Ethnopharmacological relevance: Posttraumatic epilepsy (PTE) is an acquired epilepsy caused by traumatic brain injury (TBI). From Mesopotamian civilization to Eastern medical classics, the use of Cannabis for anticonvulsant purposes has spanned three millennia of medical history. As a non-psychoactive plant extract of Cannabis, cannabidiol (CBD) has attracted considerable attention in epilepsy-related treatment. However, whether CBD exhibits an anticonvulsant effect against PTE and its underlying molecular mechanisms remains to be elucidated.

Aim of the study: This study aims to investigate the anticonvulsant and neuroprotective effect of CBD on PTE, as well as its molecular mechanisms.

Methods: Ferric chloride (FeCl₃)-induced PTE rat models were constructed in normal rats and brain-localized transient receptor potential vanilloid type 1 (TRPV1) overexpression rats. The anticonvulsant effects of CBD were evaluated by epileptic behavioral scoring and electroencephalogram (EEG) monitoring. The neuroprotective effect was measured by histopathological staining of the brain tissues. Immunofluorescence, western blot, q-PCR and Ca²⁺ fluorescence intensity detection were employed to investigate the mechanisms of CBD on PTE rats.

Results: CBD significantly reduced the seizure severity and brain damage in FeCl₃-induced PTE rat models. Besides, EEG data showed decreased amplitude, total power, and spike wave discharges in PTE rats pretreated with CBD. Moreover, CBD suppressed the phosphorylation of heat shock factor 1 (HSF1) by targeting TRPV1, thereby specifically inhibiting the stress-induced heat shock protein 70 (HSP70) increase in the brain-localized TRPV1 overexpression rats.

Conclusion: CBD exerts an anticonvulsant and neuroprotective effect on PTE rats by regulating the TRPV1/HSF1/HSP70 pathway and may be a potential drug for the prophylactic treatment of PTE.