Review of Pharmacotherapeutic Targets in Alzheimer’s Disease and Its Management Using Traditional Medicinal Plants

Figures & data

Figure 1 Biosynthesis of acetylcholine and cholinergic transmission.

Figure 2 α-, β-, and γ-secretase pathway.

Figure 3 Tau hypothesis cascade.

Table 1 USFDA-Approved Medicines for the Management of AD

Drug	Half-Life (h); Tmax (h)	Absorption (%)	Distribution& Protein Binding (%)	Type	Treatment Stage
Rivastigmine	2; 0.8–1.7	40	40	AChE and BChE inhibitor	Mild to moderate
Galantamine	5–7; 0.5–1.5	85–100	18	AChE and BChE inhibitor	Mild to moderate
Donepezil	60–90; 3–5	100	96	Selective AChE inhibitor	All stages
Memantine	60–80; 3–7	100	45	NMDA Receptor Antagonist	Moderate to severe

Figure 4 Chemical structures of FDA-approved drugs for the treatment of AD.

Figure 5 Ayurveda’s approaches to treating AD.

Figure 6 Phytoconstituents of Ayurvedic medicinal plants used for AD.

Table 2 Medicinal Plants and Their Phytoconstituents Effective Against AD.²¹

Plant Sources	Plant Part	Active Constituents	AD Drug Target	Model Used	References
Acorus calamus (Acoraceae)	Whole plant extract	β-Asarone, α-asarone	It inhibits AChE activity and increases the GSH while reducing oxidative stress markers (SOD & LPO).	Enzyme, rat and mouse	[131–133]
Ginkgo biloba (Ginkgoaceae)	Leaf extract	Ginkgolide B, flavonoids	It inhibits Aβ deposition and improves the cytochrome P-450 enzyme system through the free-radical-scavenging property (antioxidant).	Mice	[134,135]
Crocus sativus ten (Iridaceae)	Stigma dry powder	Crocin, safranin, carotenoids, Safranal	It inhibits Aβ and tau protein deposition by reducing oxidative stress. It also inhibits the cognitive dysfunctions to maintain the hippocampal synaptic plasticity and fibrillogenesis in AD.	Cell and tissue	[134]
Hancornia speciosa Gomes (Apocynaceae)	Fruit extract	Phenolic compounds, rutin	It blocks the ChEs and increases the ACh, reducing oxidative stress by inhibiting the generation of NO & LPO.	Enzyme	[136]
Ecklonia cava (Lessoniaceae)	Extract of seaweed	Dieckol, Phlorofucofuroeckol-A	It decreases inflammatory cytokine levels (NF-kB andSTAT3) andAD markers (glial fibrillary acidic protein, Aβ, β-secretase).	Enzymes& peptide	[137]
Syagrus romanzoffiana (Cham.) Glassman (Arecaceae)	Extract of leaf and fruit	Phenols & fatty acids	It inhibits AChE activity in the cerebral cortex and cerebellum of rats and exhibits the nootropic effect.	Rat	[138]
Nonea micrantha (Boraginaceae)	Whole plant Extract	Flavonoids	It inhibits AChE activity along with scavenging free radicals.	Enzyme	[139]
Convolvulus pluricaulis Choisy (Convolvulaceae)	Whole plant Extract	Triterpenoids, flavonol glycosides, anthocyanins, and steroids	It reduces mRNA expression of the M1 receptor, Choline acetyltransferase, and NGF-TrkA receptor.	Rats	[140]
Rhodiola rosea (Crassulaceae)	Root & rhizome extract	Salidroside, rosavins, and p-tyrosol	It down-regulates the expression of the following genes, such as ALOX5AP, DPEP2, and LTC4S. Also, inhibits the leukotriene biosynthesis signaling path to reduce inflammation and neurotoxicity in AD.	Human T98G neuroglia cells	[141]
Ficus carica mesocarp (Moraceae)	Mesocarp extract	C-Sitosterol	It improves neuronal bioactivity by reducing oxidative stress in AD.	Enzyme& cells	[142]
Psidium guajava (Myrtaceae)	Leaf & fruit extract	Phenolic and flavonoid molecules	It blocks ChEs and also shows free-radical-scavenging activity.	Enzymes	[143,144]
Olea europaea (Oleaceae)	Leaf	Oleuropein, hydroxytyrosol	It inhibits Aβ and tau protein deposition by decreasing oxidative stress as well as neuroinflammation (NF-κB and Nrf2 modulation).	Enzyme and cells	[145]
Sargassum sagamianum (Sargassaceae)	Seaweed extract	Ring-fused 3β-acetoxyandrost-5-ene derivatives (S)−4,4a,5,6,7,8-(hexahydronaphthalen-2-one)-fused 3β-acetoxyandrost-5-ene	It selectively inhibits BChE and shows a neuroprotective effect by regulating mitochondrial potential.	Enzymes	[146]
Curcuma longa (Zingiberaceae)	Rhizome extract	Curcumins	It is a multitargeted phytoconstituent that inhibits ChEs and Aβ protein. Also, it maintains the structure of neurons and synaptic plasticity by deferring neuronal impairment, neurogenesis pathway, and neuroinflammation.	Enzyme, cells and rodents	[147]
