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Herbal Medicines forManagement

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ofAlzheimer’s Disease

JaiMalik, SubhashC.Mandal, SunaynaChoudhary, ShwetaParihar, andMohamedRahamathulla

Abstract

The advancements in the therapeutic world have increased the average life expectancy of man, thereby causing an increase in the prevalence of degenerative disorders, especially Alzheimer’s disease. Oxidative stress, mutation in presenilin (PSEN) genes (PSEN1 and PSEN2), inammation, mitochondrial and neurovascular dysfunction, and calcium dysregulation are some of the other prominent causes of AD.Despite advancements in therapeutics, drug development for a safe and effective therapeutic regimen for AD has been challenging because of the high failure rate. During the last three decades, only six drugs (four acetylcholinesterase inhibitors, one NMDA antagonistmemantine, and one antibody-based drug-aducanumab) have been approved for AD by US FDA. The complex pathophysiology of this disease necessitates using medicines that can act on several targets at once. Mother Nature has proved herself from time to time incurring various illnesses, which is conrmed by the scientic literature. Various herbal drugs across the world have shown benecial effects in AD patients either by improving the symptoms or by modifying the disease. The present chapter overviews some of the important and widely studied plants and their constituents against AD.

J. Malik (*) · S. Parihar Department of Pharmacognosy, University Institute of Pharmaceutical Sciences—UGC Centre of Advanced Study, Panjab University, Chandigarh, India e-mail: jmalik@pu.ac.in

S. C. Mandal Pharmacognosy and Phytotherapy Research Laboratory, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

S. Choudhary Department of Pharmacognosy, M.M.College of Pharmacy, M.M. (Deemed to be University), Mullana, Ambala, Haryana, India

M. Rahamathulla Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia

Keywords

Alzheimer’s disease · Neurodegenerative disorders · Curcumin · Huperzine A · Ginsenosides · Resveratrol · Withanolides · Berberine

1 Introduction

The advancements in the therapeutic world have increased the average life expectancy of man, thereby causing an increase in the prevalence of degenerative disorders, especially neurodegenerative disorders. Alzheimer’s disease (AD) is among the most prevalent neurological conditions in geriatric population. Despite advancements in therapeutics, the drug development for a safe and an effective therapeutic regimen for AD has been challenging because of the high (almost 100%) failure rate. During the last three decades, more than 800 drugs have been approved by USFDA for different disorders, and only six drugs (four acetylcholinesterase inhibitors, one NMDA antagonist-memantine, and one antibody-based drug-aducanumab) have been approved for AD.Very recently, a controversial accelerated FDA approval has been given to another monoclonal antibody drug lecanemab for AD.Amongst these, tacrine and memantine are no longer marketed. Furthermore, according to an estimate, there has been a staggering 150% increase in AD cases in the last three decades, and by 2050, there will be more than 130 million AD patients worldwide [1]. At present in the US, about one in nine persons of age 65 or above has AD type dementia [2]. Thus, due to very limited number of drugs available in the market and compelling increase in the AD cases across the globe, there is a dire need for newer, effective and safe drugs for AD.It is not only the number of AD patients, but also the socio-economic impact of the disease that has made AD more atrocious. The overall annual cost of dementia treatment has been estimated to be a stunning gure of USD1.3 trillion, with more than 300 billion USD spent in the US only [2].

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The work done to understand the pathophysiology of AD has shown multiple pathways involved in its development. This multi-pathway nature of the disease is also one of the major reasons for high failure rate in the drug discovery for the disease. Amongst major reasons, (1) formation and deposition of Aβ plaques, (2) neurobrillary tangles (NFTs) formed by tau proteins hyperphosphorylation, and (3) cholinergic decits in the memory controlling parts (cerebral cortex, hippocampus) of the brain are considered as mainstay for the disease development (Fig.1).

