Abstract
Medicinal plants are the backbone of modern medicine. In recent times, there is a great urge to discover nootropic medicinal plants to reverse cognitive dysfunction owing to their less adverse effects. Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by the inevitable loss of cognitive function, memory and language impairment, and behavioral disturbances, which turn into gradually more severe. Alzheimer’s has no current cure, but symptomatic treatments are available and research continues. The number of patients suffering from AD continues to rise and today, there is a worldwide effort under study to find better ways to alleviate Alzheimer’s pathogenesis. In this review, the nootropic and anti-Alzheimer’s potentials of 6 medicinal plants (i.e., Centella asiatica, Clitoria ternatea, Crocus sativus, Terminalia chebula, Withania somnifera, and Asparagus racemosus) were explored through literature review. This appraisal focused on available information about neuroprotective and anti-Alzheimer’s use of these plants and their respective bioactive compounds/metabolites and associated effects in animal models and consequences of its use in human as well as proposed molecular mechanisms. This review progresses our existing knowledge to reveal the promising linkage of traditional medicine to halt AD pathogenesis. This analysis also avowed a new insight to search the promising anti-Alzheimer’s drugs.
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Abbreviations
- AD:
-
Alzheimer disease
- Aβ:
-
amyloid β
- SPs:
-
senile plaques
- NFTs:
-
neurofibrillary tangles
- OS:
-
oxidative stress
- ACh:
-
acetylcholine
- AChE:
-
acetylcholinesterase
- BChE:
-
butyrylcholinesterase
References
Uddin MS, Haque A, Mamun AA et al (2016) Searching the linkage between high fat diet and Alzheimer′s disease: a debatable proof stand for ketogenic diet to alleviate symptoms of Alzheimer′s patient with APOE ε4 allele. J Neurol Neurophysiol 07:1–9. https://doi.org/10.4172/2155-9562.1000397
Mendiola-Precoma J, Berumen LC, Padilla K, Garcia-Alcocer G (2016) Therapies for prevention and treatment of Alzheimer’s disease. Biomed Res Int 2016:1–17. https://doi.org/10.1155/2016/2589276
Uddin MS, Mamun AA, Hossain MS et al (2016) Exploring the effect of Phyllanthus emblica L. on cognitive performance, brain antioxidant markers and acetylcholinesterase activity in rats: promising natural gift for the mitigation of Alzheimer’s disease. Ann Neurosci 23:218–229. https://doi.org/10.1159/000449482
Uddin MS, Mamun AA, Labu ZK, Hidalgo-Lanussa O, Barreto GE, Ashraf G (2018) Autophagic dysfunction in Alzheimer’s disease: cellular and molecular mechanistic approaches to halt Alzheimer’s pathogenesis. J Cell Physiol. https://doi.org/10.1002/jcp.27588
Khajehnejad M, Saatlou F, Mohammadzade H (2017) Alzheimer’s disease early diagnosis using manifold-based semi-supervised learning. Brain Sci 7:109. https://doi.org/10.3390/brainsci7080109
Alzheimer’s disease statistics—Alzheimer’s news today. https://alzheimersnewstoday.com/alzheimers-disease-statistics/. Accessed 12 Oct 2018
Ohnishi T, Matsuda H, Tabira T et al (2001) Changes in brain morphology in Alzheimer disease and normal aging: is Alzheimer disease an exaggerated aging process? AJNR Am J Neuroradiol 22:1680–1685
Uddin MS, Mamun AA, Takeda S et al (2018) Analyzing the chance of developing dementia among geriatric people: a cross-sectional pilot study in Bangladesh. Psychogeriatrics. https://doi.org/10.1111/psyg.12368
Uddin MS, Amran MS (2018) Handbook of research on critical examinations of neurodegenerative disorders. IGI Global, Pennsylvania
Murphy MP, LeVine H (2010) Alzheimer’s disease and the amyloid-β peptide. J Alzheimers Dis 19:311–323. https://doi.org/10.3233/JAD-2010-1221
O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204. https://doi.org/10.1146/annurev-neuro-061010-113613
Singh S, Kushwah AS, Singh R, Farswan M, Kaur R (2012) Current therapeutic strategy in Alzheimer’s disease. Eur Rev Med Pharmacol Sci 16:1651–1664
Parra MA, Abrahams S, Fabi K et al (2008) Short-term memory binding deficits in Alzheimer’s disease. Brain 132:1057–1066. https://doi.org/10.1093/brain/awp036
Mamum AA, Uddin MS, Wahid F et al (2016) Neurodefensive effect of Olea europaea L. in Alloxan-induced cognitive dysfunction and brain tissue oxidative stress in mice: incredible natural nootropic. J Neurol Neurosci 7:1–9. https://doi.org/10.21767/2171-6625.1000126
Tarawneh R, Holtzman DM (2012) The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb Perspect Med 2:a006148–a006148. https://doi.org/10.1101/cshperspect.a006148
Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158–b158. https://doi.org/10.1136/bmj.b158
National Institute on Aging What are the signs of Alzheimer’s disease? https://www.nia.nih.gov/health/what-are-signs-alzheimers-disease. Accessed 13 Oct 2018
Uddin MS, Stachowiak A, Mamun AA et al (2018) Autophagy and Alzheimer’s disease: from molecular mechanisms to therapeutic implications. Front Aging Neurosci 10:1–18. https://doi.org/10.3389/fnagi.2018.00004
