed in polymeric particles (camptothecin, routine, and zedoaric oil) make microscopic spheres/capsules that profoundly enhance bioavailability and pharmacological activity in the brain (Paolino et al., 2016; Salehi et al., 2020).

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Curcumin loaded nanoparticles (NPs) can ferry BBB and act on brain cells, thus substantially protecting the brain against several neurological diseases (Blanco et al., 2015; Henrich-Noack et al., 2019; Salehi et al., 2020). Currently, by employing the nano-templating approach an innovative mesoporous silica NPs (MSNPs) (size of 200 nm) encapsulated with curcumin and chrysin have been designed for nose-to-brain delivery applications (Lungare et al., 2016). Curcumin nanogels designed using three-dimensional hydrophilic polymer network can imbibe a high amount of water or physiological fluids internally and can also maintain the internal structure of the network (Vaz et al., 2017; Salehi et al., 2020) (Table 1).

Polymeric nanoparticles Curcumin polymer NPs show nanometric dimensions, improved biocompatibility, and circulation time in blood (Wang et al., 2010). A few extensively used synthetic polymeric conjugates are chitosan (CS), poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and hydrophobically altered starch (Pinzaru et al., 2018). Of the numerous polymer-based systems, PLGA has been extensively used in the treatment of neurological diseases due to its robust bioavailability (Cai et al., 2016). PLGA with PEG-5000 carrier stabilizer was used to develop curcumin NPs, which showed 97.5% efficiency and 81 nm diameter (Salehi et al., 2020). They showed enhanced cellular absorption, bioavailability (Wang et al., 2010), and the ability to ferry the hematoencephalic barrier (Marin et al., 2017; Salehi et al., 2020).

Poly(lactic-co-glycolic acid) Kinetics of tissue distribution and BBB spanning of curcumin loaded PLGA nanoformulations were studied using a rat model. These formulations when administered orally or intravenously showed a 22-fold enhancement in the bioavailability of curcumin (Tsai et al., 2011a, Salehi et al., 2020). Similarly, another curcumin loaded PLGA nanoformulation considerately improved curcumin’s retention time in the cerebral cortex (96% enhancement) and hippocampus (83% enhancement) (Tsai et al., 2011b, Salehi et al., 2020). In another study, curcumin loaded PLGA NPs played a pivotal role in overcoming the oxidative damage induced by H2O2, thus substantiating its efficacy in offering protection against AD (Doggui et al., 2012; Salehi et al., 2020). In vivo evaluation of curcumin-encapsulated PLGA-PEG

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Table 1 Curcumin delivery systems. Targeted therapy

Drug delivery system

Reference

Enhancement of bioavailability and pharmacological activity Penetrate BBB and show neuroprotection

Curcumin loaded microspheres and microcapsules Curcumin loaded NPs

Paolino et al. (2016)

Nose-to-brain delivery of curcumin

MSNPs

Blanco et al. (2015) and Henrich-Noack et al. (2019) Lungare et al. (2016)

Polymeric nanoparticles

Cellular absorption, bioavailability, BBB penetration

PLGA PEG-5000 carrier curcumin NPs

22-fold enhancement in the bioavailability of curcumin and its retention time in cerebral cortex and hippocampus Overcome H2O2 induced oxidative damage and protection against AD Altered curcumin pharmacokinetics and tissue distribution

Curcumin loaded PLGA nanoformulation

Wang et al. (2010) and Marin et al. (2017) Tsai et al. (2011b)

Curcumin loaded PLGA NPs

Doggui et al. (2012)

Curcumin-encapsulated PLGA-PEG micellar nanocarriers PLGA-PEG-PLGA triblock copolymers CS NPs

Joseph et al. (2018)

Curcumin-tethered CS NPs

Yadav et al. (2012)

Improved curcumin’s chemical stability, inhibited its degradation and enhanced the uptake by the cell membrane and the contributed for the controlled release of curcumin Protective efficacy against arsenic-induced toxicity in rats

Salehi et al. (2020)

Continued

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Table 1 Curcumin delivery systems—cont’d Targeted therapy

Drug delivery system

Reference

Increased the Aβ42 phagocytosis and altered macrophage polarization in AD Improved the water solubility, bioavailability, and stability of curcumin Increased loading capacity, water solubility, decreased toxicity and metabolic degradation

Curcumin-loaded CSbovine serum albumin NPs

Salehi et al. (2020)

Curcumin polymeric micelles

Zhao et al. (2012)

Curcumin loaded in cationic micelles like dodecyl trimethyl ammonium bromide or cetyltrimethylammonium bromide

Zhao et al. (2012)

Liposomes functionalized with transferrin and lactoferrin Liposomal curcumin formed with phospholipids

Chen et al. (2010, 2016) and Gao et al. (2013) Li et al. (2005) and Mourtas et al. (2014) Mourtas et al. (2014)

Lipid-based nanocarriers

Showed enhanced BBB ferrying through receptormediated endocytosis Curcumin absorption and efficiency has been remarkably enhanced Augmented intake by the BBB cellular model

