Generic placeholder image

Central Nervous System Agents in Medicinal Chemistry


ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

Research Article

Evaluation of the Behavioural, Antioxidative and Histomorphological Effects of Folic Acid-supplemented Diet in Dexamethasone-induced Depression in Mice

Author(s): Joshua Falade*, Adejoke Y. Onaolapo and Olakunle J. Onaolapo

Volume 21, Issue 1, 2021

Published on: 14 January, 2021

Page: [73 - 81] Pages: 9

DOI: 10.2174/1871524921666210114125355

Price: $65


Background: The effect of folic acid in mitigating depression has remained pivotal in research.

Objective: To determine the effects of folate supplementation on neurobehaviour oxidative stress and cerebral cortex histomorphology in the dexamethasone mouse model of depression.

Methods: Male mice were assigned to six groups (A-F) of 10 mice each. Animals in groups A and D were fed a standard diet, while those in B and E were fed folic acid supplemented diet (25 mg/kg of feed), while C and F were fed folate supplemented diet at 50 mg/kg of feed for 8 weeks. At the beginning of the sixth 6th week, mice in groups A-C were administered distilled water, while animals in groups D-F were administered dexamethasone (DEX) at 4 mg/kg body weight by gavage. Open-field, forced swim, and tail-suspension tests were conducted at the end of the experimental period, following which animals were euthanised and blood was taken for the estimation of Malondialdehyde (MDA), reduced Glutathione, Glutathione Peroxidase, Catalase activity, and Superoxide Dismutase. Sections of the cerebral cortex were prepared for histological examination.

Results: Folic acid supplementation increased body weight, locomotor, rearing and self-grooming behaviours, and decreased immobility time in the tail suspension and forced swim tests. There was also a reduction of lipid peroxidation and an increase in the antioxidant status. Folic acid supplementation was also found to be protective against the development of dexamethasone-induced changes in body weight, open-field behaviours, behavioural despair, oxidative stress and cerebrocortical morphology.

Conclusion: Folic-acid supplementation improves the behavioral, some antioxidant, and cerebral morphological parameters.

Keywords: Depression, folic acid, antioxidant, dexamethasone, mice, cerebral morphology.