Ballard C, Gauthier S, Corbett A et al (2011) Alzheimer’s disease. Lancet 377:1019–1031. https://doi.org/10.1016/S0140-6736(10)61349-9
Uddin MS, Kabir MT, Mamun AA et al (2018) APOE and Alzheimer’s disease: evidence mounts that targeting APOE4 may combat Alzheimer’s pathogenesis. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1237-z
Armstrong RA (2011) The pathogenesis of Alzheimer’s disease: a reevaluation of the “amyloid cascade hypothesis”. Int J Alzheimers Dis 2011:630865. https://doi.org/10.4061/2011/630865
Smith AD (2002) Imaging the progression of Alzheimer pathology through the brain. Proc Natl Acad Sci 99:4135–4137. https://doi.org/10.1073/pnas.082107399
Buchman AS, Bennett DA (2011) Loss of motor function in preclinical Alzheimer’s disease. Expert Rev Neurother 11:665–676. https://doi.org/10.1586/ern.11.57
Aliev G, Obrenovich ME, Reddy VP et al (2008) Antioxidant therapy in Alzheimer’s disease: theory and practice. Mini Rev Med Chem 8:1395–1406
Moneim AEA (2015) Oxidant/antioxidant imbalance and the risk of Alzheimer’s disease. Curr Alzheimer Res 12:335–349
Zhao Y, Zhao B (2013) Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxidative Med Cell Longev 2013:1–10. https://doi.org/10.1155/2013/316523
García-Ayllón M-S, Small DH, Avila J, Sáez-Valero J (2011) Revisiting the role of acetylcholinesterase in Alzheimer’s disease: cross-talk with P-tau and β-amyloid. Front Mol Neurosci 4:22. https://doi.org/10.3389/fnmol.2011.00022
DeFina PA, Moser RS, Glenn M et al (2013) Alzheimer’s disease clinical and research update for health care practitioners. J Aging Res 2013:1–9. https://doi.org/10.1155/2013/207178
Barbosa Filho JM, Medeiros KCP, Diniz M de FFM et al (2006) Natural products inhibitors of the enzyme acetylcholinesterase. Rev Bras Farmacogn 16:258–285. https://doi.org/10.1590/S0102-695X2006000200021
Rahman K (2007) Studies on free radicals, antioxidants, and co-factors. Clin Interv Aging 2:219–236
Bredie SJH, Jong MC (2012) No significant effect of ginkgo biloba special extract EGb 761 in the treatment of primary Raynaud phenomenon. J Cardiovasc Pharmacol 59:215–221. https://doi.org/10.1097/FJC.0b013e31823c0bed
ITIS Integrated Taxonomic Information System. https://www.itis.gov. Accessed 13 Oct 2018
Zahara K, Bibi Y, Tabassum S (2014) Clinical and therapeutic benefits of Centella asiatica. Pure Appl Biol 3:152–159
Al-Snafi AE (2016) Pharmacological importance of Clitoria ternatea—a review. IOSR J Pharm www.iosrphr.org 6:68–83
Saxena RB (2010) Botany, taxonomy and cytology of Crocus sativus series. Ayu 31:374–381. https://doi.org/10.4103/0974-8520.77153
Upadhyay A, Agrahari P, Singh DK (2014) A review on the pharmacological aspects of Terminalia chebula. Int J Pharmacol 10:289–298. https://doi.org/10.3923/ijp.2014.289.298
Narinderpal K, Junaid N, Raman B (2013) A review on pharmacological profile of Withania somnifera (Ashwagandha). Res Rev J Bot Sci 2:6–14
Sachan AK, Das DR, Dohare SL, Shuaib M (2012) Asparagus racemosus (Shatavari): an overview. Int J Pharm Chem Sci ISSN 2277 5005(1):588–592
Uddin MS, Nasrullah M, Hossain MS et al (2016) Evaluation of nootropic activity of Persicaria flaccida on cognitive performance, brain antioxidant markers and acetylcholinesterase activity in rats: implication for the management of Alzheimer’s disease. Am J Psychiatry Neurosci 4:26–37. https://doi.org/10.11648/j.ajpn.20160402.12
Brinkhaus B, Lindner M, Schuppan D, Hahn EG (2000) Chemical, pharmacological and clinical profile of the East Asian medical plant Centella asiatica. Phytomedicine 7:427–448
Veerendra Kumar MH, Gupta YK (2003) Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer’s disease in rats. Clin Exp Pharmacol Physiol 30:336–342. https://doi.org/10.1046/j.1440-1681.2003.03842.x
Xu Y, Cao Z, Khan I, Luo Y (2008) Gotu Kola (Centella asiatica) extract enhances phosphorylation of cyclic AMP response element binding protein in neuroblastoma cells expressing amyloid beta peptide. J Alzheimers Dis 13:341–349
Jayashree G, Kurup Muraleedhara G, Sudarslal S, Jacob VB (2003) Anti-oxidant activity of Centella asiatica on lymphoma-bearing mice. Fitoterapia 74:431–434
Lee MK, Kim SR, Sung SH et al (2000) Asiatic acid derivatives protect cultured cortical neurons from glutamate-induced excitotoxicity. Res Commun Mol Pathol Pharmacol 108:75–86
Mook-Jung I, Shin JE, Yun SH et al (1999) Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity. J Neurosci Res 58:417–425
Kumar A, Dogra S, Prakash A (2009) Neuroprotective effects of Centella asiatica against Intracerebroventricular colchicine-induced cognitive impairment and oxidative stress. Int J Alzheimers Dis 2009:1–8. https://doi.org/10.4061/2009/972178
Bhumireddy Papireddy Venkata S, Kanniappan L, Bondha Ramakishnaiyah R et al (2014) Evaluation of the neuroprotective effects of Centella asiatica against scopolamine induced cognitive impairment in mice. Indian J Pharm Educ Res 48:31–34. https://doi.org/10.5530/ijper.48.4.5