Thunbergia grandiflora Roxb (Acanthaceae)	Leaf extract	Phenolics and flavonoids	It decreases the level of ChEs and also inhibits LPO levels from showing antioxidant activity to restore cognitive dysfunction.	Enzymes	[148]
Mangifera indica (Anacardiaceae)	Leaf & seed kernel extract	Isomangiferin & pentagalloyl glucose	It reverses the cognitive function by inhibiting AChE and Aβ as well as also showing radical-scavenging properties.	Enzymes	[149]
Andrographis paniculata (Acanthaceae)	Active compound	3,4-di-o-caffeoylquinic acid, apigenin, and 7-o-methyl wogonin	It inhibits ChEs, Aβ, and BACE-1.	In silico software and enzymes	[150]
Semecarpus anacardium (Anacardiaceae)	Leaf extract	Flavonoids, phenols	It improves learning and memory by blocking AChE & also decreases the oxidative stress markers.	Enzymes	[151]
Coriandrum sativum (Apiaceae)	Leaf extract, volatile oil	Petroselinic acid, linalool, fatty acids	It inhibits the AChE to increase the ACh level in the brain. It possesses antioxidant activity by reducing catalase and elevating GSH levels in the hippocampus region.	Enzymes & rat	[152]
Ferula asafoetida (Apiaceae)	Whole plant extract, resins	Umbelliferone, ferulic acid, coumarins, and other terpenoids	It inhibits AChE in the brain. Furthermore, it exhibits free- radical-scavenging activity.	Enzymes	[153,154]
Acanthopanax trifoliatus and Eleutherococcus senticosus (Araliaceae)	Whole Plant extract	Polyphenols, flavonoids	It inhibits lipid peroxidation and also scavenges the free radicals in the rat brain.	Stress markers	[155]
Sarcococca saligna (Buxaceae)	Whole plant extracts	Salignenamide-E, 2-hydroxysalignar ine-E, axillaridine-A	It increases the ACh level by inhibiting AChE and BChE.	Enzymes	[156]
Sarcococca hookeriana (Buxaceae)	Whole plant extracts	Hookerianamine-A, phulchowki-amideA	It selectively blocks AChE to increase the ACh.	Enzymes	[156]
Buxus papillosa (Buxaceae)	Leaf	Buxakashmir-amine	It selectively blocks BChE to increase the ACh.	Enzymes	[155,157,158]
Bauhinia forficate and Copaifera langsdorffii (Fabaceae)	Fruit extract	Polyphenols	It inhibits the AChE to increase the ACh level.	Enzymes	[159,160]
Clitoria ternatea (Fabaceae)	Root extracts	Quercetin and myricetin glycosides	It improves cognitive behavior	Rats & cells	[161,162]
Mentha piperita, Salvia longifolia, Betonica officinalis, Satureja Montana, Chamaedrys Moench, Clerodendrumcephalanthus, Teucrium polium, and Thymus vulgaris (Lamiaceae)	Aerial part and leaf extracts	Carotenoids, phenolic acids, rosmarinic acid, chlorogenic acid, caffeic acid	It displays AChE-inhibitory activity and controls the oxidative stress parameters.	Enzymes	[163]
Lavandula angustifolia (Lamiaceae)	Aerial part extract	Linalool, tannins, linalyl acetate, camphor, coumarins, triterpenes, flavonoids	It is capable of regulating the production of APP and GLT1 proteins, reducing oxidative stress, protecting neurodegeneration apoptosis, and significantly improving cognitive dysfunction in AD. It also scavenges the free radical.	Rats & cells	[164–166]
Lycopodie llacernu, Lycopodie llariofrio (Sodiro), Lycopodium clavatum, and Huperzia selagovar. serrata (Lycopodiaceae)	Whole plant extract	Huperzine A	It decreases the level of ACh and shows free-radical-scavenging activity.	Enzymes	[167,168]
Rehmannia glutinosa f. lutea (Plantaginaceae)	Root extract	Catapols, 5-hydroxymethyl furfural, bacopasaponin	It upregulates the expression of NGF in the neurons of the hippocampus. It reduces the Aβ-induced neurotoxicity. It exhibits neuroprotective activity.	Peptides & fly (Drosophila)	[169]
Bacopa monnieri (Plantaginaceae)	Leaf extracts	Brahmine, herpestine	It increases the ACh level through inhibition of AChE, activates choline acetyltransferase, and also reduces the Aβ plaques.	Enzyme, peptides, cells, and rats	[170,171]
Ashwagandha/ Withania somnifera	Roots	Sitoindoside IX, Sitoindoside X, Withanolides, withanols	It reduces the Aβ toxicity in SK-N-MC cells, lipid peroxidation, and elevates the conc. of SOD, catalase, and ascorbic acid. It also blocks the AChE in neuronal cell culture and regenerates axons, dendrites, and synapses.	Enzymes, peptides, and cells	[172]
Saururus chinensis hort. ex Loudon (Saururaceae)	Whole plant extract	Flavonoids, alkaloids, αpinene, cinnamic acid, camphene, safrole, β-caryophyllene, linalool, and humulene	It inhibits LPS-activated neuroinflammation in BV-2 microglia cells by controlling the NF-κB signaling pathway and also scavenges the free radicals.	Cells	[173,174]
