TAT-T407 Mitigates Apoptosis and Cognitive Impairments Following Cerebral Ischemia Through Disruption of TRPV1-CDK5...

Cerebral ischemia/reperfusion (I/R) injury manifests as progressive motor and cognitive dysfunction, primarily attributed to neuronal apoptosis. However, there is a lack of neuroprotective drugs targeting neuronal apoptosis in ischemic stroke. In this study, utilizing bioinformatics analysis, we hypothesized that TRPV1 could serve as a novel molecular target implicated in neuronal apoptosis during cerebral ischemia/reperfusion (I/R) injury. To validate our hypothesis in vivo, we employed mouse models of I/R injury induced by transient middle cerebral artery occlusion (tMCAO). Importantly, pre-injecting capsazepine (CPZ), a TRPV1 antagonist, significantly suppressed apoptotic pathway activity in neurons. Additionally, we investigated the regulatory role of CDK5, a well-known neuronal-specific kinase, in modulating the internalization and functionality of TRPV1 ion channels. Our findings revealed an augmented interaction between TRPV1 and CDK5 during cerebral ischemia/reperfusion (I/R) injury. The administration of the TAT-T407 interference peptide, derived from the phosphorylation site of TRPV1 for CDK5, resulted in a reduction of neuronal apoptosis within ischemic regions following cerebral ischemia/reperfusion (I/R) injury. This intervention significantly diminished cerebral infarct volume and improved neurological function. In summary, disrupting the TRPV1/CDK5 interaction through TAT-T407 peptides provides protection against neuronal apoptosis and cognitive decline, suggesting an innovative therapeutic strategy for ischemic stroke treatment.