Soumyanath A, Zhong Y-P, Henson E et al (2012) Centella asiatica extract improves behavioral deficits in a mouse model of Alzheimer’s disease: investigation of a possible mechanism of action. Int J Alzheimers Dis 2012:1–9. https://doi.org/10.1155/2012/381974
Nasir MN, Habsah M, Zamzuri I et al (2011) Effects of asiatic acid on passive and active avoidance task in male Spraque–Dawley rats. J Ethnopharmacol 134:203–209. https://doi.org/10.1016/j.jep.2010.12.010
Nasir MN, Abdullah J, Habsah M et al (2012) Inhibitory effect of asiatic acid on acetylcholinesterase, excitatory post synapticpotential and locomotor activity. Phytomedicine 19:311–316. https://doi.org/10.1016/j.phymed.2011.10.004
Zhang X, Wu J, Dou Y et al (2012) Asiatic acid protects primary neurons against C2-ceramide-induced apoptosis. Eur J Pharmacol 679:51–59. https://doi.org/10.1016/j.ejphar.2012.01.006
Xu C-L, Qu R, Zhang J, Li LF, Ma SP (2013) Neuroprotective effects of madecassoside in early stage of Parkinson’s disease induced by MPTP in rats. Fitoterapia 90:112–118. https://doi.org/10.1016/j.fitote.2013.07.009
Ling Y, Gong Q, Xiong X et al (2017) Protective effect of madecassoside on H2O2-induced oxidative stress and autophagy activation in human melanocytes. Oncotarget 8:51066–51075. https://doi.org/10.18632/oncotarget.17654
Xu C-L, Wang Q-Z, Sun L-M et al (2012) Asiaticoside: attenuation of neurotoxicity induced by MPTP in a rat model of parkinsonism via maintaining redox balance and up-regulating the ratio of Bcl-2/Bax. Pharmacol Biochem Behav 100:413–418. https://doi.org/10.1016/j.pbb.2011.09.014
Liu S, An J, Qi F, Yang L, Tian Z, Zhao MG (2014) Neuroprotective effects of Asiaticoside. Neural Regen Res 9:1275–1282. https://doi.org/10.4103/1673-5374.137574
Gupta R, Shukla RK, Chandravanshi LP et al (2017) Protective role of quercetin in cadmium-induced cholinergic dysfunctions in rat brain by modulating mitochondrial integrity and MAP kinase signaling. Mol Neurobiol 54:4560–4583. https://doi.org/10.1007/s12035-016-9950-y
Lei X, Chao H, Zhang Z et al (2015) Neuroprotective effects of quercetin in a mouse model of brain ischemic/reperfusion injury via anti-apoptotic mechanisms based on the Akt pathway. Mol Med Rep 12:3688–3696. https://doi.org/10.3892/mmr.2015.3857
Wang D-M, Li S-Q, Wu W-L et al (2014) Effects of long-term treatment with quercetin on cognition and mitochondrial function in a mouse model of Alzheimer’s disease. Neurochem Res 39:1533–1543. https://doi.org/10.1007/s11064-014-1343-x
Hong J-T, Yen J-H, Wang L, Lo YH, Chen ZT, Wu MJ (2009) Regulation of heme oxygenase-1 expression and MAPK pathways in response to kaempferol and rhamnocitrin in PC12 cells. Toxicol Appl Pharmacol 237:59–68. https://doi.org/10.1016/j.taap.2009.02.014
Jang S, Kelley KW, Johnson RW (2008) Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci 105:7534–7539. https://doi.org/10.1073/pnas.0802865105
Lin TY, Lu CW, Wang SJ (2016) Luteolin protects the hippocampus against neuron impairments induced by kainic acid in rats. Neurotoxicology 55:48–57. https://doi.org/10.1016/j.neuro.2016.05.008
Prakash A, Shur B, Kumar A (2013) Naringin protects memory impairment and mitochondrial oxidative damage against aluminum-induced neurotoxicity in rats. Int J Neurosci 123:636–645. https://doi.org/10.3109/00207454.2013.785542
Huang Y-N, Wang J-Y, Lee C-T et al (2012) l-Ascorbate attenuates methamphetamine neurotoxicity through enhancing the induction of endogenous heme oxygenase-1. Toxicol Appl Pharmacol 265:241–252. https://doi.org/10.1016/j.taap.2012.08.036
Cherdyntseva N, Ivanova A, Ivanov V et al (2013) Ascorbic acid glucoside reduces neurotoxicity and glutathione depletion in mouse brain induced by nitrotriazole radiosensitazer. J Cancer Res Ther 9:364–369. https://doi.org/10.4103/0973-1482.119303
Li Y, Shi W, Li Y et al (2008) Neuroprotective effects of chlorogenic acid against apoptosis of PC12 cells induced by methylmercury. Environ Toxicol Pharmacol 26:13–21. https://doi.org/10.1016/j.etap.2007.12.008
Lee C-W, Won T-J, Kim H-R et al (2011) Protective effect of chlorogenic acid against Aβ-induced neurotoxicity. Biomol Ther 19:181–186. https://doi.org/10.4062/biomolther.2011.19.2.181
Zhao L, Wang J, Wang Y, Fa X (2013) Apigenin attenuates copper-mediated β-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation in an AD cell model. Brain Res 1492:33–45. https://doi.org/10.1016/j.brainres.2012.11.019
Balez R, Steiner N, Engel M et al (2016) Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease. Sci Rep 6:31450. https://doi.org/10.1038/srep31450
Wattanathorn J, Mator L, Muchimapura S et al (2008) Positive modulation of cognition and mood in the healthy elderly volunteer following the administration of Centella asiatica. J Ethnopharmacol 116:325–332. https://doi.org/10.1016/j.jep.2007.11.038