Oxidative stress, mutation in presenilin (PSEN) genes (PSEN1 and PSEN2), inammation, mitochondrial and neurovascular dysfunction, and calcium dysregulation are some of the other prominent causes of AD.Synaptic dysfunction/degeneration is also emerging as one of the prominent causes of AD development [3]. Due to better understanding of pathophysiology of AD, last two decades have observed a paradigm shift in the drug discovery for AD, from the agents giving symptomatic relief to disease modifying agents. Around 53% of the total drugs went under clinical trials for AD in 2019 were disease modifying agents [4], and this gure increased to 83% in 2021 [5] and

2022 [6]. Approval of aducanumab and lecanemab, two monoclonal antibody- based drugs, are the result of this paradigm shift. Herbal drugs and their constituents due to their multifarious effects and their effects on different molecular markers of the disease, have also emerged as promising candidates for drug development of AD.Various herbal drugs across the world have shown benecial effects in AD patients either by improving the symptoms or by modifying the disease. It all started with physostigmine, an alkaloid from Physostigma venenosum (Leguminosae), that exhibited a potent acetylcholinesterase inhibitory activity which was benecial in AD type dementia. Later in 2000, its semisynthetic and more potent derivative, Rivastigmine was approved by US-FDA for AD.In the following year, 2001, another alkaloid, Galantamine obtained from Galanthus nivalis (Amaryllidaceae) was also approved by FDA due to its acetylcholinesterase inhibitory activity (Fig. 2). Since then, various herbal drugs, their preparations, and isolated chemical compounds have shown their efcacy against AD.The present chapter reviews some of the important and widely studied plants along with their constituents against AD.

Fig. 1 Pathological pathway of Alzheimer’s disease

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Fig. 2 Various compounds for AD from plants

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2 Plants withBenecial Eects inAD

2.1 Huperzia serrata (Thunb. Ex

Murray)Trev

H. serrata (syn. Lycopodium serratum Thunb. ex Murray), belonging to the family Huperziaceae, has been used in Traditional Chinese Medicine since ages under the name ‘Quian Ceng Ta’, for its benecial effects on CNS, in inammation and pain [7]. The plant has a world-wide distribution ranging from central America to Eastern, Southern or South- east Asia. The plant is known for its alkaloids that are classied (based on their structural properties) into four categories, viz., fawcettimine-type, lycodine-type, lycopodinetype, and miscellaneous-type. Among various constituents present in H. serrata, Huperzine A (HupA, Fig.2) is considered the most important constituent because majority of its biological activities have been attributed to this compound [8]. HupA was rst isolated in 1986, and since then, it is amongst the most comprehensively studied natural molecules [9, 10]. At present, it has been approved for AD treatment in China and is available as a dietary supplement in the US [11].

HupA is an unsaturated lycodine type sesquiterpene alkaloid, which is optically active and occurs as (−)-HupA or L-HupA in nature. This isomer is biologically active and more potent than (+)-HupA or D-HupA, while the potency of the racemic mixture lies between the two [12]. HupA came into the picture because of its potent, specic, and reversible acetylcholinesterase inhibitory (AChEI) activity which was even more than the approved drugs (tacrine, galantamine, donepezil, and rivastigmine) [11, 13, 14]. The AChEI activity of HupA causes accumulation of acetylcholine (ACh) which acts through α7nAChRs and α4β2nAChRs receptors modulating neural stem cells function via mitogen-

activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway, that eventually exhibits neuroprotective and neurogenetic action [15]. It has also been observed that globular tetramer of acetylcholinesterase forms a stable complex with amyloid beta (Aβ) peptides, thereby increasing the aggregation and plaque formation in brain [16, 17]. HupAdose-dependently also prevented this aggregation by its AChEI activity when studied in various transgenic animal models [18]. Inhibition of wingless-related integration site (Wnt) signaling increases tau phosphorylation and Aβ accumulation, thereby causing cognitive decline [19]. HupA inhibits the glycogen synthase kinase-3β (GSK3β), thereby stimulating the Wnt signaling which helps in inhibiting the tau phosphorylation and Aβ accumulation by promoting non-amyloidogenic pathway [20]. Besides inhibiting the AChE activity, Aβ accumulation and tau hyperphosphorylation, HupA also promotes synaptotagmin expression causing the increased release of neurotransmitters (especially ACh) in the synaptic region from synaptic vesicles through the opening of vesicle pores [21]. This increase in ACh levels and NMDA receptor antagonistic activity also stimulates the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in HT22 hippocampal cells. Stimulation of this pathway further stimulates the phosphatidylinositol 3-kinase (PI3K)/ Aktserine-threonine kinase pathway, as well as rapamycin (mTOR) signaling route that causes suppression of neuronal apoptosis and increase the neuronal survival [22]. HupA has also exhibited benecial effects through non-cholinergic mechanism, wherein it has shown to mitigate AD-induced mitochondrial perturbations and oxidative stress [23, 24].

Apart from numerous preclinical ndings, various clinical studies have also revealed the benets of HupA in improving cognition in AD and vascular dementia patients [25–29]. In another study, HupA, when given for 8 weeks to

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AD patients, exhibited improvement in their cognition and task switching abilities when evaluated using Mini-Mental State Exam (MMSE), the AD Assessment Scale-cognitive subscale (ADASCog) [30]. Another randomized clinical trial on vascular dementia patients demonstrated similar kind of results when HupA treated patients were evaluated for their cognitive abilities using MMSE and Activities of Daily Living (ADL) tests [29].

2.2 Ginkgo biloba Linn

A member of family Ginkgoaceae is also known as “Maidenhair tree” due to its resemblance with “Maidenhair fern” (Adiantum) and a “living fossil” due to its presence on this planet for the last 200 million years. G. biloba is the only plant species of its genus. It is indigenous to East Asia (China, Japan, and Korea) but one can also nd it growing in European and American continents. The plant is known for its terpene trilactone compounds, collectively known as Ginkgolides which consists of diterpene trilactones ginkgolide A, B, C, J, K, L, and M, a sesquiterpene trilactone, bilobalide, and various avonoids - quercetin, kaempferol, myricetin, apigenin, isorhamnetin, luteolin, and their glycosides (Fig.3). A standardized commercial extract, EGb 761 (manufactured by Beaufour-Ipsen Pharma, France, and Dr. Willmar Schwabe Pharmaceuticals, Germany), containing 5–7% ginkgolides and bilobalide (BB), along with22–24% of avonoids and ginkgolic acids or anacardic acids (< 5ppm, due to their cytotoxic and contact dermatitis properties) has been widely used for studying the effects of the plant [31, 32].

The efcacy of the G. biloba extract (GBE) against AD has been reviewed by various groups over the period [33–

36]. Experts have suggested that GBE can have benecial

effects on cognition in the patients that are unresponsive to the treatment of AChEIs or NMDA receptor antagonists [37]. GBE has exhibited its benecial effects through multifarious activities on the nervous system (Fig. 4). Various studies have shown the antioxidant potential of GBE as one of the major neuroprotective mechanisms. It has shown neuroprotective activity against oxidative stress induced by H2O2 [38], FeSO4 [39], and Aβ [40] in brain cells. The antioxidant effect exhibited by GBE was mainly due to the upregulation of the antioxidant enzymes, including glutathione reductase, catalase, and superoxide dismutase [41]. Subsequently, its antioxidant potential has also been attributed to the modulation of certain genes [42]. The antioxidant effect of GBE has been found mainly due to avonoids as inconsistent results have been observed with different ginkgolides [43]. The GBE, EGb761, has also shown protection against Aβ, one of the major hallmarks of AD.It prevents the toxic effects of Aβ by promoting the action of α-secretase enzyme which promotes non-amyloidogenic pathway (Fig.4) of amyloid precursor proteins, thus inhibiting amyloidogenesis [44]. Free and high levels of cholesterol have shown to increase the formation of amyloid plaques by modulating the α-secretase activity [45]. Depletion in cholesterol levels in brain has shown to prevent the formation of Aβ [46]. EGb761 has shown to attenuate the increased free cholesterol levels, thereby preventing the formation/accumulation of Aβ plaques [47]. GBE administration has also shown to decrease levels of Aβ and tau proteins by stimulation of Heat shock factor (HSF-1) and increasing the expression of HSPs [48].

