Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4) Mitigates Seizures.

Abstract

Astrocytes are critical regulators of the immune/inflammatory response in several human central nervous system (CNS) diseases. Emerging evidence suggests that dysfunctional astrocytes are crucial players in seizures. The objective of this study was to investigate the role of transient receptor potential vanilloid 4 (TRPV4) in 4-aminopyridine (4-AP)-induced seizures and the underlying mechanism. We also provide evidence for the role of Yes-associated protein (YAP) in seizures. 4-AP was administered to mice or primary cultured astrocytes. YAP-specific small interfering RNA (siRNA) was administered to primary cultured astrocytes. Mouse brain tissue and surgical specimens from epileptic patient brains were examined, and the results showed that TRPV4 was upregulated, while astrocytes were activated and polarized to the A1 phenotype. The levels of glial fibrillary acidic protein (GFAP), cytokine production, YAP, signal transducer activator of transcription 3 (STAT3), intracellular Ca2+([Ca2+]i) and the third component of complement (C3) were increased in 4-AP-induced mice and astrocytes. Perturbations in the immune microenvironment in the brain were balanced by TRPV4 inhibition or the manipulation of [Ca2+]i in astrocytes. Knocking down YAP with siRNA significantly inhibited 4-AP-induced pathological changes in astrocytes. Our study demonstrated that astrocytic TRPV4 activation promoted neuroinflammation through the TRPV4/Ca2+/YAP/STAT3 signaling pathway in mice with seizures. Astrocyte TRPV4 inhibition attenuated neuroinflammation, reduced neuronal injury, and improved neurobehavioral function. Targeting astrocytic TRPV4 activation may provide a promising therapeutic approach for managing epilepsy.

• Authors: Meng-Liu Zeng, Jing-Jing Cheng, Shuo Kong, Xing-Liang Yang, Xiang-Lei Jia, Xue-Lei Cheng, Ling Chen, Fang-Gang He, Yu-Min Liu, Yuan-Teng Fan, Lanzi Gongga, Tao-Xiang Chen, Wan-Hong Liu, Xiao-Hua He, Bi-Wen Peng
• Journal: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (Neurotherapeutics) Vol. 19 Issue 2 Pg. 660-681 (03 2022) ISSN: 1878-7479 [Electronic] United States
• PMID: 35182379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The American Society for Experimental NeuroTherapeutics, Inc.

Chemical References

• RNA, Small Interfering
• TRPV Cation Channels
• TRPV4 protein, human
• Trpv4 protein, mouse

Topics

• Animals
• Astrocytes (metabolism)
• Humans
• Mice
• Neurons (metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Seizures (chemically induced, genetics, metabolism)
• TRPV Cation Channels (genetics, metabolism)