Tiwari S, Singh S, Patwardhan K et al (2008) Effect of Centella asiatica on mild cognitive impairment (mci) and other common age-related clinical problems. Dig J Nanomater Biostructures 3:215–220
Rai KS, Murthy KD, Karanth KS, Rao MS (2001) Clitoria ternatea (Linn) root extract treatment during growth spurt period enhances learning and memory in rats. Indian J Physiol Pharmacol 45:305–313
Taranalli AD, Cheeramkuzhy TC (2000) Influence of Clitoria ternatea extracts on memory and central cholinergic activity in rats. Pharm Biol 38:51–56. https://doi.org/10.1076/1388-0209(200001)3811-BFT051
Rai KS, Murthy KD, Karanth KS et al (2002) Clitoria ternatea root extract enhances acetylcholine content in rat hippocampus. Fitoterapia 73:685–689
Mukherjee PK, Kumar V, Houghton PJ (2007) Screening of Indian medicinal plants for acetylcholinesterase inhibitory activity. Phyther Res 21:1142–1145. https://doi.org/10.1002/ptr.2224
Ng TB, Wang HX, Liu F, Xia LX (2004) Plants beneficial to the aging brain. Neuroembryology Aging 3:136–141. https://doi.org/10.1159/000094576
Rai KS, Dilip Murthy K, Karanth KS, Rao MS (2001) Clitoria ternatea (linn) root extract treatment during growth spurt period enhances learning and memory in rats. Indian J Physiol Pharmacol 45(3):305–313
Rai KS, Murthy KD, Rao MS, Karanth KS (2005) Altered dendritic arborization of amygdala neurons in young adult rats orally intubated withClitorea ternatea aqueous root extract. Phyther Res 19:592–598. https://doi.org/10.1002/ptr.1657
Talpate KA, Bhosale UA, Zambare MR, Somani RS (2014) Neuroprotective and nootropic activity of Clitorea ternatea Linn. (Fabaceae) leaves on diabetes induced cognitive decline in experimental animals. J Pharm Bioallied Sci 6:48–55. https://doi.org/10.4103/0975-7406.124317
Rajashree R, Patil R, Khlokute SD, Goudar SS (2017) Effect of Salacia reticulata W. and Clitoria ternatea L. on the cognitive and behavioral changes in the streptozotocin-induced young diabetic rats. J Basic Clin Physiol Pharmacol 28:107–114. https://doi.org/10.1515/jbcpp-2016-0024
Ravishankar K, Parvathi M (2012) Study of protective effect of ethanolic root extract of Clitoria ternatea against stress induced amnesia. J Pharm Res 5:2763–2766
Kulkarni C, Pattanshetty JR, Amruthraj G (1988) Effect of alcoholic extract of Clitoria ternatea Linn. on central nervous system in rodents. Indian J Exp Biol 26:957–960
Jain NN, Ohal CC, Shroff SK et al (2003) Clitoria ternatea and the CNS. Pharmacol Biochem Behav 75:529–536
Yao X-Y, Bai Q (2017) Taraxerol protects the human hepatic L02 cells from hydrogen peroxide-induced apoptosis. Bangladesh J Pharmacol 12:20. https://doi.org/10.3329/bjp.v12i2.30985
Berté TE, Dalmagro AP, Zimath PL et al (2018) Taraxerol as a possible therapeutic agent on memory impairments and Alzheimer’s disease: effects against scopolamine and streptozotocin-induced cognitive dysfunctions. Steroids 132:5–11. https://doi.org/10.1016/J.STEROIDS.2018.01.002
Kiliç I, Yeşiloğlu Y (2013) Spectroscopic studies on the antioxidant activity of p-coumaric acid. Spectrochim Acta A Mol Biomol Spectrosc 115:719–724. https://doi.org/10.1016/j.saa.2013.06.110
Guven M, Aras AB, Akman T, Sen HM, Ozkan A, Salis O, Sehitoglu I, Kalkan Y et al (2015) Neuroprotective effect of p-coumaric acid in rat model of embolic cerebral ischemia. Iran J Basic Med Sci 18:356–363
Rao N, Mittal S, Menghani E (2013) Antioxidant potential and validation of bioactive Β-Sitosterol in Eulophia campestris wall. Adv Biores 4:136–142
Ayaz M, Junaid M, Ullah F et al (2017) Anti-Alzheimer’s studies on β-Sitosterol isolated from Polygonum hydropiper L. Front Pharmacol 8:697. https://doi.org/10.3389/fphar.2017.00697
Tzeng C-W, Yen F-L, Wu T-H et al (2011) Enhancement of dissolution and antioxidant activity of Kaempferol using a nanoparticle engineering process. J Agric Food Chem 59:5073–5080. https://doi.org/10.1021/jf200354y
Kähkönen MP, Heinonen M (2003) Antioxidant activity of anthocyanins and their aglycons. J Agric Food Chem 51:628–633. https://doi.org/10.1021/JF025551I
Pojer E, Mattivi F, Johnson D, Stockley CS (2013) The case for anthocyanin consumption to promote human health: a review. Compr Rev Food Sci Food Saf 12:483–508. https://doi.org/10.1111/1541-4337.12024
Mo EK, Han BH, Kim SM et al (2012) Identification of d-friedoolean-13-en-3-one (Taraxerone) as an antioxidant compound from sedom (Sedum sarmentosum). Food Sci Biotechnol 21:485–489. https://doi.org/10.1007/s10068-012-0061-x
Estévez L, Mosquera RA (2008) Molecular structure and antioxidant properties of delphinidin. J Phys Chem A 112:10614–10623. https://doi.org/10.1021/jp8043237
Boominathan R, Parimaladevi B, Mandal SC (2003) Studies on Neuropharmacological effects of Clitoria ternatea Linn. Root extract in rats and mice. Nat Prod Sci 9:260–263
Malik J, Karan M, Vasisht K (2011) Nootropic, anxiolytic and CNS-depressant studies on different plant sources of shankhpushpi. Pharm Biol 49:1234–1242. https://doi.org/10.3109/13880209.2011.584539
