An Insight into Molecular Mechanisms and Novel Therapeutic Approaches in Epileptogenesis

Abstract

Epilepsy is the second most common neurological disease with abnormal neural activity involving the activation of various intracellular signalling transduction mechanisms. The molecular and system biology mechanisms responsible for epileptogenesis are not well defined or understood. Neuroinflammation, neurodegeneration and Epigenetic modification elicit epileptogenesis. The excessive neuronal activities in the brain are associated with neurochemical changes underlying the deleterious consequences of excitotoxicity. The prolonged repetitive excessive neuronal activities extended to brain tissue injury by the activation of microglia regulating abnormal neuroglia remodelling and monocyte infiltration in response to brain lesions inducing axonal sprouting contributing to neurodegeneration. The alteration of various downstream transduction pathways resulted in intracellular stress responses associating endoplasmic reticulum, mitochondrial and lysosomal dysfunction, activation of nucleases, proteases mediated neuronal death. The recently novel pharmacological agents modulate various receptors like mTOR, COX-2, TRK, JAK-STAT, epigenetic modulators and neurosteroids are used for attenuation of epileptogenesis. Whereas the various molecular changes like the mutation of the cell surface, nuclear receptor and ion channels focusing on repetitive episodic seizures have been explored by preclinical and clinical studies. Despite effective pharmacotherapy for epilepsy, the inadequate understanding of precise mechanisms, drug resistance and therapeutic failure are the current fundamental problems in epilepsy. Therefore, the novel pharmacological approaches evaluated for efficacy on experimental models of epilepsy need to be identified and validated. In addition, we need to understand the downstream signalling pathways of new targets for the treatment of epilepsy. This review emphasizes on the current state of novel molecular targets as therapeutic approaches and future directions for the management of epileptogenesis. Novel pharmacological approaches and clinical exploration are essential to make new frontiers in curing epilepsy.

Keywords: Epilepsy; excitotoxicity; microglia; mitochondrial dysfunction; neurodegeneration; seizures.