« Previous
Graphical Abstract
Friedrich MJ. Depression is the leading cause of disability around the world. JAMA 2017; 317(15): 1517.
[] [PMID: 28418490]
Wang W, Xiao C, Yao X, Yang Y, Yan H, Li S. Psychosocial health and suicidal ideation among people living with HIV/AIDS: A cross-sectional study in Nanjing, China. PLoS One 2018; 13(2): e0192940.
[] [PMID: 29470532]
Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, et al. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388(10053): 1545-602.
[] [PMID: 27733282]
Wang J, Wu X, Lai W, et al. Prevalence of depression and depressive symptoms among outpatients: A systematic review and meta-analysis. BMJ Open 2017; 7(8): e017173.
[] [PMID: 28838903]
Sugawara N, Yasui-Furukori N, Tsuchimine S, et al. No association between dietary patterns and depressive symptoms among a community-dwelling population in Japan. Ann Gen Psychiatry 2012; 11(1): 24.
[] [PMID: 23006931]
Steel Z, Marnane C, Iranpour C, et al. The global prevalence of common mental disorders: A systematic review and meta-analysis 1980-2013. Int J Epidemiol 2014; 43(2): 476-93.
[] [PMID: 24648481]
Patel V, Chisholm D, Parikh R, et al. DCP MNS Author Group. Addressing the burden of mental, neurological, and substance use disorders: Key messages from Disease Control Priorities, 3rd edition. In: Lancet . 2016; 387: pp. (10028)1672-85.
[] [PMID: 26454360]
Woo J, Lynn H, Lau W, et al. Nutrient intake and psychological health in an elderly Chinese population. Int J Geriatr Psychiatry 2006; 21(11): 1036-43.
Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health 2007; 61(7): 631-7.
[] [PMID: 17568057]
Shakur YA, Garriguet D, Corey P, O’Connor DL. Folic acid fortification above mandated levels results in a low prevalence of folate inadequacy among Canadians. The American journal of clinical nutrition 2010; 92(4): 818-25.
Empty C. Nootropic vitamins and minerals-essential nutrients for optimal brain health and cognitive function. Brain 2018. Available from:
Quang DD. Antioxidant properties of folic acid: A dft study. Vietnam J Sci Technol 2018; 56(4A): 39.
Patel N, Viguera AC, Baldessarini RJ. Mood-stabilizing anticonvulsants, spina bifida, and folate supplementation. J Clin Psychopharmacol 2018; 38(1): 7-10.
[] [PMID: 29215383]
Meadows DN, Bahous RH, Best AF, Rozen R. High dietary folate in mice alters immune response and reduces survival after malarial infection. PLoS One 2015; 10(11): e0143738.
[] [PMID: 26599510]
Skupio U, Tertil M, Sikora M, Golda S, Wawrzczak-Bargiela A, Przewlocki R. Behavioral and molecular alterations in mice resulting from chronic treatment with dexamethasone: Relevance to depression. Neuroscience 2015; 286: 141-50.
[] [PMID: 25433240]
Onaolapo OJ, Aremu OS, Onaolapo AY. Monosodium glutamate-associated alterations in open field, anxiety-related and conditioned place preference behaviours in mice. Naunyn Schmiedebergs Arch Pharmacol 2017; 390(7): 677-89.
[] [PMID: 28357464]
Onaolapo AY, Olawore OI, Yusuf FO, Adeyemo AM, Onaolapo OJ. Oral Monosodium glutamate differentially affects open-field behaviours, behavioural despair and place preference in male and female mice. Curr Psychopharmacol 2019; 8(2): 130-45.
Olofinnade AT, Onaolapo AY, Stefanucci A, Mollica A, Olowe OA, Onaolapo OJ. Cucumeropsis mannii reverses high-fat diet induced metabolic derangement and oxidative stress. Front Biosci (Elite Ed) 2021; 13: 54-76.
[] [PMID: 33048776]
Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology (Berl) 1985; 85(3): 367-70.
[] [PMID: 3923523]
Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: A primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977; 229(2): 327-36.
[PMID: 596982]
Onaolapo OJ, Onaolapo AY, Akanmu MA, Gbola O. Evidence of alterations in brain structure and antioxidant status following ‘low-dose’ monosodium glutamate ingestion. Pathophysiology 2016; 23(3): 147-56.
[] [PMID: 27312658]
Olofinnade AT, Onaolapo AY, Onaolapo OJ, et al. Corylus avellana L. modulates neurobehaviour and brain chemistry following high-fat diet. Front Biosci 2021; 26: 537-51.
[] [PMID: 33049682]
Olofinnade AT, Alawode A, Onaolapo AY, Onaolapo OJ. Lepidium meyenii supplemented diet modulates neurobehavioral and biochemical parameters in mice fed high-fat-high-sugar diet. Endocr Metab Immune Disord Drug Targets 2020. Epub ahead of print