Chusak C, Thilavech T, Henry CJ, Adisakwattana S (2018) Acute effect of Clitoria ternatea flower beverage on glycemic response and antioxidant capacity in healthy subjects: a randomized crossover trial. BMC Complement Altern Med 18:6. https://doi.org/10.1186/s12906-017-2075-7
Nair V, Bang WY, Schreckinger E et al (2015) Protective role of ternatin anthocyanins and quercetin glycosides from butterfly pea (Clitoria ternatea Leguminosae) blue flower petals against lipopolysaccharide (LPS)-induced inflammation in macrophage cells. J Agric Food Chem 63:6355–6365. https://doi.org/10.1021/acs.jafc.5b00928
Papandreou MA, Kanakis CD, Polissiou MG et al (2006) Inhibitory activity on amyloid-β aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J Agric Food Chem 54:8762–8768. https://doi.org/10.1021/jf061932a
Lannert H, Hoyer S (1998) Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208
Labak M, Foniok T, Kirk D, Rushforth D, Tomanek B, Jasiński A, Grieb P (2010) Metabolic changes in rat brain following intracerebroventricular injections of streptozotocin: a model of sporadic Alzheimer’s disease. Acta Neurochir Suppl 106:177–181
Khalili M, Kiasalari Z, Rahmati B, Narenjkar J (2010) Behavioral and histological analysis of Crocus sativus effect in intracerebroventricular streptozotocin model of Alzheimer disease in rats. Iran J Pathol 5:27–33
Khalili M, Hamzeh F (2010) Effects of active constituents of Crocus sativus L., crocin on streptozocin-induced model of sporadic Alzheimer’s disease in male rats. Iran Biomed J 14:59–65
Geromichalos GD, Lamari FN, Papandreou MA et al (2012) Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies. J Agric Food Chem 60:6131–6138. https://doi.org/10.1021/jf300589c
Zhang Y, Shoyama Y, Sugiura M, Saito H (1994) Effects of Crocus sativus L. on the ethanol-induced impairment of passive avoidance performances in mice. Biol Pharm Bull 17:217–221
Pitsikas N, Sakellaridis N (2006) Crocus sativus L. extracts antagonize memory impairments in different behavioural tasks in the rat. Behav Brain Res 173:112–115. https://doi.org/10.1016/j.bbr.2006.06.005
Papandreou MA, Tsachaki M, Efthimiopoulos S et al (2011) Memory enhancing effects of saffron in aged mice are correlated with antioxidant protection. Behav Brain Res 219:197–204. https://doi.org/10.1016/j.bbr.2011.01.007
Ghadrdoost B, Vafaei AA, Rashidy-Pour A et al (2011) Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol 667:222–229. https://doi.org/10.1016/j.ejphar.2011.05.012
Linardaki ZI, Orkoula MG, Kokkosis AG et al (2013) Investigation of the neuroprotective action of saffron (Crocus sativus L.) in aluminum-exposed adult mice through behavioral and neurobiochemical assessment. Food Chem Toxicol 52:163–170. https://doi.org/10.1016/j.fct.2012.11.016
Hosseinzadeh H, Sadeghnia HR, Ghaeni FA et al (2011) Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phyther Res 26:n/a-n/a. https://doi.org/10.1002/ptr.3566
Escribano J, Alonso GL, Coca-Prados M, Fernandez JA (1996) Crocin, safranal and picrocrocin from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro. Cancer Lett 100:23–30
Farkhondeh T, Samarghandian S, Shaterzadeh Yazdi H, Samini F (2018) The protective effects of crocin in the management of neurodegenerative diseases: a review. Am J Neurodegener Dis 7:1–10
Heidari S, Mehri S, Hosseinzadeh H (2017) Memory enhancement and protective effects of crocin against D-galactose aging model in the hippocampus of Wistar rats. Mashhad Univ Med Sci 20:1250–1259. https://doi.org/10.22038/IJBMS.2017.9541
Mohamadpour AH, Ayati Z, Parizadeh M-R et al (2013) Safety evaluation of crocin (a constituent of saffron) tablets in healthy volunteers. Iran J Basic Med Sci 16:39–46
Yoshino Y, Ishisaka M, Umigai N et al (2014) Crocetin prevents amyloid β1-42-induced cell death in murine hippocampal cells. Pharmacol Pharm 05:37–42. https://doi.org/10.4236/pp.2014.51007
Power R, Coen RF, Beatty S et al (2018) Supplemental retinal carotenoids enhance memory in healthy individuals with low levels of macular pigment in a randomized, double-blind, placebo-controlled clinical trial. J Alzheimers Dis 61:947–961. https://doi.org/10.3233/JAD-170713
Xue C, Rosen R, Jordan A, Hu D-N (2015) Management of ocular diseases using lutein and zeaxanthin: what have we learned from experimental animal studies? J Ophthalmol 2015:1–11. https://doi.org/10.1155/2015/523027
Wang Z, Fan J, Wang J et al (2016) Protective effect of lycopene on high-fat diet-induced cognitive impairment in rats. Neurosci Lett 627:185–191. https://doi.org/10.1016/j.neulet.2016.05.014
Akhondzadeh S, Shafiee Sabet M, Harirchian MH et al (2010) A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology 207:637–643. https://doi.org/10.1007/s00213-009-1706-1
Farokhnia M, Shafiee Sabet M, Iranpour N et al (2014) Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer’s disease: a double-blind randomized clinical trial. Hum Psychopharmacol Clin Exp 29:351–359. https://doi.org/10.1002/hup.2412
