The MID1IP1/S100A10-mGluR5 Axis in Seizures: Immune-Metabolic Crosstalk and Enhanced Therapeutic Efficacy of Benfotiamine/Phenytoin Combination.

Authors

Sijun Li, Muhua Zhou, Xing Wei, Yingying Cao, Xibao Luo, Dongmei Li, Baoren Kang, Xiaojuan Wang, Kunmei He, Junrui He, Yuan Lv

Published in

Current neuropharmacology. Jul 26, 2026. Epub Jul 26, 2026.

Abstract

Epilepsy, characterized by recurrent seizures, is associated with dysregu-lated Fatty Acid (FA) metabolism and metabotropic glutamate receptor 5 (mGluR5) signaling. However, the contribution of FA metabolism-related molecules (FAMs) to these pathological pro-cesses remains poorly characterized.
Integrated bioinformatics was conducted to identify epilepsy-associated FAMs. Next, machine learning algorithms identified midline 1 interacting protein 1 (MID1IP1) and S100 calcium-binding protein A10 (S100A10) as key targets. These findings were validated through immune cell correlation analysis, in vitro seizure models (using magnesium-free cultured neurons), in vivo seizure induction (using pentylenetetrazol), and network pharmacology-based drug screening.
MID1IP1 expression showed significant negative correlations with markers of adaptive immune cells but positive correlations with markers of innate immune populations. S100A10 exhib-ited distinct yet complementary immune-interaction patterns. MID1IP1/S100A10 upregulation was associated with increased mGluR5 expression and neuronal hyperexcitability. Genetic inhibition of this pathway attenuated seizure activity. Benfotiamine (BFT) improved neuronal survival but demonstrated limited anticonvulsant effects. Phenytoin (PHT) effectively controlled seizures but in-duced neuronal toxicity at higher doses. The combination of BFT and PHT further enhanced neuro-protection, reduced seizure severity, and potently downregulated the MID1IP1/S100A10/mGluR5 pathway compared with either agent alone.
These findings identify the MID1IP1/S100A10-mGluR5 axis as a critical mediator of metabolic-immune crosstalk in seizure pathogenesis. The complementary targeting of this pathway by BFT and PHT offers a promising strategy to enhance antiseizure efficacy while mitigating PHT-induced neurotoxicity, warranting further investigation in drug-resistant epilepsy models.
The MID1IP1/S100A10-mGluR5 axis drives seizure pathogenesis through metabolic-immune crosstalk. BFT and PHT target complementary nodes of this pathway, demonstrating enhanced efficacy in preclinical models.

PMID:
42522649
Bibliographic data and abstract were imported from PubMed on 29 Jul 2026.

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