Unifying mechanism behind the onset of acquired epilepsy. (February 2022)

• Record Type: Journal Article
• Authors: Zilberter, Yuri; Popova, Irina; Zilberter, Misha
• Is Part Of: Trends in pharmacological sciences. Volume 43:Number 2(2022)
• Page Start: 87
• Page End: 96
• Publication Date: 2022-02
• Subjects: acquired epilepsy -- Alzheimer's disease -- oxidative stress -- glucose hypometabolism -- NADPH oxidase -- ketogenic diet; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2021.11.009
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Acquired epilepsy (AE) can result from a number of brain insults and neurological diseases with wide etiological diversity sharing one common outcome of brain epileptiform activity. This implies that despite their disparity, all these initiating pathologies affect the same fundamental brain functions underlying network excitability. Identifying such mechanisms and their availability as therapeutic targets would help develop an effective strategy for epileptogenesis prevention. In this opinion article, we propose that the vicious cycle of NADPH oxidase (NOX)-mediated oxidative stress and glucose hypometabolism is the underlying cause of AE, as available data reveal a critical role for both pathologies in epileptogenesis and the process of seizure initiation. Altogether, here we present a novel view on the mechanisms behind the onset of AE and identify therapeutic targets for potential clinical applications. Highlights: Risk factors for acquired epileptogenesis can drastically differ in their etiology, varying from acute brain injury to neurodegenerative diseases (e.g., Alzheimer's disease). Widely recognized biomarkers of early-stage acquired epilepsy are oxidative stress and glucose hypometabolism. The dominant source of acquired epileptogenesis-associated oxidative stress is NADPH oxidase (NOX). Epileptiform activity is accompanied by the rapid release of H2 O2 from activated NOX and results in a long-lasting and pronounced decrease in glucose consumption. Glucose hypometabolism initiates epileptogenesis. Aβ1-42 induces NOX activation, which inhibits glycolysis and results in long-lasting network hyperactivity. Existing data indicate that activated NOX is the likely enzyme behind early acquired epilepsy-associated oxidative stress, which induces brain glucose hypometabolism and the resulting epileptogenesis.