1. Academic Validation
  2. Blockage of TRPV4 Downregulates the Nuclear Factor-Kappa B Signaling Pathway to Inhibit Inflammatory Responses and Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus

Blockage of TRPV4 Downregulates the Nuclear Factor-Kappa B Signaling Pathway to Inhibit Inflammatory Responses and Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus

  • Cell Mol Neurobiol. 2022 Jul 15. doi: 10.1007/s10571-022-01249-w.
Dong An 1 2 Xiuting Qi 1 Kunpeng Li 1 Weixing Xu 1 Yue Wang 1 Xi Chen 1 Sha Sha 1 Chunfeng Wu 3 Yimei Du 4 5 Lei Chen 6
Affiliations

Affiliations

  • 1 Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China.
  • 2 Center for Analysis and Testing, Nanjing Medical University, Nanjing, People's Republic of China.
  • 3 Department of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
  • 4 Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. yimeidu@mail.hust.edu.cn.
  • 5 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. yimeidu@mail.hust.edu.cn.
  • 6 Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China. chenl@njmu.edu.cn.
Abstract

The blockage of transient receptor potential vanilloid 4 (TRPV4) inhibits inflammation and reduces hippocampal neuronal injury in a pilocarpine-induced mouse model of temporal lobe epilepsy. However, the underlying mechanisms remain largely unclear. NF-κB signaling pathway is responsible for the inflammation and neuronal injury during epilepsy. Here, we explored whether TRPV4 blockage could affect the NF-κB pathway in mice with pilocarpine-induced status epilepticus (PISE). Application of a TRPV4 antagonist markedly attenuated the PISE-induced increase in hippocampal HMGB1, TLR4, phospho (p)-IκK (p-IκK), and p-IκBα protein levels, as well as those of cytoplasmic p-NF-κB p65 (p-p65) and nuclear NF-κB p65 and p50; in contrast, the application of GSK1016790A, a TRPV4 agonist, showed similar changes to PISE mice. Administration of the TLR4 Antagonist TAK-242 or the NF-κB pathway inhibitor BAY 11-7082 led to a noticeable reduction in the hippocampal protein levels of cleaved IL-1β, IL-6 and TNF, as well as those of cytoplasmic p-p65 and nuclear p65 and p50 in GSK1016790A-injected mice. Finally, administration of either TAK-242 or BAY 11-7082 greatly increased neuronal survival in hippocampal CA1 and CA2/3 regions in GSK1016790A-injected mice. Therefore, TRPV4 activation increases HMGB1 and TLR4 expression, leading to IκK and IκBα phosphorylation and, consequently, NF-κB activation and nuclear translocation. The resulting increase in pro-inflammatory cytokine production is responsible for TRPV4 activation-induced neuronal injury. We conclude that blocking TRPV4 can downregulate HMGB1/TLR4/IκK/κBα/NF-κB signaling following PISE onset, an effect that may underlie the anti-inflammatory response and neuroprotective ability of TRPV4 blockage in mice with PISE.

Keywords

Inflammatory cytokines; NF-κB signaling pathway; Neuronal injury; Temporal lobe epilepsy; Transient receptor potential vanilloid 4 (TRPV4).

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