Planta Med 2024; 90(04): 286-297
DOI: 10.1055/a-2245-3624
Biological and Pharmacological Activity
Original Papers

Memantine versus Ginkgo biloba Extract: A Comparative Study on Cognitive Dysfunction Treatment in a Novel Rat Model

Essmat A. H. Allam
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Assiut University, Assiut, Egypt
,
Abdel-Azim Assi
2   Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
,
Dalia M. Badary
3   Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
,
Magda M. Y. Farrag
2   Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
,
Mariam A. Nicola
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Assiut University, Assiut, Egypt
› Author Affiliations
We would like to express our deepest gratitude to the Science and Technology Development Fund (STDF) of the Ministry of State for Scientific Research in Egypt for their generous support (Grant # 43 688). This funding was instrumental in the purchase of materials necessary for our research. We are truly appreciative of their commitment to advancing scientific knowledge and innovation.

Abstract

Extracellular senile plaques and intraneuronal neurofibrillary tangles are two devastating brain proteinopathies that are indicative of Alzheimerʼs disease, the most prevalent type of dementia. Currently, no effective medications are available to stop or reverse Alzheimerʼs disease. Ginkgo biloba extract, commonly referred to as EGb 761, is a natural product made from the leaves of the G. biloba tree. It has long been demonstrated to have therapeutic benefits in Alzheimerʼs disease. The current study assessed the beneficial effects of EGb 761 against Alzheimerʼs disease in comparison with memantine, a standard treatment for Alzheimerʼs disease. The scopolamine-heavy metals mixture rat Alzheimerʼs disease model is a newly created model to study the effects of EGb 761 oral therapy on cognitive performance and other Alzheimerʼs disease-like changes over a 28-day experimental period. This new Alzheimerʼs disease model provides better criteria for Alzheimerʼs disease hallmarks than the conventional scopolamine model. The EGb 761 reversed memory and learning deficits induced by the scopolamine-heavy metals mixture. These outcomes were linked to a more pronounced inhibitory effect on acetylcholinesterase, caspase-3, hippocampal amyloid-beta protein (Aβ1 – 42), phosphorylated tau protein counts, and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) compared to the memantine-treated group. Furthermore, EGb 761 treatment considerably reduced lipid peroxidation (malondialdehyde) and improved reduced glutathione levels compared to memantine. Our results suggest EGb 761′s potential in treating central nervous system disorders. Itʼs a promising candidate for future Alzheimerʼs disease therapeutic exploration. This study also highlights the need for future research to focus on the positive benefits of herbal medicines.



Publication History

Received: 22 July 2023

Accepted after revision: 03 January 2024

Article published online:
29 January 2024

© 2024. Thieme. All rights reserved.

