Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

Abstract

This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982-2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy.

Keywords: Epigenetics; Epilepsy; Epileptogenesis; JAK-Stat; Neurosteroid; Rapamycin.

Conflict of interest statement

Conflict of Interest Statement. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2017 Elsevier B.V. All rights reserved.

Figures

Figure 1. An overview of the pathophysiology of epileptogenesis

Epileptogenesis is the process whereby a normal brain becomes progressively epileptic because of precipitating injury or risk factors such as TBI, stroke, brain infections or prolonged seizures. Epilepsy development can be described in three stages: (1) the initial injury (epileptogenic event); (2) the latent period (silent period with no seizure activity); and (3) chronic period with spontaneous recurrent seizures. Although the precise mechanisms underlying spatial and temporal events remain unclear, epileptogenesis may involve an interaction of acute and delayed anatomic, molecular, and physiological events that are both complex and multifaceted. The initial precipitating factor activates diverse signaling events, such as inflammation, oxidation, apoptosis, neurogenesis and synaptic plasticity, which eventually lead to structural and functional changes in neurons. These changes are eventually manifested as abnormal hyperexcitability and spontaneous seizures. Around two-dozen antiepileptic drugs are available for treating seizures by blocking ion channels. Current drug therapy is symptomatic in that available drugs inhibit seizures, but neither effective prophylaxis nor cure is available. Presently, there is no “antiepileptogenic” drug for cure of epilepsy. Thus, newer drugs that can better prevent and modify the disease are needed for curing epilepsy.

Figure 2. The mTOR pathway in epileptogenesis

mTOR mediates a number of developmental processes including neurogenesis and cellular proliferation and migration. It is also involved in a handful of more specific processes related to epilepsy, such as axonal sprouting, axonal regeneration, dendritic development, and structural microtubule dynamics. mTOR signaling indirectly influences neuronal excitability through modulation of synaptic structure and plasticity.

Figure 3. Potential molecular mechanisms of neurosteroid interruption of epileptogenesis

In the brain, allopregnanolone and related neurosteroids may retard epileptogenesis by the interruption of one or more of the pathways leading to development of epilepsy, which generally occurs following an initial precipitating event. Neurosteroids such as allopregnanolone binds to synaptic and extrasynaptic GABA-A receptors and enhances phasic and tonic inhibition within the brain. Synaptic GABA-A receptors, which are pentameric chloride channels composed of 2α2βγ subunits, largely mediate the phasic portion of GABAergic inhibition, while extra-synaptic GABA-A receptors, pentamers composed of 2α2βδ subunits, primarily contribute to tonic inhibition in the hippocampus. Neurosteroids binds to the “neurosteroid site(s)” on GABA-A receptors, which are distinct from sites for GABA, benzodiazepines, and barbiturates. Neurosteroids activate both synaptic and extrasynaptic receptors, enhance the phasic and tonic inhibition, and promote maximal net inhibition, and thereby may affect epileptogenesis.