Batarseh YS, Bharate SS, Kumar V et al (2017) Crocus sativus extract tightens the blood-brain barrier, reduces amyloid β load and related toxicity in 5XFAD mice. ACS Chem Neurosci 8:1756–1766. https://doi.org/10.1021/acschemneuro.7b00101
Vinutha B, Prashanth D, Salma K et al (2007) Screening of selected Indian medicinal plants for acetylcholinesterase inhibitory activity. J Ethnopharmacol 109:359–363. https://doi.org/10.1016/j.jep.2006.06.014
Sancheti S, Sancheti S, Um B-H, Seo S-Y (2010) 1,2,3,4,6-penta-O-galloyl-β-d-glucose: a cholinesterase inhibitor from Terminalia chebula. South African J Bot 76:285–288. https://doi.org/10.1016/J.SAJB.2009.11.006
Murray AP, Faraoni MB, Castro MJ et al (2013) Natural AChE inhibitors from plants and their contribution to Alzheimer’s disease therapy. Curr Neuropharmacol 11:388–413. https://doi.org/10.2174/1570159X11311040004
Upadhyay A, Singh DK (2011) Inhibition kinetics of certain enzymes in the nervous tissue of vector snail Lymnaea acuminata by active molluscicidal components of Sapindus mukorossi and Terminalia chebula. Chemosphere 85:1095–1100. https://doi.org/10.1016/j.chemosphere.2011.07.041
Parle M, Vasudevan M (2007) Memory enhancing activity of Abana : an Indian ayurvedic poly-herbal formulation
Nag G, De B (2011) Acetylcholinesterase inhibitory activity of Terminalia chebula, terminalia bellerica and Emblica officinalis and some phenolic compounds. Int J Pharm Pharm Sci 3:121–124
Dhivya P, Sobiya M, Selvamani P, Latha S (2014) An approach to Alzheimer’s disease treatment with cholinesterase inhibitory activity from various plant species. Int J PharmTech Res 6:1450–1467
Sulaiman CT, Sadashiva CT, George S, Balachandran I (2012) Journal of tropical medicinal plants. Tropical Botanics Sdn Bhd
Surveswaran S, Cai Y-Z, Xing J et al (2010) Antioxidant properties and principal phenolic phytochemicals of Indian medicinal plants from Asclepiadoideae and Periplocoideae. Nat Prod Res 24:206–221. https://doi.org/10.1080/14786410802228827
Mathew M, Subramanian S (2014) In vitro screening for anti-cholinesterase and antioxidant activity of methanolic extracts of ayurvedic medicinal plants used for cognitive disorders. PLoS One 9:e86804. https://doi.org/10.1371/journal.pone.0086804
Ali SK, Hamed AR, Soltan MM, Hegazy UM, Elgorashi EE, El-Garf IA, Hussein AA (2013) In-vitro evaluation of selected Egyptian traditional herbal medicines for treatment of alzheimer disease. BMC Complement Altern Med 13:121. https://doi.org/10.1186/1472-6882-13-121
Rao N, Palaksha MN, Satish S, Ravishankar (2013) The effects of Ethanolic extract in dried fruits of Terminalia chebula on learning and memory in mice. Asian J Biomed Pharm Sci 3(20):59–62
Surveswaran S, Cai Y-Z, Corke H, Sun M (2007) Systematic evaluation of natural phenolic antioxidants from 133 Indian medicinal plants. Food Chem 102:938–953. https://doi.org/10.1016/J.FOODCHEM.2006.06.033
Kim HJ, Kim J, Kang KS et al (2014) Neuroprotective effect of Chebulagic acid via autophagy induction in SH-SY5Y cells. Biomol Ther (Seoul) 22:275–281. https://doi.org/10.4062/biomolther.2014.068
Bhadoriya U, Sharma P, Solanki SS (2012) In vitro free radical scavenging activity of gallic acid isolated from Caesalpinia Decapetala wood. Asian Pacific J Trop Dis 2:S833–S836. https://doi.org/10.1016/S2222-1808(12)60274-6
Ibrahim AE, El Kareem RA, Sheir MA (2015) Elucidation of acrylamide genotoxicity and neurotoxicity and the protective role of gallic acid and green tea. J Forensic Toxicol Pharmacol 04. https://doi.org/10.4172/2325-9841.1000135
Kilic I, Yeşiloğlu Y, Bayrak Y (2014) Spectroscopic studies on the antioxidant activity of ellagic acid. Spectrochim Acta A Mol Biomol Spectrosc 130:447–452. https://doi.org/10.1016/j.saa.2014.04.052
Farbood Y, Sarkaki A, Dianat M et al (2015) Ellagic acid prevents cognitive and hippocampal long-term potentiation deficits and brain inflammation in rat with traumatic brain injury. Life Sci 124:120–127. https://doi.org/10.1016/j.lfs.2015.01.013
Zhao X, Sun H, Hou A et al (2005) Antioxidant properties of two gallotannins isolated from the leaves of Pistacia weinmannifolia. Biochim Biophys Acta Gen Subj 1725:103–110. https://doi.org/10.1016/j.bbagen.2005.04.015
Kujawski R, Kujawska M, Ożarowski M, Baraniak J, Laskowska H, Nowocień T, Borowska M, Szulc M et al (2016) Perspectives for gallotannins neuroprotective potential-current experimental evidences Comparison of extracts from root of Rhodiola rosea inhibitory action on EtOH tolerance development in rats View project Małgorzata Kujawska. J Med Sci 85:313–318. https://doi.org/10.20883/jms.2016.172
Kähkönen M, Kylli P, Ollilainen V, Salminen JP, Heinonen M (2012) Antioxidant activity of isolated Ellagitannins from red raspberries and cloudberries. J Agric Food Chem 60:1167–1174. https://doi.org/10.1021/jf203431g
Sowndhararajan K, Kim S (2017) Neuroprotective and cognitive enhancement potentials of Angelica gigas Nakai root: a review. Sci Pharm 85:21. https://doi.org/10.3390/scipharm85020021
