Peptyd pochodzący z apoptyny łagodzi padaczkę płata skroniowego przez ograniczenie przeciążenia wapniem w neuronach poprzez szlak HSPA1A-AP2B1

AIMS: To determine whether the apoptin-derived peptide (also named B9) reduces evoked seizure susceptibility and kainic acid (KA)-associated cognitive and molecular abnormalities, and to define whether these effects involve the heat shock protein family A member 1A (HSPA1A)-adaptor protein complex 2 subunit beta 1 (AP2B1) pathway. METHODS: The therapeutic efficacy of B9 was examined in a pentylenetetrazol (PTZ)-induced acute seizure model and a KA-induced temporal lobe epilepsy (TLE) model. Electroencephalographic (EEG) recordings were performed to evaluate epileptiform activity. The Barnes maze test was used to assess cognitive function in epileptic mice. Western blotting, co-immunoprecipitation (Co-IP), immunofluorescence (IF), and calcium imaging were used to investigate the underlying mechanism. RESULTS: B9 reduced seizure susceptibility, attenuated epileptiform activity, and improved spatial learning and memory. HSPA1A was markedly upregulated in TLE-related datasets and experimental models. B9 suppressed the expression of HSPA1A and disrupted its interaction with AP2B1, which restored O-linked β-N-acetylglucosamine (O-GlcNAc) modification and protein stability of AP2B1, preserved GluA2 expression, and limited neuronal Ca overload. Knockdown of AP2B1 abolished the effects of B9 on evoked seizure susceptibility, cognitive performance, GluA2 abundance, and neuronal Ca overload, whereas AP2B1 overexpression reproduced the reductions in PTZ-evoked seizure susceptibility and EEG activity observed with B9. CONCLUSION: B9 reduces PTZ-evoked seizure susceptibility and ameliorates KA-associated cognitive and molecular abnormalities through modulation of the HSPA1A-AP2B1 axis. These findings support B9 as a potential therapeutic strategy for TLE.