Mechanisms and morpho-pathophysiological levels of epileptogenesis

This review elucidates the concept of levels of epileptogenesis, including the effector level of ion channels, the mechanisms that ensure their functionality, and the maintenance of ionic equilibrium, both intracellular, involving specific proteins, and extracellular, encompassing astroglia. Moreover, the discussion extends to the level of mediator systems, including glutamate, gamma-aminobutyric acid (GABA), and acetylcholine, as well as the propagation of excitation to adjacent neurons (plasticity) and the emergence of secondary excited neurons that contribute to the formation of a hyper-excited neural network. Drawing on both the existing literature and original research findings, this article addresses the ion channel dysfunction, the implicated protein systems that support channel function, and the relevance of synaptic and extrasynaptic localizations. The role of neuroinflammation, endocrine factors, and the establishment of aberrant hyperexcitable neural networks are also analyzed. The presented findings underscore that epileptogenesis is a multifaceted process, characterized by numerous pathophysiological factors that interact in complex, overlapping, and interdependent ways. While it is established that ion channels are the definitive effector of epileptogenesis, the significance of ancillary factors must not be overlooked. Such factors include the activities of glial components, synaptic proteins, and neuroinflammatory processes, which serve dual roles as effectors and contributors to the progression of epilepsy as a chronic condition. This integrated approach to understanding epileptogenesis is essential for the efficacy of current treatment methodologies, including pharmacotherapy, dietary interventions, and neurosurgical procedures. Furthermore, this approach can drive the exploration of innovative therapeutic strategies for the management of epilepsy.