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<p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年5月3日

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  • Qian Feng,
  • Ying Li,
  • Xiangru Wen,
  • Hui Li,
  • Chengyu Qi,
  • Nan Wang,
  • Guang Zhu,
  • Yanyan Fu,
  • Changdong Liu,
  • Dan Liu,
  • Zhen Zhang,
  • Fan Yang,
  • Zhongyuan Zhou,
  • Jinjin Song,
  • Jia Liang,
  • Yuling Chen,
  • Xiaoyan Zhou,
  • Yan Liu,
  • Yuanjian Song

摘要

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.

Graphical Abstract