Ziziphus jujuba Lam (Rhamnaceae)	Whole plant extract	Flavonoids, polysaccharides, phenolics, terpenes	It inhibits the Aβ deposition and exhibits antioxidant activity through scavenging the free radicals.	Peptide	[175]
Nigella sativa (Ranunculaceae)	Seed extract	Thymoquinone, phenols	It blocks the AChE to increase the ACh and strengthens the neuroprotective action in neuronal injury via toluene exposure.	Rats & oxidative stress markers	[176–178]
Sesamum indicum (Pedaliaceae)	Seed extract	Sesamin, sesaminol, terpenes, flavonoids	It inhibits the AChE and generation of the free radical.	Rats	[179]
Lawsonia inermis (Lythraceae)	Leaf extract	Phytol, pseudoephedrine, aspidofractinine-3-methanol, phenol, 2.6-bis(1,1-dimethylethyl)-4-methyl	It inhibits the AChE activity in the hippocampus region and increases the nootropic effect. It also possesses the scavenging ability against the free radicals.	Mice & oxidative stress markers	[180]
Panax notoginseng (Araliaceae)	Root extract	Ginsenoside Rg1	It inhibits the expression of inflammatory factors TNF and Toll-like receptors. It also reduces the secretase enzymes.	Enzyme, peptide and cell	[181,182]
Ginkgo biloba (Ginkgoaceae)	Leaves extract	Ginkgetin, bilobalide, ginkgolide	It increases the ACh level through inhibition of AChE.	Enzymes	[183,184]
Dipsacus asper Wall (DAW) (Caprifoliaceae)	Bark extract	Akebia saponin D	It shows neuroprotective action against Aβ25-35-induced cytotoxicity in PC-12 cells and may be beneficial in the treatment of AD.	Peptides, cells, and rats,	[111,185]
Paeonia suffruticosa (Paeoniaceae)	Plant extract	1,2,3,4,6-Penta- O-galloyleta-d-glucopyranose	It inhibits both types of Aβ1–40 and Aβ1–42 aggregation and also destabilizes Aβ fibrils.	Peptide & transgenic mice	[186]
Polygala tenuifolia (Polygalaceae)	Root extract	Tenuifolin	It possesses inhibitory activity against β-secretase enzymes and maintains neuronal plasticity. Also, it reduces the Aβ formation in cultured cells.	Peptide& cultured cell lines	[187]
Radix Salviae miltiorrhizae (Lamiaceae)	Rhizoma extract	Triterpenoids, Tanshinone	It shows AChE inhibitory activity and reduces the Aβ toxicity.	Rats	[188,189]
Monascus purpureus (Monascaceae)	Fermented red mold rice	Monascus fermented red rice	It inhibits enzymes, such as AChE and secretase, and scavenges the free radicals.	Enzyme, peptides and Mice	[189,190]
Uncaria rhynchophylla (Rubiaceae)	Stem with hooks	Triterpene esters, muscarinic acids	It reduces the Aβ aggregation and stabilizes Aβ fibril. It also inhibits the tau hyperphosphorylation, maintains the synaptic function, and reduces the neuronal loss.	Peptides & Mice	[191,192]
Bacopa monnieri (Scrophulariaceae)	Whole plant extract	Bogenines, steroids, Triterpene	It regulates the MARK4 to reduce the kinase activity. It also increases the ACh to improve learning and memory.	Rats	[193,194]
Salvia officinalis (Lamiaceae)	Aerial parts extract	Essential oils having cineole and thujone	It shows inhibitory action against AChE and scavenges the free radicals to elevate cognitive functions and treat mild-moderate AD. Now, it is in the clinical phase.	Enzyme, and Human	[195,196]
Melissa officinalis (Lamiaceae)	Whole plant extract	Terpenes, tannins, eugenol, rosmarinic acid	It displays inhibition action against the AChE and shows antioxidant activity.	Rats & humans	[197,198]
Murraya koenigii (Rutaceae)	Leaves extract	Carbazole alkaloids, Scoponin	It reduces the ChEs action in the hippocampus region of the brain to increase the nootropic effect.	Enzyme, mice and oxidative stress markers	[199,200]
Cassia obtusifolia (Legumes)	Seed extract	Gluco-obtusifolin, Obtusifolin	It increases the ACh level through inhibition of AChE.	Mice	[201,202]
Centella asiatica (Umbellifers)	Extract of whole plant	Triterpene glycosides, saponins	It increases the ACh level through inhibition of AChE and also reduces the formation of Aβ plaques.	Mice, peptide and oxidative stress markers	[203]
Fungus Ganoderma lucidum (Ganodermataceae)	Ethanol extract	Ganoderic acid (Triterpene glycoside)	It preserves the neuronal plasticity and decreases the Aβ-induced apoptosis. It may be beneficial in the treatment of AD and dementia.	Peptide, and cortical neuronal culture	[204]
