Laboratory of the systemic organization of neurons named after O.S. Vinogradova

The mechanisms of acquired epileptogenesis and the initiation of seizures are still unknown. This is a major obstacle to the development of effective antiepileptic and anticonvulsant therapeutic approaches. The results of our recent studies indicate that glucose hypometabolism is the main trigger factor for acquired epileptogenesis (1-4). Moreover, our pilot studies show that glutamate-induced activation of NADPH oxidase (NOX) is the main cause of most seizures. In both cases, oxidative stress comes out on top as the main initiating factor of pathology. Glucose metabolism deficiency (5-7) associated with oxidative stress (8-10) may be the trigger and driving force of acquired epileptogenesis. The relationship of epileptogenesis with hypometabolism has been established both in animals (5,6) and in clinical studies (11,12). Recently, in vivo experiments, we have shown that chronic inhibition of energy metabolism by reducing glucose utilization initiates epileptogenesis (1). We also demonstrated that seizures in turn inhibit glucose utilization (3), revealing a bidirectional positive feedback linking seizures and hypometabolism. At the same time, exogenous pyruvate is able to restore glucose consumption disrupted by seizures (3). Fundamentally, metabolic correction by chronic administration of pyruvate (13) was highly effective in three fundamentally different models of acquired epilepsy - focal, generalized and associated with Alzheimer's disease (2). The main objective of this study is to identify mechanisms for reducing the level of utilization Glucose is apparently caused by oxidative stress and plays a trigger role in all major neurodegenerative diseases. In most focal seizures in humans, a large DC amplitude shift (the so-called DC shift) is detected in the EEG at the beginning of the attack, which is often preceded by a high-amplitude interictal spike (14-20). The DC shift, the origin of which is still unknown, probably reflects a massive transient network depolarization that triggers subsequent ictal network activity. In pilot experiments, using several models of seizures, we have shown that high-amplitude interictal spike is associated with rapid high-voltage release of H2O2 as a result of glutamate-induced NOX activation. NOX inhibition prevented the rapid release of H2O2, as well as subsequent DC shift and seizure triggering, while at the same time not affecting interictal network activity. Similarly, in vivo experiments, NOX antagonists injected intracerebroventrically prevented acute seizures induced by 4-aminopyridine without inhibiting interictal network activity. The main goal of this project is to develop a unified metabolic concept of acquired epileptogenesis and initiation of seizures, as well as an effective strategy for preventing pathology. The project will investigate: the role of NOX activation in the induction of seizures; the effect of oxidative stress on the metabolic and electrical parameters of the neural network in sections of the hippocampus; the participation of microglia in the release of ROS during the generation of seizures; prevention of seizures in vivo by inhibiting NOX; combinatorial treatment that prevents acquired epileptogenesis.