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  • References

  • 1 Braak H, Del Tredici K. Spreading of tau pathology in sporadic Alzheimerʼs disease along cortico-cortical top-down connections. Cereb Cortex 2018; 28: 3372-3384
  • 2 Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 2004; 62: 925-931
  • 3 Dhapola R, Hota SS, Sarma P, Bhattacharyya A, Medhi B, Reddy DH. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimerʼs disease. Inflammopharmacology 2021; 29: 1669-1681
  • 4 Yiannopoulou KG, Papageorgiou SG. Current and future treatments in Alzheimer disease: An update. J Cent Nerv Syst Dis 2020; 12: 1179573520907397
  • 5 Nguyen TT, Nguyen TTD, Nguyen TKO, Vo TK, Vo VG. Advances in developing therapeutic strategies for Alzheimerʼs disease. Biomed Pharmacother 2021; 139: 111623
  • 6 Natsume M. Polyphenols: Inflammation. Curr Pharm Des 2018; 24: 191-202
  • 7 Gertz HJ, Kiefer M. Review about Ginkgo biloba special extract EGb 761 (Ginkgo). Curr Pharm Des 2004; 10: 261-264
  • 8 Kandiah N, Ong PA, Yuda T, Ng LL, Mamun K, Merchant RA, Chen C, Dominguez J, Marasigan S, Ampil E, Nguyen VT, Yusoff S, Chan YF, Yong FM, Krairit O, Suthisisang C, Senanarong V, Ji Y, Thukral R, Ihl R. Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761® . CNS Neurosci Ther 2019; 25: 288-298
  • 9 Liu Y, Xin H, Zhang Y, Che F, Shen N, Cui Y. Leaves, seeds and exocarp of Ginkgo biloba L. (Ginkgoaceae): A Comprehensive Review of Traditional Uses, phytochemistry, pharmacology, resource utilization and toxicity. J Ethnopharmacol 2022; 298: 115645
  • 10 DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, Lopez OL, Burke G, Carlson MC, Fried LP, Kuller LH, Robbins JA, Tracy RP, Woolard NF, Dunn L, Snitz BE, Nahin RL, Furberg CD. Ginkgo Evaluation of Memory (GEM) Study Investigators. Ginkgo biloba for prevention of dementia: A randomized controlled trial. JAMA 2008; 300: 2253-2262
  • 11 McCarney R, Fisher P, Iliffe S, van Haselen R, Griffin M, van der Meulen J, Warner J. Ginkgo biloba for mild to moderate dementia in a community setting: A pragmatic, randomised, parallel-group, double-blind, placebo-controlled trial. Int J Geriatr Psychiatry 2008; 23: 1222-1230
  • 12 OʼHara M, Kiefer D, Farrell K, Kemper K. A review of 12 commonly used medicinal herbs. Arch Fam Med 1998; 7: 523
  • 13 Nathan M, Sholten R. The complete German commission E monographs: Therapeutic guide to herbal medicines. Ann Intern Med 1999; 130: 459
  • 14 Kasper S, Bancher C, Eckert A, Förstl H, Frölich L, Hort J, Korczyn AD, Kressig RW, Levin O, Palomo MSM. Management of mild cognitive impairment (MCI): The need for national and international guidelines. World J Biol Psychiatry 2020; 21: 579-594
  • 15 Council of Europe. European Pharmacopoeia, (7th ed., Vol. 1); Council of Europe: Strasbourg, France, 2011.
  • 16 Müller WE, Eckert A, Eckert GP, Fink H, Friedland K, Gauthier S, Hoerr R, Ihl R, Kasper S, Möller HJ. Therapeutic efficacy of the Ginkgo special extract EGb761® within the framework of the mitochondrial cascade hypothesis of Alzheimerʼs disease. World J Biol Psychiatry 2019; 20: 173-189
  • 17 Balkis A, Tran K, Lee YZ, Ng K. Screening flavonoids for inhibition of acetylcholinesterase identified baicalein as the most potent inhibitor. J Agric Sci 2015; 7: 26-35
  • 18 Canevelli M, Adali N, Kelaiditi E, Cantet C, Ousset PJ, Cesari M. ICTUS/DSA Group. Effects of Gingko biloba supplementation in Alzheimerʼs disease patien ts receiving cholinesterase inhibitors: Data from the ICTUS study. Phytomedicine 2014; 21: 888-892
  • 19 García-Alberca JM, Mendoza S, Gris E. Benefits of treatment with Ginkgo Biloba Extract EGb 761 alone or combined with acetylcholinesterase inhibitors in vascular dementia. Clin Drug Investig 2022; 42: 391-402