Hussein RH, Khalifa FK (2014) The protective role of ellagitannins flavonoids pretreatment against N-nitrosodiethylamine induced-hepatocellular carcinoma. Saudi J Biol Sci 21:589–596. https://doi.org/10.1016/j.sjbs.2014.03.004
Lee H-S, Jung S-H, Yun B-S, Lee K-W (2007) Isolation of chebulic acid from Terminalia chebula Retz. and its antioxidant effect in isolated rat hepatocytes. Arch Toxicol 81:211–218. https://doi.org/10.1007/s00204-006-0139-4
Klika KD, Saleem A, Sinkkonen J et al (2004) The structural and conformational analyses and antioxidant activities of chebulinic acid and its thrice-hydrolyzed derivative, 2,4-chebuloyl-β-D-glucopyranoside, isolated from the fruit of Terminalia chebula. ARKIVOC 7:83–105
Romanová D, Vachálková A, Cipák L et al (2001) Study of antioxidant effect of apigenin, luteolin and quercetin by DNA protective method. Neoplasma 48:104–107
Aloqbi A, Omar U, Yousr M, Grace M, Lila MA, Howell N (2016) Antioxidant activity of pomegranate juice and Punicalagin. Antioxid Act Pomegranate Juice Punicalagin Nat Sci 8:235–246. https://doi.org/10.4236/ns.2016.86028
Shanmuganathan S, Angayarkanni N (2018) Chebulagic acid Chebulinic acid and Gallic acid, the active principles of Triphala, inhibit TNFα induced pro-angiogenic and pro-inflammatory activities in retinal capillary endothelial cells by inhibiting p38, ERK and NFkB phosphorylation. Vasc Pharmacol 108:23–35. https://doi.org/10.1016/J.VPH.2018.04.005
Lee Y, Byun HS, Seok JH et al (2016) Terminalia Chebula provides protection against dual modes of necroptotic and apoptotic cell death upon death receptor ligation. Sci Rep 6:25094. https://doi.org/10.1038/srep25094
Schliebs R, Liebmann A, Bhattacharya SK et al (1997) Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain. Neurochem Int 30:181–190
Zhao J, Nakamura N, Hattori M et al (2002) Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities. Chem Pharm Bull (Tokyo) 50:760–765
Naidu PS, Singh A, Kulkarni SK (2006) Effect of Withania somnifera root extract on reserpine-induced orofacial dyskinesia and cognitive dysfunction. Phyther Res 20:140–146. https://doi.org/10.1002/ptr.1823
Dhuley JN (2001) Nootropic-like effect of ashwagandha (Withania somnifera L.) in mice. Phytother Res 15:524–528
Kumar V, Dey A, Hadimani MB et al (2015) Chemistry and pharmacology of withania somnifera: An update. TANG [HUMANITAS Med] 5:1.1–1.13. https://doi.org/10.5667/tang.2014.0030
Tohda C, Joyashiki E (2009) Sominone enhances neurite outgrowth and spatial memory mediated by the neurotrophic factor receptor, RET. Br J Pharmacol 157:1427–1440. https://doi.org/10.1111/j.1476-5381.2009.00313.x
Kuboyama T, Tohda C, Komatsu K (2006) Withanoside IV and its active metabolite, sominone, attenuate Aβ(25-35)-induced neurodegeneration. Eur J Neurosci 23:1417–1426. https://doi.org/10.1111/j.1460-9568.2006.04664.x
Ostrovskaya RU, Gruden MA, Bobkova NA et al (2007) The nootropic and neuroprotective proline-containing dipeptide noopept restores spatial memory and increases immunoreactivity to amyloid in an Alzheimer’s disease model. J Psychopharmacol 21:611–619. https://doi.org/10.1177/0269881106071335
Li T, Wang L, Hu Q et al (2017) Neuroprotective roles of l-cysteine in attenuating early brain injury and improving synaptic density via the CBS/H2S pathway following subarachnoid hemorrhage in rats. Front Neurol 8:176. https://doi.org/10.3389/fneur.2017.00176
Batumalaie K, Amin MA, Murugan DD et al (2016) Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation. Sci Rep 6:27236. https://doi.org/10.1038/srep27236
Murugan S, Ameesh M, Devaraja R et al (2015) A study on the efficacy of Withaferin-A in reducing oxidative stress against DEN induced hepatocellular carcinoma. IOSR J Dent Med Sci e-ISSN 14:23–31. https://doi.org/10.9790/0853-14922331
Kuboyama T, Tohda C, Komatsu K (2005) Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharmacol 144:961–971. https://doi.org/10.1038/sj.bjp.0706122
Jayaprakasam B, Padmanabhan K, Nair MG (2010) Withanamides in Withania somnifera fruit protect PC-12 cells from Î2-amyloid responsible for Alzheimer’s disease. Phyther Res 24:859–863. https://doi.org/10.1002/ptr.3033
Bone K (1996) Clinical applications of Ayurvedic and Chinese herbs : monographs for the Western herbal practitioner. Phytotherapy Press
Choudhary D, Bhattacharyya S, Bose S (2017) Efficacy and safety of Ashwagandha (Withania somnifera (L.) Dunal ) root extract in improving memory and cognitive functions. J Diet Suppl 14:599–612. https://doi.org/10.1080/19390211.2017.1284970
Kurapati KRV, Atluri VSR, Samikkannu T, Nair MPN (2013) Ashwagandha (Withania somnifera) reverses β-Amyloid1-42 induced toxicity in human neuronal cells: implications in HIV-associated neurocognitive disorders (HAND). PLoS One 8:e77624. https://doi.org/10.1371/journal.pone.0077624
Bhattacharya A, Ghosal S, Bhattacharya SK (2001) Anti-oxidant effect of Withania somnifera glycowithanolides in chronic footshock stress-induced perturbations of oxidative free radical scavenging enzymes and lipid peroxidation in rat frontal cortex and striatum. J Ethnopharmacol 74:1–6
