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.
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Funding
This work was supported by National Natural Science Foundation of China (81971274 and 81571270) to Lei Chen; National Natural Science Foundation of China (82170326 and 81770328) to Yimei Du, Foundation of Nanjing Health Committee (YKK19101) to Chunfeng Wu and Nanjing Medical University Science and Technology Development Project (NMUB20210003) to Dong An.
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LC designed the study and wrote the manuscript. DA, XQ, KL and WX performed the experiments. YW and XC did the data analysis. SS, CW and YD helped to revise the manuscript. All authors approved the manuscript.
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This study was approved by the Ethics Committee of Nanjing Medical University (No. IACUC2009007) and all animal experiments were performed in accordance with the Guidelines for Laboratory Animal Research set by Nanjing Medical University.
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An, D., Qi, X., Li, K. et al. 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 43, 1283–1300 (2023). https://doi.org/10.1007/s10571-022-01249-w
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DOI: https://doi.org/10.1007/s10571-022-01249-w