  • 20 Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y. EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimerʼs disease. FASEB J 2007; 21: 2400-2408
  • 21 De Smet PA. Herbal remedies. N Engl J Med 2002; 347: 2046-2056
  • 22 Esposito Z, Belli L, Toniolo S, Sancesario G, Bianconi C, Martorana A. Amyloid β, glutamate, excitotoxicity in Alzheimerʼs disease: Are we on the right track?. CNS Neurosci Ther 2013; 19: 549-555
  • 23 van Marum RJ. Update on the use of memantine in Alzheimerʼs disease. Neuropsychiatr Dis Treat 2009; 5: 237-247
  • 24 Schneider LS, Dagerman KS, Higgins JPT, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011; 68: 991-998
  • 25 Burke D. ACP Journal Club. Donepezil or memantine improved cognitive functioning in moderate-to-severe Alzheimer disease. Ann Intern Med 2012; 156: JC6-JC10
  • 26 Matsunaga S, Kishi T, Iwata N. Memantine monotherapy for Alzheimerʼs disease: A systematic review and meta-analysis. PLoS One 2015; 10: e0123289
  • 27 Yang Z, Zhou X, Zhang Q. Effectiveness and safety of memantine treatment for Alzheimerʼs disease. J Alzheimers Dis 2013; 36: 445-458
  • 28 Van Dam D, De Deyn PP. Animal models in the drug discovery pipeline for Alzheimerʼs disease. Br J Pharmacol 2011; 164: 1285-1300
  • 29 Tahami Monfared AA, Byrnes MJ, White LA, Zhang Q. Alzheimerʼs disease: Epidemiology and clinical progression. Neurol Ther 2022; 11: 553-569
  • 30 Ashok A, Rai NK, Tripathi S, Bandyopadhyay S. Exposure to As-, Cd-, and Pb-mixture induces Aβ, amyloidogenic APP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young rats. Toxicol Sci 2015; 143: 64-80
  • 31 Bihaqi SW, Singh AP, Tiwari M. Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and amyloid precursor protein (AβPP) expression in rat brain. Indian J Pharmacol 2012; 44: 593-598
  • 32 Tang KS. The cellular and molecular processes associated with scopolamine-induced memory deficit: A model of Alzheimerʼs biomarkers. Life Sci 2019; 233: 116695
  • 33 Das A, Shanker G, Nath C, Pal R, Singh S, Singh H. A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba: anticholinesterase and cognitive enhancing activities. Pharmacol Biochem Behav 2002; 73: 893-900
  • 34 Liu X, Hao W, Qin Y, Decker Y, Wang X, Burkart M, Schötz K, Menger MD, Fassbender K, Liu Y. Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimerʼs disease. Brain Behav Immun 2015; 46: 121-131
  • 35 Verma S, Sharma S, Ranawat P, Nehru B. Modulatory effects of Ginkgo biloba against amyloid aggregation through induction of heat shock proteins in aluminium induced neurotoxicity. Neurochem Res 2020; 45: 465-490
  • 36 Zeng K, Li M, Hu J, Mahaman YAR, Bao J, Huang F, Xia Y, Liu X, Wang Q, Wang JZ, Yang Y, Liu R, Wang X. Ginkgo biloba Extract EGb761 Attenuates Hyperhomocysteinemia-induced AD Like Tau Hyperphosphorylation and Cognitive Impairment in Rats. Curr Alzheimer Res 2018; 15: 89-99
  • 37 Buisson B, Bertrand D. Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor. Mol Pharmacol 1998; 53: 555-563
  • 38 Botton PH, Costa MS, Ardais AP, Mioranzza S, Souza DO, da Rocha JBT, Porciúncula LO. Caffeine prevents disruption of memory consolidation in the inhibitory avoidance and novel object recognition tasks by scopolamine in adult mice. Behav Brain Res 2010; 214: 254-259
  • 39 Rehman MU, Ali N, Jamal M, Kousar R, Ishaq M, Awan AA, Hussain I, Sherkheli MA, Ul Haq R. Comparison of acute and chronic effects of Bacopa monnieri, Ginkgo biloba, and Lavandula angustifolia and their mixture on learning and memory in mice. Phytother Res 2021; 35: 2703-2710
  • 40 El Tabaa MM, Sokkar SS, Ramadan ES, Abd El Salam IZ, Zaid A. Neuroprotective role of Ginkgo biloba against cognitive deficits associated with Bisphenol A exposure: An animal model study. Neurochem Int 2017; 108: 199-212