Fig. 3 Chemical constituents of Ginkgo biloba

Herbal Medicines forManagement ofAlzheimer’s Disease

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Fig. 4 Multifarious effects of

G. biloba

235

Antioxidant

Anti-amyloid

Aβ also activates N-methyl-D-aspartate (NMDA) receptors leading to increased Ca2+ inux causing neuronal toxicity [49], and also reduces synaptic plasticity by dysregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [50]. Ginkgolide A inhibits both AMPA and NMDA receptors, thereby protecting neurons from Aβ toxicity [51]. Furthermore, ginkgolide A also inhibits the Aβ induced phosphorylation of c-Jun N-terminal kinase (JNK) and prevents the neuronal apoptosis [52]. Ginkgolide A also prevents the tau protein hyperphosphorylation by activating phosphatidylinositol-3-kinase (PI3K) and kinase AKT (AKT) pathway [53], which is responsible for cell survival and downregulation of apoptotic signals [54]. In another study, ginkgolide A, bilobalide, and avonoids promoted the tau protein degradation in the neurons by increasing the LC3B-II protein expression in tau-transgenic AD mice [55]. Inammation and enhanced levels of platelet activating factor (PAF) have also been implicated in AD. GBE inhibits neuroinammation by downregulating the LCN2-activated JAK2/STAT3 signaling pathway and astrocyte proliferation [56]. In another study, GBE mitigates the lead induced increase in myeloperoxidase activity, suppresses TNF-α & IL-6 secretion, and decreases the expression of NF-κB in mice hippocampus, indicating its anti- inammatory potential [57]. The extract also attenuated the increased TNF-α and IL-1β levels and decreased the mRNA expression of NF-κB, p65and Bax, thereby increasing the neuronal survivability in APP/PS1 double gene-transfected HEK293 (APP/PS1-HEK293) cell line model of AD [58]. According to the inammation hypothesis of AD, inammasome (“a cytoplasmic polymeric protein complex that functions as the platform for Caspase-1 activation and for the maturation of

Anti-

inflammatory

Ginkgo

biloba

Anti-

apoptotic

Mitochondrial

protective

the pro-inammatory cytokine interleukin-1β”) of NLR family– pyrin domain containing 3 (NLRP3) inammasome has a vital role in AD pathogenesis [59]. Ginkgolide B decreased the intracellular pro-inammatory cytokine levels to improve cognition in SAMP8 mice. Furthermore, ginkgolide B also deactivated the NLRP3 inammasome through ubiquitination and autophagic degradation [60].

GBE, for its efcacy in AD patients, has also been evaluated in various clinical trials that have been reviewed by various groups highlighting mixed results [43, 61–64]. But a recent report compiled various pre-clinical and clinical studies since 1980, and suggested that detailed, well planned and large-scale clinical studies are required to evaluate the benets of long-term GBE treatment on individuals with earlystage AD [65].

2.3 Panax ginseng C.A.Mey

Ginseng of family Araliaceae is a popular immunomodulator drug whose roots have been used since yesteryears in China, Japan, Korea, and other East Asian countries for vitality, antiaging, as general tonic, for strengthening CNS, and other systems of the body [66–68]. The Genus name Panax, was given by Charles Linnaeus and is derived from Greek word ‘panacea’ (total healing for all), owing to its wide range of therapeutic efcacy. At present, Genus Panax contains 11 species spread across around 35 countries [69]. Among these, Panax ginseng (Korean and Chinese ginseng, both varieties, white and red) along with P. quinquefolium (American ginseng), are the most widely investigated ginseng species. Commercially, three types of ginseng are avail-

