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 Ca 2+ ([Ca 2+ ] 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 [Ca 2+ ] 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/Ca 2+ / 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.

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

“…Similarly, TRPA1 and TRPV1, and TRPV4 channels have also been detected in the CNS. This is particularly the case with the high expression of TRPV4 which occurs in astrocytes [ 53 ]. However, the influence of TRPV4 on inflammation tends to be clearer.…”

“…However, the influence of TRPV4 on inflammation tends to be clearer. To the date, it is established that the activation of TRPV4 exacerbates inflammatory responses and triggers neuroinflammation, while TRPV4 inhibitors exert a neuroprotective effect [ 53 , 54 ]. TRPV4 is a nonselective Ca 2+ channel, and its activation results in an increased intracellular Ca 2+ concentration and increased iNOS activity, which leads to the production of pro-inflammatory mediators, such as eicosanoids [ 55 ].…”

Electroacupuncture ameliorates neuroinflammation by inhibiting TRPV4 channel in ischemic stroke

“…Activation of TRPV4 significantly increases neuronal excitability, 36 and enhances neuronal excitability which leads to an increase in extracellular ATP, resulting in targeted motility of microglia 37 . Upregulation of TRPV4 also activates astrocytes, 29 and activated astrocytes can promote microglial activation and modulate their functions. Conversely, the activated microglia can also stimulate the activation of astrocytes 38,39 .…”

Blockade of Kv1.3 Potassium Channel Inhibits Microglia-Mediated Neuroinflammation in Epilepsy

“…Activated neuroinflammatory microglia induced A1 neurotoxic astrocytes through secreting IL-1α, TNF, and C1q [ 50 ]. It was reported that A1 astrocytes promoted the progression of epilepsy [ 51 ]. Whether blockade of Kv1.3 regulated the phenotypic transition of astrocytes via microglia is an interesting research direction.…”

“…The total protein concentration was quantified using a BCA protein assay (Beyotime Biotechnology, Shanghai, China). The detailed western blot procedure was previously described [ 51 ]. Finally, the fluorescence signal was determined by super Western blot ECL substrates (PUMOKE, Wuhan, China).…”