Desmodium gangeticum (Legumes)	Aqueous extract	Aminoglucosyl- glycerolipids, cerebrosides	It inhibits AChE from elevating the ACh to improve the working memory. It also exhibits neuroprotective action and free-radical-scavenging activity.	Mice	[205]
Lycium barbarum (Solanaceae)	Whole plant extract	Polysaccharides	It reverses Aβ and homocysteine-induced apoptosis to treat AD.	Peptide, and rat cortical neurons	[206]
*Yokukansan	Extracted from 7- medicinal herbs	Composition of crude herbs	It reduces the Aβ-induced neurotoxicity and enhances motor activity.	Tg2576 mice	[207]
**Zokumei-to	Combination of 9 crude drugs	Composition of crude herbs	It reduces Aβ-induced neurotoxicity and eliminates neuronal loss.	Mice & peptide	[208]
Guggulu/ Commiphora whighitti	Resin	Guggulsterones, manusumbionic acid	It inhibits AChE to increase the ACh to show a nootropic effect. It also scavenges free radicals.	Mice& oxidative stress markers	[209]
Ardraka/ Zingiber officinale	Rhizome	Zingerone; (4-hydroxy-3-methoxyphenyl-yl-2-butanone)	It inhibits the Aβ deposition, tau hyperphosphorylation mRNA expression of LPS, TNF-α, IL-1β, and decreased levels of TNF-α, IL-1β, COX-2, MIP-1α, MCP-1, and IP-10. Thus, it enhances the working memory.	Enzymes, peptide, rats, and cell lines	[210]
Amalaki /Emblica officinalis	Fruit	Tannins, Phyllembelin, Pectins, Vitamin C	It inhibits the AChE activity to enhance the ACh level in the brain.	Mice	[211]
Brahmi/ Bacopa monnieri	Roots & leaves	Bacoside A	It inhibits the AChE to increase the ACh level in the brain and scavenge the free radicals.	Rats	[212]
Guduchi/ Tinospora cordifolia	Stem	Tinosporine, Giloin, Tinosporide, Magnoflorine	It blocks ChEs from showing a nootropic effect in AD. It also scavenges the free radicals to show neuroprotective activity.	Rats & Humans	[213]
Harinda/ Curcuma longa	Roots/ rhizomes	Curcumin	It blocks stimulatory proinflammatory cytokines, such as TNF-α and IL-1β. It also prevents Aβdeposition, oxidative stress markers, and neurotoxicity in AD.	Proinflammatory cytokines parameters	[214]
Jatamansi/ Nardostachys jatamansi	Roots & rhizomes	Jatamansic acid, Jatamansone, Jatamansinol, Valeranone	It inhibits the AChE, BChE, GSK3β, and Keap1.	Rodents	[215]
Falgu/ Ficus carica	Fruit	Anthocyanin, triterpenoids, coumarins	It inhibits the AChE action to improve the nootropic effect and also shows potential chelating and radical-scavenging properties.	Mice	[216]
Paatha/ Cissampelos pareira	Whole vine	Hayatine, hayatidine, berberine	It suppresses the AChE and free radical activity. Also, it diminishes the oxidative stress markers in the hippocampus.	Mice	[217]
Kushmanda/ Benincasa hispida	Fruit	Triterpenes, sterols, and glycosides	It increases the ACh level and reduces the oxidative stress markers (SOD, catalase, MDA) while increasing the GSH level. It also reduces inflammatory cytokines, such as TNF-α and IL-1β, and reduces AlCl3-induced AD in rats.	Rats	[218]
Nithyakalyani/ Catharanthus roseus	Dried root	Serpentine, ajmalicine, catharanthine	It shows potential inhibitory action against AChE and also exhibits low cholinergic receptor affinity.	Rats	[219]
Puga/ Areca catechu	Fruit	Arecaidine, Arecoline,	It reduces AChE action and increases the ACh in the brain, and it also shows agonistic activity on the muscarinic-2 receptor.	Rats	[220,221]
Shatavari/ Asparagus racemosus	Fresh tuber	Sarsasapogenin	It acts as a multitargeted ligand to inhibit ChEs, Aβ aggregates, BACE1, and MAO-B. It also shows neuroprotective activity on PC12 cells against Aβ42 and H2O2-induced cytotoxicity.	Enzymes, peptide, cells	[222]
Glycyrrhiza glabra	Root extract	Glycyrrhizin; 2.2′,4′-Trihydroxychal- cone	It improves spatial learning and memory-enhancing activities.	Mice	[132]
Shalparni/ Desmodium gangeticum	Root extract	Aminoglucosyl-glycerolipids, cerebrosides, pterocarpan, pterocarpanoids, gangetin, gangetinin, desmodin	It reduces the brain AChE in scopolamine-induced AD at doses of 50, 100, and 200 mg/kg, p.o. Thus, it improves learning and memory.	Mice	[205]
Aparajita/ Clitoria ternatea	Root extract	Inositol, cyclohexen, 1-methyl-4-(1- methylethylideme)	It enhances the ACh level in the hippocampus region to improve the nootropic action at a dose of 100 mg/kg.	Rat	[223]
Dadima/ Punica granatum	Flower, fruits	Anthocyanin compounds	It prevents oxidative stress and reduces Aβ42-induced cytotoxicity. It also maintains mitochondrial homeostasis in cultured neuronal cells.	Rat, peptide	[224]