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able- raw (extracted from the soil with at least 75% moisture content); white (4-year-old raw ginseng thinly peeled and sun-dried with less than 15% moisture); and red (raw ginseng steamed with water and then dried to get 15–18% moisture to increases the storage duration up to 15years) [70]. Ginseng’s pharmacological effects are believed to be due to its dammarane type triterpenoidal saponin compounds that are collectively known as ginsenosides. Depending upon the positioning of sugar moieties, these ginsenosides (Fig.5) can be categorized into protopanaxadiol type (Ginsenosides Rb1, Rc, Rb2, Rd., and Rg3) and protopanaxatriol type (Ginsenosides Rg1, Re, Rg2, and Rh1). Till date, more than 100 ginsenosides have been isolated and identied from different parts of P. ginseng. Ginsenosides Rbl, Rb2, Rc, Rd., Rgl, Rg2, and Re are major constituents (75–80% of total ginsenosides) of fresh, white and red ginsengs, while ginsenosides Rg3, Rg5, and Rg6 are specically found in red ginseng [67, 71].

Ginsenosides have proved themselves as potent biologically active compounds against AD by acting through multiple pathways viz., antioxidant effects [72], modulation of cholinergic pathway [73], effect on amyloid [74] and tau proteins [75], anti-inammatory, and antiapoptotic activities [76]. Ginsenosides Rb1, Rb2, Rc, Re, Rg1, and Rg3 have signicantly inhibited AChE and BChE.The order of activity of different ginsenosides was found to be Re > Rg3 > Rg1 > Rb1 > Rb2 > Rc for AChE and

Rg3>Rg1>Rb2>Rb1>Re>Rc for BChE [73]. It is well known that β-secretase (BACE1) is the enzyme that leads to the formation of Aβ from amyloid precursor proteins. Various ginsenosides have shown to inhibit this enzyme, thereby preventing the formation of Aβ [73]. The β-secretase inhibition by different ginsenosides was in the order of Rc >Rg1>Rb2>Rb1>Rg3>Re. Another saponin, ginsenoside Rd, improved cognition by decreasing the Aβ levels via promoting non-amyloidogenic pathway, by upregulating estrogenic receptor expression, and α-secretase enzyme activity in ovariectomized rats [77]. It also decreased the expression of BACE1and showed neuroprotection by stimulating MAPK/ERK and PI3K/AKT pathways. Similar results were obtained when ginsenoside Rg1 was evaluated in ovariectomized rats and menopausal women [78, 79]. Aβ also increases the inow of Ca2+ ions in the neurons causing stimulation of proteolytic enzymes, production of ROS leading to neurodegeneration [80]. Ginsenoside Rb1 [81], Rg1 [82], and Rg2 [76] have shown neuroprotective effect by mitigating the Aβ induced increase in not only Ca2+ ions, but also ROS and oxidative stress in the neurons. Ginsenoside Rg2 not only controlled the Ca+2 ion concentration, but it also prevented the neuronal apoptosis by activating the PI3K/AKT pathway [76]. Ginsenoside Rg1 also reduces the Aβ levels by modulating the activities of α-, β-, and γ-secretase enzymes which are involved in the production and degradation of Aβ. It was further found that Rg1 down

