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.