Notes: *Atractylodes Lancea rhizome, Poria sclerotium, Cnidium rhizome, Uncaria hook, Japanese angelica root, Bupleurum root, and Glycyrrhiza.**Armeniacae Semen (Prunus armeniacaL.), Ephedrae Herba (Ephedra sinica Stapf), Cinnamomi Cortex (Cinnamomum cassia Blume), Ginseng Radix (Panax ginseng C.A. Meyer), Angelicae Radix (Angelica acutiloba Kitagawa), Cnidii Rhizoma (Cnidium officinale Makino), Zingiberis Siccatum Rhizoma (Zingiber officinale Roscoe), Glycyrrhizae Radix (Glycyrrhiza uralensis Fisch.), and Gypsum Fibrosum (gypsum).

Abbreviations: AD, Alzheimer’s disease; ACh, acetylcholine; AChE, acetylcholinesterase; BChE, Butyrylcholinesterase; Aβ, amyloid beta; NO, nitric oxide; GSH, glutathione; CAT, catalase; SOD, superoxide dismutase; MDA, malondialdehyde; MAO, monoamine oxidase; COX, cyclooxygenase; LPO, Lipid peroxidation; STAT, Signal transducer and activator of transcription; NF-κB, Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells; NGF-TrkA, Nerve Growth Factor-Tropomyosin-related kinase A receptor; BACE1, Beta-site APP-cleaving enzyme 1; GLT-1, Glutamate transporter 1; NGF, Nerve growth factor; LPS, Lipopolysaccharide; TNF, Tumor necrosis factor; MARK4, Microtubule affinity-regulating kinase 4; IL, Interleukins; MIP-1α, Macrophage inflammatory protein-1α; MCP-1, Monocyte chemoattractant protein-1; GSK3β, Glycogen synthase kinase 3 beta; KEAP1, Kelch-like ECH-associated protein 1; Nrf2, Nuclear factor erythroid.

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