Fig. 5 Various ginsenosides from P. ginseng

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regulates the CDK5 pathway by inhibiting the PPARγ thereby limiting the β-secretase expression and reduced the levels of Aβ in the hippocampal neurons [74]. Ginsenoside Rg1 also exhibited neuronal protection by stimulating protein kinase/c-AMP-response element-binding protein (PKA/ CREB) signaling in the hippocampal region [83]. It also decreased the levels of hyperphosphorylated tau proteins in the hippocampus and cortex region of brain by upregulating PP2A expression and suppressing the GSK-3β signaling pathway [75], and by altering the gut microbiota [84]. Very recently, it has been shown that it also combats AD by restoring mitophagy [85]. Ginsenoside Rg1 has also improved AD symptoms by synaptic development. It increases the levels of synaptic formation proteins like microtubule-associated protein 2 (MAP-2) and synaptophysin [86], and also increases the expression of choline acetyltransferase, thereby improving the ACh levels in synapses [87]. Furthermore, Chen (2011) [88] improved the absorption and time of onset of action of Rg1 by preparing its nasal formulation. The results showed that there was a considerable increase in the distribution, transport efciency, and a signicant decrease in time taken by the compound to reach brain (fast onset of action). Various preclinical studies of ginsenoside Rg1 pertaining to its effect against AD have been reviewed by Liang etal. (2021), [89] while Wu etal. (2022) [90] have reviewed the mechanistic insights of Rg1 against AD.Ginsenosides Rg1 and Rg2 also decreased the deposition of Aβ and inuenced the levels of biomarkers such as hypoxanthine, dihydrosphingosine, and hexadecasphinganine in the hippocampus of AD mice [91]. Studies have also shown the efcacy of ginsenoside Rg3 against AD [92, 93]. Ginsenoside Rb1 also prevented the Aβ induced tau hyperphosphorylation in cortical neurons [81]. Apart from ginsenosides, gintonin, a lysophosphatidic acid (LPA) receptor- activating ligand isolated from ginseng, has also exhibited signicant improvement in cognition in preclinical [94, 95] and clinical studies [96]. Ginseng and ginsenosides have also been found effective clinically in various clinical trials [97–100], making them a strong contender for drug development for AD.However, some of the trials have

shown contradictory results wherein no improvement in cognition of the subjects was recorded [101, 102].

2.4 Resveratrol (Trans-3,40,5-Trihydroxystilbene)

A natural phenol (stilbene, Fig.6), rst isolated in 1939 from Veratrum grandiorum, is found in signicant concentrations in the skin of red grapes and grape wines [103]. It has also been found in berries (cranberries, strawberries, blueberries, etc.), nuts, tea, and dark chocolates, though variation in the concentration is reported. It is found in two isomeric forms, trans- and cis-, and the former is predominant in nature.

It has shown protective effects against AD through multipathway action by acting on synaptic plasticity, Aβ peptides and tau proteins by inhibiting GSK3β [104], activating AMPK (AMP-activated protein kinase) and SIRT1 (silent information regulator 1) [105], antioxidant action and acting on PI3K/AKT [105, 106]. Chen etal., (2019) have reviewed various preclinical studies pertaining to the role of resveratrol in experimental AD models [107]. Synaptic plasticity plays avital role in normal brain functions such as learning and memory [108]. Any alteration in the synaptic strength leads to impairment in the storage and consolidation of the information. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) also mediate in maintaining the synaptic plasticity [108]. Aβ proteins have been found to cause signicant loss of AMPARs, thereby causing loss of synaptic plasticity and memory functions in AD [50]. Furthermore, AMPARs also cause the release and abnormal tau proteins phosphorylation, another hallmark of AD [109]. Thus, such evidences highlight the role of AMPARs in AD pathophysiology. Resveratrol activates AMPK and downstream PI3K/AKT signaling leading to increased AMPAR proteins expression, thereby exhibiting neuroprotective action [110, 111].

SIRT1 is a homologue of NAD-dependent deacetylase sirtuin family and has been found responsible for synaptic plasticity, dendrite branching, and axon elongation [112].

Fig. 6 Main curcuminoids from C. longa and resveratrol

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Furthermore, SIRT1 also increases the Aβ degradation and processing of APP through α-secretase, thereby leading to decreased toxicity and production of Aβ [113]. Furthermore, resveratrol, through SIRT1, also activates AMPK-PI3K/ AKT signaling pathway to exhibit neuroprotective effects [114]. Intriguingly, SIRT1 has also been to be associated with increasing the sensitivity of neurons towards oxidative damage through IGF-1/IRS-2/Ras/ERK1/2 signaling [115].

