TPPU protects against seizures and seizure-associated comorbidities by inhibiting the Akt/mTOR signaling pathway in KA-induced convulsant mice.

Abstract

Shared pathophysiological mechanisms exist between epilepsy and its associated comorbidities, with neuroinflammation playing a key role. 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a soluble epoxide hydrolase (sEH) inhibitor that exhibits potent, broad-spectrum anti-inflammatory effects by preventing the hydrolysis of epoxyeicosatrienoic acids (EETs). However, the potential anti-epileptic and comorbidity-alleviating effects of TPPU, along with the underlying molecular mechanisms, remain to be elucidated. Electroencephalogram (EEG) recordings and Racine score were used to monitor seizures. Behavioral tests were employed to assess seizure-associated cognitive and anxiety-like comorbidities in mice. Whole-cell patch-clamp recordings were used to evaluate synaptic function. RNA-sequencing was conducted to elucidate the molecular mechanisms underlying the neuroprotective effects of TPPU in the KA-induced chronic epileptic model. Behavioral assessments, EEG monitoring, and whole-cell patch-clamp recordings revealed that TPPU significantly mitigated seizure severity and anxiety/depressive-like behaviors, and enhanced cognitive function in kainic acid (KA)-induced chronic epileptic mice. TPPU exhibited neuroprotective properties by reducing neuronal apoptosis and neuroinflammation. Bulk RNA-sequencing analysis indicated that TPPU protected against neuroinflammation during epileptogenesis. Mechanistic investigations revealed that TPPU suppresses Akt/mTOR pathway activation. Our findings establish the Akt/mTOR axis as a critical pathway mediating the protective actions of TPPU against epilepsy and its comorbidities in murine models. This work not only advances our understanding of epilepsy pathophysiology but also identifies novel targets for the development of comprehensive therapeutic strategies.