Diosgenin promoted OPCs differentiation via blocking GLUR2/GAPDH interaction in a pilocarpine rat model of epilepsy.

Background: Central nervous system (CNS) demyelination is associated with the occurrence of epileptic seizure, highlighting the imperative need for myelin repair strategy. Inefficient differentiation of naïve oligodendrocyte precursor cells (OPCs) into myelin-producing oligodendrocytes (OLs) is an essential pathological obstacle and a therapeutic target of myelin sheath repair.

Purpose: Our work discovers that diosgenin, a natural steroid sapogenin, distinct from its classic cardioprotective effects, directly stimulates OPCs maturation predominantly in the corpus callosum, assuring CNS myelin recovery.

Methods: To study the action of diosgenin on CNS myelin repair, we developed a pilocarpine mouse model of epilepsy and an in vitro seizure model. Co-immunoprecipitation (Co-IP), ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), cellular thermal shift assay (CETSA) and molecular docking map were employed to clarify the target and underlying mechanism of diosgenin on myelin repair promotion.

Results: Diosgenin greatly fostered OPCs differentiation in the corpus callosum. Of note, this action of diosgenin on OPCs was via targeting and stabilizing 122∼221 amino acid residues of GLUR2 subunit, thereby disrupted its interaction with GAPDH protein and subsequent GAPDH nucleus translocation in vitro.

Conclusion: Our findings demonstrated that diosgenin acted as a direct GLUR2 ligand, thereby enhanced the intrinsic differentiation capacities of OPCs by blunting GLUR2/GAPDH interaction and highlighted that diosgenin may serve as a promising natural compound for the remission of CNS demyelination in epilepsy condition.