Differential potency of vitamin D3, folic acid and memantine in protecting against neurobehavioral alterations of scopolamine induced Alzheimer’s model in rats

Abeer A. Eldeeb, Amira E. Fathy, Salwa A. Elgendy


Background: Alzheimer disease is the cause of 60% to 70% of cases of dementia in elderly people, it is a chronic neurodegenerative disease that usually starts slowly and worsens over time. AD is characterized by the presence of senile plaques enriched with insoluble aggregate of beta-amyloid, neurofibrillary tangles and cholinergic neuronal degeneration in the brain tissue, leading to neural dysfunction, neuroinflammation, and critical pathological perturbations.

Methods: Thirty-six males were classified into control group, Alzheimer-induced model (scopolamine 2.5 mg/kg IP once daily for 21 days). Folic acid-treated group (4 mg/kg, IP) once daily for 21 days with scopolamine. Vitamin D3-treated group (42 IU/kg, SC) once daily for 21 days with scopolamine. Vitamin D3 and folic acid-treated group (vitamin D3; 42 IU/kg, SC and folic acid; 4 mg/kg, IP) once daily with scopolamine for 21 days. Memantine-treated group (20 mg/kg IP) once daily with scopolamine for 21 days.

Results: Induction of Alzheimer’s showed significant decrease in brain tissue levels of BDNF, Ach, glutathione reductase and significant increase in amyloid peptide 1-42 level with significant memory impairment, significant increase of initial acquisition latency, firstt retention latency and second retention latency. While administration of folic acid, vitamin D3, memantine separately or in combination resulted insignificant increase of brain tissue levels of BDNF, Ach, glutathione reductase with significant reduction of amyloid peptide 1-42 level with significant memory improvement (significant decrease IAL, first RL and second RL). Also showed improvement of histopathological changes occurred in the brain.

Conclusions: Data obtained in the present study revealed that treatment of experimentally induced alzheimer rats with folic acid or vitamin D3 or memantine separately or combined group (folic acid+vitamin D3) resulted in significant increase of brain tissue levels of BDNF, acetyl choline, glutathione reductase with significant reduction of amyloid peptide 1-42 level with significant decrease of IAL, first RL and second RL to reach the platform with improvement of histopathological changes occurred in the brain. But combined and memantine-treated groups resulted in more significant improvement than other treated groups.


Alzheimer, Vitamin D3, Folic acid, Memantine, BDNF, Glutathione reductase, Cognitive function

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Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer's disease: Past, present and future. Neuropharmacol. 2014;76:27-50.

Mayeux R1, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(8): 45-9.

Querfurth HW, LaFerla FM. Alzheimer’s disease biomarkers: more than molecular diagnostics. Drug Develop Res. 2013;74:92-111.

Anderson DC. Alzheimer’s disease biomarkers: more than molecular diagnostics. Drug Develop Res. 2013; 74:92-111.

Galasko D, Montine TJ. Biomarkers of oxidative damage and inflammation in Alzheimer's disease. Biomark Med. 2010;4:27-36.

Annweiler C, Beauchet O. Vitamin dementia: randomized clinical trials should be the next step. Neuroepidemiol. 2013;37:249-58.

Chabas JF, Alluin O, Rao G. Vitamin D2 potentiates axon regeneration. J Neurotrauma. 2008;25(10):1247-56.

Pludowski P, Holick MF, Pilz S. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmun Rev. 2013;12(10):976-89.

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013;34(1):47-64.

Fernandes DA, Eyles D, Féron F. Vitamin D, a neuro-immunomodulator: Implications for neuro-degenerative and autoimmune diseases. Psychoneuroendocrinol. 2009;34:S265-277.

Weinstein SJ, Hartman TJ, Stolzenberg-Solomon R, Pietinen P, Barrett MJ, Taylor PR. Null association between prostate cancer and serum folate, vitamin B (6), vitamin B (12), and homocysteine. Cancer Epidemiol Biomarkers Prev. 2003;12:1271-2.

Singh R, Kanwar SS, Sood PK, Nehru B. Beneficial effects of folic acid on enhancement of memory and antioxidant status in aged rat brain. Cell Mol Neurobiol. 2011;31:83-91.

Tsuneki H, Sekizaki N, Suzuki T, Kobayashi S, Wada T, Okamoto T, et al. Coenzyme Q10 prevents high glucose-induced oxidative stress in human umbilical vein endothelial cells. Eur J Pharmacology. 2007;566: 1-10.

Das UN. Folic acid and polyunsaturated fatty acids improve cognitive function and prevent depression, dementia, and Alzheimer's disease-But how and why?. Prostaglandins Leukot Essent Fatty Acids. 2008;78:11-9.

Mattson MP. Pathways towards and away from Alzheimer’sdisease. Nature. 2004;430:631-9.

Wu TY, Chen CP. Dual action of memantine in Alzheimer disease: a hypothesis. Taiwan J Obstet Gynecol. 2009;48(3):273-7.

Saima K, Kaneez FS, Fatima, SK. Neuroprotective effect of curcumin and vitamin D3 on scopolamine hydro-bromide treated rat model of alzheimer’s disease. EC Neurology. 2015;155-161.

Dehghani DHR, Reisi P, Azizi MHR, Alaei H, Pilehvarian AA. Effects of folic acid on passive avoidance learning and memory in rat alzheimer model by intracerebroventricular injection of streptozotocin. J Isfahan Med school. 2010; 647-55.

Teresita LB, Darwish H. Vitamin D mitigates age-related cognitive decline through the modulation of pro-inflammatory state and decrease in amyloid burden. J Neuroinflamm. 2012; 9:244.

