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

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Maria V. Zakharova¹, Anna A. Kovalenko¹, Yuliy A. Gorgul¹, Aleksandr P. Schwarz¹, Olga E. Zubareva¹, Adelia R. Kharisova¹, Georgy P. Diespirov¹, and Aleksey V. Zaitsev^1,a*

¹Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 Saint-Petersburg, Russia

^* To whom correspondence should be addressed.

Received: March 19, 2026; Revised: April 18, 2026; Accepted: April 21, 2026

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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.

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KEY WORDS: astrocytes, microglia, epileptogenesis, neuroinflammation, oxidative stress, glucose metabolism, lactate shuttle

DOI: 10.1134/S0006297926600857

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