  • 41 Sohn E, Kim YJ, Kim JH, Jeong SJ. Ficus erecta Thunb leaves alleviate memory loss induced by scopolamine in mice via regulation of oxidative stress and cholinergic system. Mol Neurobiol 2021; 58: 3665-3676
  • 42 Tian X, Zhang L, Wang J, Dai J, Shen S, Yang L, Huang P. The protective effect of hyperbaric oxygen and Ginkgo biloba extract on Aβ25–35-induced oxidative stress and neuronal apoptosis in rats. Behav Brain Res 2013; 242: 1-8
  • 43 Verma S, Ranawat P, Sharma N, Nehru B. Ginkgo biloba attenuates aluminum lactate-induced neurotoxicity in reproductive senescent female rats: behavioral, biochemical, and histopathological study. Environ Sci Pollut Res Int 2019; 26: 27148-27167
  • 44 Abdou HM, Yousef MI, El Mekkawy DA, Al-Shami AS. Prophylactic neuroprotective efficiency of co-administration of Ginkgo biloba and Trifolium pretense against sodium arsenite-induced neurotoxicity and dementia in different regions of brain and spinal cord of rats. Food Chem Toxicol 2016; 94: 112-127
  • 45 Adebayo OG, Ben-Azu B, Ajayi AM, Wopara I, Aduema W, Kolawole TA, Umoren EB, Onyeleonu I, Ebo OT, Ajibo DN, Akpotu AE. Gingko biloba abrogate lead-induced neurodegeneration in mice hippocampus: involvement of NF-κB expression, myeloperoxidase activity and pro-inflammatory mediators. Biol Trace Elem Res 2022; 200: 1736-1749
  • 46 Dong H, Yuede CM, Coughlan CA, Murphy KM, Csernansky JG. Effects of donepezil on amyloid-beta and synapse density in the Tg2576 mouse model of Alzheimerʼs disease. Brain Res 2009; 1303: 169-178
  • 47 Wan W, Zhang C, Danielsen M, Li Q, Chen W, Chan Y, Li Y. EGb761 improves cognitive function and regulates inflammatory responses in the APP/PS1 mouse. Exp Gerontol 2016; 81: 92-100
  • 48 Gastard MC, Troncoso JC, Koliatsos VE. Caspase activation in the limbic cortex of subjects with early Alzheimerʼs disease. Ann Neurol 2003; 54: 393-398
  • 49 Gong QH, Wu Q, Huang XN, Sun AS, Shi JS. Protective effects of Ginkgo biloba leaf extract on aluminum-induced brain dysfunction in rats. Life Sci 2005; 77: 140-148
  • 50 Pandareesh MD, Anand T, Khanum F. Cognition enhancing and neuromodulatory propensity of Bacopa monniera extract against scopolamine induced cognitive impairments in rat hippocampus. Neurochem Res 2016; 41: 985-999
  • 51 Hafez HS, Ghareeb DA, Saleh SR, Abady MM, El Demellawy MA, Hussien H, Abdel-Monem N. Neuroprotective effect of ipriflavone against scopolamine-induced memory impairment in rats. Psychopharmacology (Berl) 2017; 234: 3037-3053
  • 52 Aykac A, Ozbeyli D, Uncu M, Ertaş B, Kılınc O, Şen A, Orun O, Sener G. Evaluation of the protective effect of Myrtus communis in scopolamine-induced Alzheimer model through cholinergic receptors. Gene 2019; 689: 194-201
  • 53 Assi AA, Abdelnabi S, Attaai A, Abd-ellatief RB. Effect of ivabradine on cognitive functions of rats with scopolamine-induced dementia. Sci Rep 2022; 12: 16970
  • 54 Chopin P, Briley M. Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats. Psychopharmacology (Berl) 1992; 106: 26-30
  • 55 Antunes M, Biala G. The novel object recognition memory: Neurobiology, test procedure, and its modifications. Cogn Process 2012; 13: 93-110
  • 56 Li W, Tao S, Wu Q, Wu T, Tao R, Fan J. Glutamine reduces myocardial cell apoptosis in a rat model of sepsis by promoting expression of heat shock protein 90. J Surg Res 2017; 220: 247-254
  • 57 Barichello T, dos Santos I, Savi GD, Simões LR, Silvestre T, Comim CM, Sachs D, Teixeira MM, Teixeira AL, Quevedo J. TNF-α, IL-1β, IL-6, and cinc-1 levels in rat brain after meningitis induced by Streptococcus pneumoniae . J Neuroimmunol 2010; 221: 42-45
  • 58 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351-358
  • 59 Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963; 61: 882-888