Catherine C, David FW, Joanne L, George, TT, John WO. Low Doses of Memantine Disrupt Memory in Adult Rats. J Neurosci. 2006;26(15):3923-32.

Aaro JJ, Katja AP, Jarkko IV, Veijo S, Anne M, Sirja R, et al. Beneficial effect of prolyl oligopeptidase inhibition on spatial memory in young but not in old scopolamine-treated rats. Basic Clin Pharm Tox. 2007;100(2):132-8.

Gacar N, Mutlu O, Utkan T, Komsuoglu I, Gocmez SS, Ulak G. Beneficial effects of resveratrol on scopolamine but not mecamylamine induced memory impairment in the passive avoidance and Morris water maze tests in rats. Pharmacol, Biochem Behav. 2011;99(3):316-23.

Jamali-Raeufy N, Nasehi M, Ebrahimi-ghiri M, Zarrindast MR. Cross state-dependency of learning between WIN55, 212-2 and scopolamine in rat dorsal hippocampus. Neurosci Let. 2011;491(3):227-31.

Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK. Protective role of ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PloS one. 2011;6(11): e27265.

Aly HF, Metwally FM, Ahmed HH. Neuroptective effect of dehydroepiandrosterone (DHEA) in rat model of Alzheimer’s disease. Acta Biochim Pol. 2011;58(4):513-20.

Kirk L, Ruchika S, Michelle W, Laura C, Suise H, MollyM, et al. Brain derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci. 2010;30(15):5368-75.

Sutherland MK, Somerville MJ, Yoong LK, Bergeron C, Haussler DR, McLachlan DR. Reduction of vitamin D hormone receptor mRNA levels in Alzheimer as compared to Huntington hippocampus: correlation with calbindin-28k mRNA levels. Brain Res Mol Brain Res. 1992;13:239-50.

Hanaa HA, Samiha MA, Fatma MA, Heba AM. Significance of vitamin D in combination with calcium in modulation of depression in the experimental model. Der Pharma Chemica. 2015;7(1): 128-47.

Shingo L, Sumio O, Yasuko N, Yusuke K, Sho M, Testsuya T. 1α25-dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-β peptide (1–40) from mouse brain across the blood-brain barrier. Fluids Barriers CNS. 2011;8:20-9.

Briones TL, Darwish H. Vitamin D mitigates age-related cognitive decline through the modulation of pro-inflammatory state and decrease in amyloid burden. J Neuroinflamm. 2012;9:24.

Yu J, Gattoni CM, Zhu H, Sambamurti K, Gattoni CS, Kindy MS. Vitamin D3 enriched diet correlates with a decrease of amyloid plaques in the brain of AbPP transgenic mice. J Alzheimers Dis. 2011;25(2):295-307.

Garcion E, Wion-Barbot N, Montero-Menei C, Berger F, Wion D. New clues about vitamin D in the nervous system. Trends Endocrinol Metab. 2002;13:100-5.

Jain SK, Micinski D. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013;437(1):7-11.

Humble MB. Vitamin D, light and mental health. J Photochem Photobiol. 2010;10:142-9.

West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM, Shaywitz AJ, et al. Calcium regulation of neuronal gene expression. Proceed Nat Acad Sci Am. 2001;11024-31.

MatteC, Pereira LO, Dos Santos TM, Mackedanz V, Cunha AA, Netto CA, et al. Acute homocysteine administration impairs memory consolidation on inhibitory avoidance task and decreases hippocampal brain-derived neurotrophic factor immunocontent: prevention by folic acid treatment. Neurosci. 2009; 163(4):1039-45.

Troen AM, Chao WH, Crivello NA, D'Anci KE, Shukitt-Hale B, Smith DE, et al. Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine. J Nutr. 2008;138(12):2502-9.

Chen TF, Huang RF, Lin SE, Lu JF, Tang MC, Chiu MJ. Folic Acid potentiates the effect of memantine on spatial learning and neuronal protection in an Alzheimer's disease transgenic model. J Alzheimers Dis. 2010;20(2):607-15.

Marvanová M, Lakso M, Pirhonen J, Nawa H, Wong G, Castrén E. The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain. Mol Cell Neurosci. 2001;18(3):247-58.

Klyubin I, Wang Q, Reed MN. Protection against Abeta-mediated rapid disruption of synaptic plasticity and memory by memantine. Neurobiol Aging. 2011;32:614-23.

Floden AM, Li S, Combs CK. b-Amyloid-stimulated microgliainduce neuron death via synergistic stimulation of tumor necrosis factor aand NMDA receptors. J Neurosci. 2005;25:2566-75.

Ong KT. Aβ imaging with 18F florbetaben in prodromal Alzheimer;8’s disease: a prospective outcome study. J Neurol Neurosurg Psychiatry. 2014; 86:431-6.

Hori K, Konishi K, Tomioka H, Tani M, Minegishi G, et al. Reviews: Serum anticholinergic activity: A biomarker for rapid progression of Alzheimer’s disease. J Autacoids. 2012;4:1.

Ihalainen J, Sarajärvi T, Rasmusson D, Kemppainen S, Keski-Rahkonen P, Lehtonen M, et al. Effects of memantine and donepezil on cortical and hippocampal acetylcholine levels and object recognition memory in rats. Neuropharmacol. 2011; 61(5-6):891-9.

Dashniani M, Chighladze M, Burjanadze M, Beselia G, Kruashvili L. Memantine attenuates the okadaic acid induced short-term spatial memory impairment and hippocampal cell loss in rats. Georgian Med News. 2016;(252):59-63.