Envisioning the neuroprotective effect of Metformin in experimental epilepsy: A portrait of molecular crosstalk

Epilepsy is a neurological disorder characterized by an enduring predisposition to generate and aggravate epileptic seizures affecting around 1% of global population making it a serious health concern. Despite the recent advances in epilepsy research, no disease-modifying treatment able to terminate epileptogenesis have been reported yet reflecting the complexity in understanding the disease pathogenesis. To overcome the current treatment gap against epilepsy, one effective approach is to explore anti-epileptic effects from a drug that are approved to treat non-epileptic diseases. In this regard, Metformin emerged as an ideal candidate which is a first line treatment option for type 2 diabetes mellitus (T2DM), has conferred neuroprotection in several in vivo neurological disorders such as Alzheimer's diseases (AD), Parkinson's disease (PD), Stroke, Huntington's diseases (HD) including epilepsy. In addition, Metformin has ameliorated cognitive alteration, learning and memory induced by epilepsy as well as in animal model of AD. Herein, we review the promising findings demonstrated upon Metformin treatment against animal model of epilepsy however, the precise underlying mechanism of anti-epileptic potential of Metformin is not well understood. However, there is a growing understanding that Metformin demonstrates its anti-epileptic effect mainly via ameliorating brain oxidative damage, activation of AMPK, inhibition of mTOR pathway, downregulation of α-synuclein, reducing apoptosis, downregulation of BDNF and TrkB level. These reflects that Metformin being non-anti-epileptic drug (AED) has a potential to ameliorate the cellular pathways that were impaired in epilepsy reflecting its therapeutical potential against epileptic seizure that might plausibly overcome the limitations of today epilepsy treatment.