Afshari AR, Sadeghnia HR, Mollazadeh H (2016) A review on potential mechanisms of Terminalia chebula in Alzheimer’s disease. Adv Pharmacol Sci 2016:1–14. https://doi.org/10.1155/2016/8964849
Parihar MS, Hemnani T (2004) Experimental excitotoxicity provokes oxidative damage in mice brain and attenuation by extract of Asparagus racemosus. J Neural Transm 111:1–12. https://doi.org/10.1007/s00702-003-0069-8
Lalert L, Kruevaisayawan H, Amatyakul P et al (2018) Neuroprotective effect of Asparagus racemosus root extract via the enhancement of brain-derived neurotrophic factor and estrogen receptor in ovariectomized rats. J Ethnopharmacol 225:336–341. https://doi.org/10.1016/J.JEP.2018.07.014
Saxena G, Singh M, Meena P, Barber S, Sharma D, Shukla S, Bhatnagar M (2007) Neuroprotective effects of Asparagus racemosus Linn root extract: an experimental and clinical evidence. Ann Neurosci 14:57–63. https://doi.org/10.5214/156
Ahmad MP, Hussain A, Siddiqui HH et al (2015) Effect of methanolic extract of Asparagus racemosus Willd. on lipopolysaccharide induced-oxidative stress in rats. Pak J Pharm Sci 28:509–513
Sarbishegi M, Heidari Z, Mahmoudzadeh-Sagheb H et al (2016) Neuroprotective effects of Withania coagulans root extract on CA1 hippocampus following cerebral ischemia in rats. Avicenna J phytomedicine 6:399–409
Maheep B, Prahlad M, Satyendra B, Chetan J (2013) Neuroprotective response of the hippocampus region of the brain to Withania somnifera and Asparagus racemosus root extract: an in vitro study. J Med Plants Res 7:2259–2264. https://doi.org/10.5897/JMPR12.497
Sharma K, Bhatnagar M, Kulkarni SK (2010) Effect of Convolvulus pluricaulis Choisy and Asparagus racemosus Willd on learning and memory in young and old mice: a comparative evaluation. Indian J Exp Biol 48:479–485
Almutairi MM, Alanazi WA, Alshammari MA, Alotaibi MR, Alhoshani AR, al-Rejaie SS, Hafez MM, al-Shabanah OA (2017) Neuro-protective effect of rutin against cisplatin-induced neurotoxic rat model. BMC Complement Altern Med 17:472. https://doi.org/10.1186/s12906-017-1976-9
Sharma S, Ali A, Ali J et al (2013) Rutin: therapeutic potential and recent advances in drug delivery. Expert Opin Investig Drugs 22:1063–1079. https://doi.org/10.1517/13543784.2013.805744
Pany S, Pal A, Sahu PK (2014) Neuroprotective effect of quercetin in neurotoxicity induced rats: role of neuroinflammation in neurodegeneration. Asian J Pharm Clin Res 7:152–156
Sarkar S, Mukherjee A, Swarnakar S, Das N (2016) Nanocapsulated ascorbic acid in combating cerebral ischemia reperfusion- induced oxidative injury in rat brain. Curr Alzheimer Res 13:1363–1373
Dolu N, Khan A, Dokutan Ş (2015) Effect of vitamin E administration on learning of the young male rats. J Exp Neurosci 9:81–85. https://doi.org/10.4137/JEN.S29843
Zandi PP, Anthony JC, Khachaturian AS et al (2004) Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements. Arch Neurol 61:82–88. https://doi.org/10.1001/archneur.61.1.82
Hu Y, Xia Z, Sun Q et al (2005) A new approach to the pharmacological regulation of memory: sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res 1060:26–39. https://doi.org/10.1016/j.brainres.2005.08.019
Sarkaki A, Amani R, Badavi M et al (2008) Pre-treatment effect of different doses of soy isoflavones on spatial learning and memory in an ovariectomized animal model of Alzheimer’s disease. Pak J Biol Sci 11:1114–1119
Carlson LE, Sherwin BB (1999) Relationships among cortisol (CRT), dehydroepiandrosterone-sulfate (DHEAS), and memory in a longitudinal study of healthy elderly men and women. Neurobiol Aging 20:315–324
Dhandapani KM, Brann DW (2002) Protective effects of estrogen and selective estrogen receptor modulators in the brain. Biol Reprod 67:1379–1385
Alkayed NJ, Murphy SJ, Traystman RJ, Hurn PD, Miller VM (2000) Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke 31:161–168
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The authors are grateful to the Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
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This work was carried out in collaboration between all authors. MSU and GMA designed the study, wrote the protocol, and managed the analyses of the study. MSU, AAM, and MTK prepared the draft of the manuscript. MSU prepared the figures for the manuscript. MJ and BM participated in literature searches. GEB reviewed the scientific contents of the manuscript. All authors read and approved the final submitted version of the manuscript.
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Uddin, M.S., Al Mamun, A., Kabir, M.T. et al. Nootropic and Anti-Alzheimer’s Actions of Medicinal Plants: Molecular Insight into Therapeutic Potential to Alleviate Alzheimer’s Neuropathology. Mol Neurobiol 56, 4925–4944 (2019). https://doi.org/10.1007/s12035-018-1420-2
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DOI: https://doi.org/10.1007/s12035-018-1420-2