Protective Effect of Metformin Alone or in Combination with Valproic acid on Pentylenetetrazole-Induced Seizures in Mice
Abstract
Abstract
Objective: The aim of this study was to investigate the effects of metformin on pentylenetetrazole (PTZ)-induced seizures and the neuroprotective effect of metformin on neuronal damage after pentylenetetrazole administration.
Material and Methods: Thirty-five (35) Male BALB-c Albino mice weighing 35-38 g were divided randomly into five groups: Control group (1), Saline+PTZ group (2), Valproic Acid (VPA, 200 mg/kg intraperitoneal-i.p.)+PTZ group (3), Metformin (200 mg/kg i.p.)+PTZ group (4), and VPA+Metformin+PTZ
group (5). The PTZ (60 mg/kg, i.p.) was injected 30 min after drugs injection to induce seizures and seizure stages and behavioral scoring were evaluated. After completing procedure, brain tissues were removed and analyzed with biochemical and histopathological procedures. The hippocampal Cornu Ammonis (CA) 1, CA2, CA3 and DG (dentate gyrus) regions were histopathologically evaluated and oxidative stress markers (total antioxidant status (TAS), total oxidant status (TOS)) were measured.
Results: Compare to Saline+PTZ group, metformin administration alone did not affect the onset time of the first myoclonic jerk (FMJ), but combination of VPA and metformin significantly increased FMJ onset time (p<0.05). Additionally, the treatment of metformin with or without VPA reduced the brain oxidative
stress (p<0.05). Furthermore, histopathological assessment demonstrated that metformin administration and the combination of VPA and metformin decreased dark neuron formation in the hippocampal CA1, CA2, CA3, and DG areas (p<0.05).
Conclusion: Metformin was found to be significantly effective in reducing epileptic seizures, brain oxidative stress, and preventing neural damage after PTZ-induced seizure
Keywords
References
- Maiha BB, Magaji MG, Yaro AH, Hamza AH, Ahmed SJ, Magaj AR. Anticonvulsant studies on Cochlospermum tinctorium and Paullinia pinnata extracts in laboratory animals. Nig J Pharm Sci 2009;8:102-108.
- Carpio A, Hauser WA. Epilepsy in the developing world. Curr Neurol Neurosci Rep 2009;9:319-326.
- Curia G, Lucchi C, Vinet J, Gualtieri F, Marinelli C, Torsello A et al. Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic? Curr.Med.Chem 2014;21:663-688.
- Akkaya R, Gümüş E, Akkaya B, Karabulut S, Gülmez K, Karademir M et al. Wi-Fi decreases melatonin protective effect and increases hippocampal neuronal damage in pentylenetetrazole induced model seizures in rats. Pathophysiology 2019;26:375-379.
- Tastemur Y, Gumus E, Ergul M, Ulu M, Akkaya R, Ozturk A et al. Positive effects of angiotensin-converting enzyme (ACE) inhibitor, captopril, on pentylenetetrazole-induced epileptic seizures in mice. Trop J Pharm Res 2020;19:637-643.
- Thom M, Zhou J, Martinian L, Sisodiya S. Quantitative post‐mortem study of the hippocampus in chronic epilepsy: Seizures do not inevitably cause neuronal loss. Brain 2005;128:1344–1357.
- Sato H, Takahashi T, Sumitani K, Takatsu H, Urano S. Glucocorticoid generates ROS to induce oxidative injury in the hippocampus, leading to impairment of cognitive function of rats. J Clin Biochem Nutr 2010;47:224-232.
- Lim DW, Park J, Jung J, Kim SH, Um MY, Yoon M et al. Dicaffeoylquinic acids alleviate memory loss via reduction of oxidative stress in stress-hormone-induced depressive mice. Pharmacol Res 2020;161:105252.
- Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997;102:99-110.
- Cheng YY, Leu HB, Chen TJ, Chen CL, Kuo CH, Lee SD et al. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: A 4-year follow-up study. J Stroke Cerebrovasc Dis 2014;23:99-105.