SVHRSP Attenuates PTZ-Induced Seizure-Like Behavior in C. elegans: Involvement of HSF-1 and Associated Changes in...

Epilepsy is a prevalent neurological disorder. Nevertheless, approximately one-third of patients fail to achieve sufficient seizure control through current pharmacological treatments. This unmet need underscores the importance of developing new antiseizure treatments for drug-resistant epilepsy. Scorpion venom heat-resistant synthetic peptide (SVHRSP), which is derived from scorpion venom and chemically synthesized, has demonstrated promising activity against acute PTZ-evoked seizure-like behaviors. In this study, the effects of SVHRSP pretreatment on acute PTZ-evoked seizure-like behavior were evaluated in Caenorhabditis elegans. Our findings indicate that SVHRSP (50 μM) significantly alleviated the seizure-like behavioral symptoms induced by PTZ (30 mg/mL). Specifically, behavioral assessments showed that SVHRSP improved survival and attenuated PTZ-associated deficits in locomotion, food preference, chemotaxis, and pharyngeal pumping in PTZ-exposed nematodes. Furthermore, SVHRSP pretreatment partially reversed PTZ-associated changes in GABAergic and glutamatergic reporter fluorescence and in the transcript abundance of unc-25, gat-1, and eat-4. SVHRSP also ameliorated mitochondrial dysfunction and reduced oxidative stress. SVHRSP pretreatment was also associated with increased ced-9 transcript abundance, reduced cep-1 transcript abundance, lower intracellular ferrous iron (Fe²⁺) levels, and attenuation of PTZ-associated changes in GABAergic reporter morphology. The attenuation of these SVHRSP-associated changes in hsf-1(sy441) animals supports the involvement of HSF-1-dependent processes; however, direct HSF-1 activation and the downstream causal relationships were not established. These findings show that SVHRSP pretreatment attenuated acute PTZ-evoked seizure-like phenotypes in C. elegans and support further evaluation in mammalian seizure and epilepsy models.