{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T20:02:10Z","timestamp":1781726530535,"version":"3.54.5"},"reference-count":137,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2024-548"],"award-info":[{"award-number":["075-15-2024-548"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Temporal lobe epilepsy (TLE) remains pharmacoresistant in 30\u201340% of patients. Peroxisome proliferator-activated receptor alpha (PPAR\u03b1) agonists like fenofibrate exhibit anti-inflammatory and neuroprotective properties, but their region-specific effects during epileptogenesis and on behavioral comorbidities are unknown. We investigated fenofibrate (100 mg\/kg, 7 days) in the lithium-pilocarpine rat model during the latent phase. Fenofibrate (1) reduced anxiety-like behaviors and improved exploratory deficits; (2) decreased plasma short-chain fatty acids (butyric, pentanoic, hexanoic acids); (3) exerted region-specific modulation of glutamate receptors: restored N-methyl-D-aspartate receptor (NMDAR)\/\u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit gene expression in temporal cortex but failed to reverse and further exacerbated the downregulation of AMPAR subunits in the dorsal hippocampus; (4) prevented the upregulation of cortical neuroinflammation markers (reduced Nlrp3, Il1rn); and (5) enhanced the A2 astrocyte marker Ptx3 in the hippocampus while reducing the M2 microglial marker Arg1 in the temporal cortex. No effects on astrogliosis (Gfap), microgliosis (Aif1), or trophic factors (Bdnf, Tgfb1) were observed. This first comprehensive study demonstrates that fenofibrate differentially modulates neuroinflammation and synaptic plasticity across brain regions during epileptogenesis, providing behavioral benefits but highlighting potential hippocampal drawbacks. Its PPAR\u03b1-mediated actions support further investigation as a complementary strategy for TLE, pending optimization of dosing\/timing to mitigate regional disparities.<\/jats:p>","DOI":"10.3390\/ijms26189054","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T14:10:19Z","timestamp":1758118219000},"page":"9054","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Fenofibrate as a PPAR\u03b1 Agonist Modulates Neuroinflammation and Glutamate Receptors in a Rat Model of Temporal Lobe Epilepsy: Region-Specific Effects and Behavioral Outcomes"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3790-2396","authenticated-orcid":false,"given":"Anna A.","family":"Kovalenko","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria V.","family":"Zakharova","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga E.","family":"Zubareva","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-1397","authenticated-orcid":false,"given":"Alexander P.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9731-6399","authenticated-orcid":false,"given":"Yury A.","family":"Skorik","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint Petersburg, Russia"},{"name":"Almazov National Medical Research Centre, 197341 Saint Petersburg, Russia"},{"name":"Branch of Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre \u00abKurchatov Institute\u00bb\u2014Institute of Macromolecular Compounds, 199004 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4503-0647","authenticated-orcid":false,"given":"Aleksey V.","family":"Zaitsev","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.amjmed.2021.01.038","article-title":"Epilepsy: A Clinical Overview","volume":"134","author":"Milligan","year":"2021","journal-title":"Am. J. 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