Dose-Dependent Effects of Myo-Inositol on Kainic Acid-Induced Epilepsy: Electrophysiological, Behavioral, Transcriptomic, and DNA Methylome Studies.

Epilepsy is a prevalent neurological disorder characterized by spontaneous recurrent seizures (SRS). Epileptogenesis is a multifaceted pathophysiological process that transforms a normal brain into one prone to chronic seizures. Targeting epileptogenesis is a compelling line of epilepsy therapy. Thus, discovering new drugs that oppose, mitigate, or modify epileptogenesis is a significant challenge in modern neuroscience. Our previous work demonstrated that, in a kainic acid (KA)-induced post-status epilepticus model, 28 days myo-inositol (MI) treatment reduces frequency and duration of motor and electrographic SRS even following cessation of treatment, for the following 4 weeks and identified MI as a promising antiepileptogenic compound To further evaluate the dose-dependent efficacy of MI, we applied the same experimental model using 30 mg/kg (dose used in earlier studies), 60 mg/kg, and 120 mg/kg to assess effects on hippocampal electrographic and motor SRS, as well as KA-induced spatial learning and memory impairment in a Morris water maze test. We found that MI had long-lasting, dose-dependent suppressive effects on behavioral and electrographic manifestations of epileptogenesis and ameliorated spatial learning and memory deficit induced by SE, with 60 mg/kg emerging as the most effective dose. Furthermore, we investigated transcriptomic and epigenetic alterations associated with the optimal MI dose and identified multiple affected pathways in the hippocampus. Interestingly, MI treatment resulted in transcriptomic upregulation and prevention of downregulation of several ion channel subunits, including GRIK3 and GRIN3A (kainate and NMDA receptor subunits) and the sodium channel subunit SCNB4. The obtained data highlight new molecular targets for epilepsy therapy and support the translational potential of MI.