New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway

Abstract

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

Keywords: epilepsy; metformin; seizure.

FIGURE 1

Pathophysiology of epilepsy. Oxidative stress, reduction of inhibitory gamma‐aminobutyric acid (GABA) and increase of excitatory glutamate induce the development and progression of epileptogenesis with the development of epilepsy. Mutation of voltage‐gated Na⁺, Ca²⁺ and K⁺ channels provokes neuronal hyper‐excitability.

FIGURE 2

Mechanisms underlying the antiepileptic effect of metformin. Metformin has anti‐seizure activity by activating AMPK signalling and inhibiting the mechanistic target of the rapamycin (mTOR) pathway which are dysregulated in epilepsy. AMPK induces the expression of peroxisome proliferator‐activated receptor gamma co‐activator 1 alpha (PGC1‐α) which improves mitochondrial biogenesis and upregulates sirtuin 1 (SIRT1) and forkhead box o3 (FOXO3) which induces neuroprotection. AMPK enhances glucose uptake and glycolysis of astrocytes by increasing the translocation of membrane glucose transporter 1 (GLUT1). AMPK increases progranulin and brain‐derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) and inhibits the synthesis of fatty acids and increases their degradation by increasing the expression of malonyl‐CoA which inhibits fatty acid oxidation.