Thioredoxin-mimetic peptide attenuates epilepsy progression and neurocognitive deficits.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, in which oxidative stress and neuroinflammation play central roles in driving disease progression and pharmacoresistance. Approximately 30-40 % of patients are resistant to current antiseizure medications, which suppress symptoms but do not prevent epilepsy development or modify its progression. There is an urgent need for therapies with true disease-modifying potential. TXM-CB3 (CB3), a thioredoxin-mimetic tripeptide, has been reported to modulate redox and inflammatory pathways. In this study, we evaluated the therapeutic potential of CB3 in preclinical models of temporal lobe epilepsy, focusing on its capacity to suppress seizures, preserve neuronal integrity, and mitigate epilepsy-associated behavioral impairments. We first examined CB3 in an in vitro model of low-Mg(2+)-induced epileptiform activity, where pretreatment with CB3 (50, 100 μM) attenuated oxidative activity and reduced proinflammatory cytokine expression (IL-6, IL-1β, TNF-α), while enhancing IL-10 levels. In vivo, early CB3 intervention (20 mg/kg/day, i.p.) following kainic acid-induced status epilepticus significantly delayed seizure onset, reduced seizure frequency and cumulative burden, and preserved hippocampal neuronal integrity. Treated animals also showed improved locomotor activity, reduced anxiety-like behavior, and better performance in spatial working memory tasks. In established chronic epilepsy, CB3 treatment (20 mg/kg/day, i.p.) produced a sustained reduction in recurrent seizure activity and seizure burden, with additional effects on anxiety-like behavior, though memory and learning deficits remained unchanged. Together, these findings highlight CB3's potential as a disease-modifying therapy. By reducing seizure recurrence, preserving neuronal integrity, and alleviating selected behavioral impairments, CB3 offers therapeutic benefits that extend beyond conventional ASMs and warrants further investigation for translation into clinical epilepsy treatment.