Controlled drug release, enhanced drug bioavailability and decreased chemical and physiological degradation and side effects Showed improvement in the colloidal stability of curcumin BBB ferrying Augment bioavailability and cellular absorption of curcumin

Curcumin tethered lipidPEG with a BBB transport mediator (antitransferrin) antibody LCN

Curcumin encapsulated monoolein based liquid crystalline NP dispersion SLNs Curcumin SLNs made up of natural lipids like lecithins or triglycerides

Wei et al. (2018) and Angelova et al. (2018)

Baskaran et al. (2014) Salehi et al. (2020) Salehi et al. (2020)

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Table 1 Curcumin delivery systems—cont’d Targeted therapy

Drug delivery system

Reference

Curcumin loaded into Fe3O4-curcumin conjugate with oleic acid or chitosan on the exterior Anti-amyloid antibody (IgG4.1)-functionalized gadolinium/magnetic nanocarriers encapsulated with curcumin/ dexamethasone

Cheng et al. (2015)

Magnetic nanoparticles

Enhanced cellular absorption and bioavailability Early diagnosis, targeting, and therapy of cerebrovascular amyloid

Jaruszewski et al. (2014)

micellar nanocarriers showed profound improvement in pharmacokinetic parameters ( Joseph et al., 2018). In addition, micelles of PLGA-PEG-PLGA triblock copolymers substantially altered curcumin pharmacokinetics and tissue distribution (Song et al., 2011).

Surface modification Simple PLGA NPs without additional modifications encountered a few challenges such as short systemic circulation, insufficient ability to ferry BBB, and insufficient tissue distribution in the disease region. To overcome these challenges, researchers have developed manifold modified PLGA nanocarriers (with targeting ligands) to increase drug delivery to the brain and the central nervous system (CNS) (Cai et al., 2016; Salehi et al., 2020). In vitro evaluation of curcumin encapsulated PLGA NPs were tethered with Tet-1 peptide and used for in vitro AD studies (Mathew et al., 2012). Similarly, glutathione modified NPs could alter the route of internalization (potentiating them to get away from the uptake via micropinocytosis) and preventing the lysosomal degradation (Paka and Ramassamy, 2017). Bifunctional liposomes were designed with a peptide obtained from ApoE receptor-binding domain (for BBB targeting) and with phosphatidic acid (for Aβ binding). The electron microscopy experiments showed that the bifunctional liposomes are capable of disassembling and stopping the Aβ accumulation in vitro. These studies have also shown that bifunctional liposomes weaken Aβ aggregates, facilitate peptide elimination

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Turmeric and curcumin for neurodegenerative diseases

through the BBB and its eventual scavenging (Balducci et al., 2014). In addition, curcumin tethered nanoliposomes with increased affinity for Aβ deposits showed their potential in AD theranostics. Interestingly, nanoliposomes substantially labeled Aβ deposits in the postmortem AD brain tissue and the APPxPS1 mice. The administration of curcumin-conjugated nanoliposomes in the neocortex and hippocampus of mice showed the potential to stain the Aβ deposits in vivo (Lazar et al., 2013). Alternatively, the nonspecific interaction of liposomes with the BBB was explored using cellpenetrating peptide (CPP). The CPP primarily shows the interaction between positively charged amino acids with the negatively charged components existing at the surface of the biomembranes such as the BBB (Lindgren et al., 2000). The existence of amino acids like arginine and lysine helps the formation of hydrogen bonds with the negatively charged phosphates, which are available on the (bio-) membranes. CPP with various characteristics probably undertakes little different internalization mechanisms such as (specific and nonspecific) endocytosis, pore formation, and energy-dependent and independent mechanism (through caveolin- and clathrin-independent lipid rafts) (Ross et al., 2018). Of the numerous CPPs, the altered human immunodeficiency virus-1 (HIV-1) transactivating transcriptional activator (TAT) peptide (with positive charges that can interact with the negative charges of the BBB) has been extensively used to accomplish endocytosis of liposomal NPs into the brain (Vives et al., 2003). It has been shown that nanoliposomes double-functionalized with curcumin derivative and TAT peptide improves BBB spanning in vitro and binds to Aβ peptide (Sancini et al., 2013). Additionally, curcumin derivatives with lipid ligands can be explored for drug delivery to the brain and treat various brain diseases. Curcumin or curcumin derivatives comprising lipid ligands (phosphatidic acid, cardiolipin, GM1 ganglioside) substantially attenuated the formation of fibrillar and/or oligomeric Aβ in vitro (Taylor et al., 2011) (Table 2).

Chitosan Chitosan (CS), a natural polysaccharide with adequate biocompatibility and biodegradability, has been a potential polymer for brain delivery as it shows low toxicity and immunogenicity. CS polymer has primary amine groups that make these carriers positively charged devices and appropriate systems for brain targeting (Yadav et al., 2012; Karewicz et al., 2013; Yang et al., 2018; Salehi et al., 2020). CS NPs ameliorated curcumin’s chemical stability,

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inhibited its degradation, and enhanced the uptake by the cell membrane and the controlled release of curcumin (Salehi et al., 2020). In a study, curcumin-tethered CS NPs with diameter