Resveratrol has also exhibited direct effects on Aβ by inhibiting its aggregation and stabilizing its structure [116], enhancing its clearance through proteasomal degradation [117]; altering the amyloid brillar intermediates into nontoxic fragments [118]; reducing the length and number of Aβ brils [119] and reducing the Aβ plaque formation [120]. It also inhibits β-secretase activity, thereby reducing the formation of pathogenic Aβ. On the contrary, reports have stated that though it can change the conguration of Aβ oligomer [121] but it cannot reduce its formation as it has no direct interaction with β-secretase [117]. It also decreased Aβ induced rise in the pro-inammatory molecules such as monocyte chemoattractant protein-1, nitric oxide, interleukins, [122] and nuclear factor-κB [123]. Resveratrol has also exhibited its protective effects against AD by its anti-tau action. It signicantly prevented the tau phosphorylation [124], reduced the levels of phosphorylated tau and inhibited its aggregation, thereby by preventing tau induced synaptic loss [125, 126]. Multifarious mechanisms of resveratrol are summarized in Table1 below.

2.5 Curcuma longa

Curcuma longa (Fam: Zingiberaceae), has been used in India, Asia and Middle Eastern countries as an important

ingredient of curries and other spicy dishes. C. longa like other botanical remedies, was rst used as a food ingredient before it was discovered to have powerful medicinal properties. For centuries, Indian system of medicine has used it extensively as a pain relieving and anti-inammatory agent, in the skin ailments like acne, eczema, and other skin infections [132–134]. Among various constituents present in C. longa, curcumin (1,7-bis [4-hydroxy-3-methoxyphenyl]-1,6heptadiene-3,5-dione, also named diferuloyl-methane) is considered as most important because majority of its biological activities have been attributed to this compound [135]. It is a phenolic compound with two ferulic acid moieties attached through their carboxyl groups by an additional carbon (methane) inbetween (Fig.6). Curcumin was isolated in 1815 by Vogel and Pelletier for the rst time from the rhizomes of C. longa. Curcumin and it is derivative bisdemethoxycurcumin are considered to be the most active constituents. But majority of studies have been done keeping curcumin in focus. It exhibits its protective effects against AD through its multifarious and multitargeted effect. Cholinergic, anti-oxidative, anti-amyloid, anti-tau, antiinammatory and anti-apoptotic properties of curcumin have been found responsible for its benecial effects in AD.Curcumin inhibits the AChE, maintains the acetylcholine levels and strengthens the cholinergic system. The antiamyloid property of curcumin is an amalgamation of its ability to inhibit β-secretase enzyme, Aβ oligomerization and promote the disaggregation of the existing Aβ brils [136] and destabilization of the Aβ brils [137]. It has also been found that curcumin stimulates the estrogen receptor β (ERβ), and this estrogenic action is believed to also contribute towards its β-secretase inhibitory property [138]. Curcumin binds to the Aβ bril at the hydrophobic sites present on the bril and this hydrophobic interaction converts

Table 1 Neuroprotective mechanisms of resveratrol

S.no Molecular target Mechanism Reference 1 SIRT 1 Stimulate its activity

3 Tau Prevent its phosphorylation

4 Oxidative markers Antioxidant

5 Inammatory markers

6 Neuronal apoptotic markers Reduce Bax/Bcl ratio

7 AMPK-PI3K/AKT Stimulate this pathway, inhibit m-TOR, increase

Aβ proteins

Increase axon length, dendrite branching and synaptic plasticity

Increase its degradation Prevent oligomerization, Aggregation and formation

Prevent aggregation Upregulate BAG2

Reduce ROS Increase endogenous antioxidant levels

Reduce levels of interleukines, NF-κB and NO

Increase levels of protein kinase JNK, PKC

autophagy Neuroprotection by decreasing Aβ and tau formation

[112]

[117] [116, 120]

[124–126]

[127, 128]

[123]

[129–131]

[114] [111]

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