[] [PMID: 32955007]
Onaolapo AY, Odetunde I, Akintola AS, et al. Dietary composition modulates impact of food-added monosodium glutamate on behaviour, metabolic status and cerebral cortical morphology in mice. Biomed Pharmacother 2019; 109: 417-28.
[] [PMID: 30399577]
Mollica A, Zengin G, Locatelli M, et al. An assessment of the nutraceutical potential of Juglans regia L. leaf powder in diabetic rats. Food Chem Toxicol 2017; 107(Pt B): 554-64.
[] [PMID: 28366844]
Aebi H. Catalase. Methods of enzymatic analysis. Verlag Chemie, Weinhem, 1983; 273-86.
Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochimicaetbiophysicaacta (BBA)-general subjects 1979; 582(1): 67-78.
Onaolapo AY, Aina OA, Onaolapo OJ. Melatonin attenuates behavioural deficits and reduces brain oxidative stress in a rodent model of schizophrenia. Biomed Pharmacother 2017; 92: 373-83.
[] [PMID: 28554133]
Hafeman DG, Sunde RA, Hoekstra WG. Effect of dietary selenium on erythrocyte and liver glutathione peroxidase in the rat. J Nutr 1974; 104(5): 580-7.
[] [PMID: 4823943]
Onaolapo AY, Abdusalam SZ, Onaolapo OJ. Silymarin attenuates aspartame-induced variation in mouse behaviour, cerebrocortical morphology and oxidative stress markers. Pathophysiology 2017; 24(2): 51-62.
[] [PMID: 28254270]
Cho CE, Sánchez-Hernández D, Reza-López SA, Huot PS, Kim Y-I, Anderson GH. High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics 2013; 8(7): 710-9.
[] [PMID: 23803567]
Hoile SP, Lillycrop KA, Grenfell LR, Hanson MA, Burdge GC. Increasing the folic acid content of maternal or post-weaning diets induces differential changes in phosphoenolpyruvate carboxykinase mRNA expression and promoter methylation in rats. Br J Nutr 2012; 108(5): 852-7.
[] [PMID: 22136740]
McKay JA, Mathers JC. Diet induced epigenetic changes and their implications for health. Acta Physiol (Oxf) 2011; 202(2): 103-18.
[] [PMID: 21401888]
Budni J, Zomkowski AD, Engel D, et al. Folic acid prevents depressive-like behavior and hippocampal antioxidant imbalance induced by restraint stress in mice. Exp Neurol 2013; 240: 112-21.
[] [PMID: 23142187]
Chruvattil R, Banerjee S, Nath S, et al. Dexamethasone alters the appetite regulation via induction of hypothalamic insulin resistance in rat brain. Mol Neurobiol 2017; 54(9): 7483-96.
[] [PMID: 27822713]
Brocardo PS, Budni J, Kaster MP, Santos AR, Rodrigues ALS. Folic acid administration produces an antidepressant-like effect in mice: Evidence for the involvement of the serotonergic and noradrenergic systems. Neuropharmacology 2008; 54(2): 464-73.
[] [PMID: 18078962]
de Souza BP, Budni J, Lobato KR, Kaster MP, Rodrigues ALS. Antidepressant-like effect of folic acid: Involvement of NMDA receptors and L-arginine-nitric oxide-cyclic guanosine monophosphate pathway. Eur J Pharmacol 2008; 598(1-3): 37-42.
[] [PMID: 18789921]
Sahin K, Onderci M, Sahin N, Gursu MF, Kucuk O. Dietary vitamin C and folic acid supplementation ameliorates the detrimental effects of heat stress in Japanese quail. J Nutr 2003; 133(6): 1882-6.
[] [PMID: 12771333]
Rathor L, Akhoon BA, Pandey S, Srivastava S, Pandey R. Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans. Age (Dordr) 2015; 37(6): 113.
[] [PMID: 26546011]
Sarna LK, Wu N, Wang P, Hwang S-Y, Siow YL. O K. Folic acid supplementation attenuates high fat diet induced hepatic oxidative stress via regulation of NADPH oxidase. Can J Physiol Pharmacol 2012; 90(2): 155-65.
[] [PMID: 22309437]
Suwanjang W, Abramov AY, Charngkaew K, Govitrapong P, Chetsawang B. Melatonin prevents cytosolic calcium overload, mitochondrial damage and cell death due to toxically high doses of dexamethasone-induced oxidative stress in human neuroblastoma SH-SY5Y cells. Neurochem Int 2016; 97: 34-41.
[] [PMID: 27155536]
McGarel C, Pentieva K, Strain JJ, McNulty H. Emerging roles for folate and related B-vitamins in brain health across the lifecycle. Proc Nutr Soc 2015; 74(1): 46-55.
[] [PMID: 25371067]
Zhang X, Huang G, Liu H, Chang H, Wilson JX. Folic acid enhances notch signaling, hippocampal neurogenesis, and cognitive function in a rat model of cerebral ischemia. Nutr Neurosci 2012; 15(2): 55-61.
[] [PMID: 22334042]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy