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Abstract <p>Metabolic reprogramming of astrocytes and microglia is considered a significant component of epileptogenesis, associated with the development of neuronal network hyperexcitability, neuroinflammation, and oxidative stress. This review analyzes key mechanisms of glial dysfunction, such as the shift toward aerobic glycolysis (the Warburg effect), mitochondrial disturbances, and generation of reactive oxygen species. These processes are regulated by the Wnt/GSK3β and mTOR signaling cascades, forming a vicious cycle of energy deficit, NLRP3 inflammasome activation, and excitotoxicity. Particular attention is given to strategies for correcting glial metabolism. The greatest therapeutic interest lies in systemic approaches that correct metabolism (ketogenic diet, GLP-1 and PPAR receptor agonists) and high-precision technologies for selective modulation of glial functions (RNA therapy, nanodelivery). Targeted intervention in glial metabolism opens ways to the development of anti-epileptogenic drugs capable of modifying the disease course rather than merely alleviating the symptoms. However, translation of these approaches into clinical practice requires clarification of therapeutic windows for the intervention and development of biomarkers of glial status.</p>

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Metabolic Reprogramming of Astrocytes and Microglia as a Driver and Therapeutic Target in Epileptogenesis

  • 期刊论文

  • 发表日期：

    2026年5月27日

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  • Maria V. Zakharova,
  • Anna A. Kovalenko,
  • Yuliy A. Gorgul,
  • Aleksandr P. Schwarz,
  • Olga E. Zubareva,
  • Adelia R. Kharisova,
  • Georgy P. Diespirov,
  • Aleksey V. Zaitsev

摘要

Abstract

Metabolic reprogramming of astrocytes and microglia is considered a significant component of epileptogenesis, associated with the development of neuronal network hyperexcitability, neuroinflammation, and oxidative stress. This review analyzes key mechanisms of glial dysfunction, such as the shift toward aerobic glycolysis (the Warburg effect), mitochondrial disturbances, and generation of reactive oxygen species. These processes are regulated by the Wnt/GSK3β and mTOR signaling cascades, forming a vicious cycle of energy deficit, NLRP3 inflammasome activation, and excitotoxicity. Particular attention is given to strategies for correcting glial metabolism. The greatest therapeutic interest lies in systemic approaches that correct metabolism (ketogenic diet, GLP-1 and PPAR receptor agonists) and high-precision technologies for selective modulation of glial functions (RNA therapy, nanodelivery). Targeted intervention in glial metabolism opens ways to the development of anti-epileptogenic drugs capable of modifying the disease course rather than merely alleviating the symptoms. However, translation of these approaches into clinical practice requires clarification of therapeutic windows for the intervention and development of biomarkers of glial status.