TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice

Wang, Zhouqing; Zhou, Li; An, Dong Sung; Xu, Weixing; Wu, Chunfeng; Sha, Sha; Li, Yingchun; Zhu, Yazhou; Chen, Aidong; Du, Yumin; Chen, Lei; Chen, Ling

doi:10.1038/s41419-019-1612-3

Cited by 110 publications

(96 citation statements)

References 43 publications

(79 reference statements)

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“…TRPV4 agonist-induced neuronal cell death in hippocampal CA1 was inhibited by treatment with ROS scavengers such as Trolox or ARL-17477. In a recent report, TRPV4 enhanced neuronal inflammatory responses and proinflammatory cytokine release (Figure 2F; Wang et al, 2019). GSK1016790A-injected mice also showed increased levels of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 and showed TRPV4-mediated microglial and astrocyte activation.…”

Section: Trpv4supporting

confidence: 51%

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

et al. 2020

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The development of treatment for neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is facing medical challenges due to the increasingly aging population. However, some pharmaceutical companies have ceased the development of therapeutics for NDs, and no new treatments for NDs have been established during the last decade. The relationship between ND pathogenesis and risk factors has not been completely elucidated. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where oxidative stress and disrupted Ca 2+ homeostasis consequently lead to neuronal apoptosis. Reactive oxygen species (ROS) -sensitive TRP channels can be key risk factors as polymodal sensors, since progressive late onset with secondary pathological damage after initial toxic insult is one of the typical characteristics of NDs. Recent evidence indicates that the dysregulation of TRP channels is a missing link between disruption of Ca 2+ homeostasis and neuronal loss in NDs. In this review, we discuss the latest findings regarding TRP channels to provide insights into the research and quests for alternative therapeutic candidates for NDs. As the structures of TRP channels have recently been revealed by cryo-electron microscopy, it is necessary to develop new TRP channel antagonists and reevaluate existing drugs.

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Section: Trpv4supporting

confidence: 51%

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

et al. 2020

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“…Blockage of TRPV4 could inhibit hyperthermia-induced seizures in the larval zebra sh forebrain [23]. Application of TRPV4 antagonists markedly attenuated the neuronal death after the induction of status epilepticus [22]. These results indicate an involvement of TRPV4 in the pathogenesis of epilepsy.…”

Section: Introductionmentioning

confidence: 76%

“…After 30 min, pilocarpine (300 mg/kg, ip.) was injected to induce status epilepticus (SE) [21,22]. Seizure behavioural severity was rated using the Racine scale, as follows: category 1, immobility and facial twitch; category 2, head nodding; category 3, forelimb clonus; category 4, rearing; and category 5, rearing and falling.…”

Section: Pise Preparationmentioning

confidence: 99%

“…(1 µM/mouse) or HC-067047 (10 µM/mouse) was injected once daily for 3 consecutive days. To block TRPV4 in PISE mice, HC-067047 was injected 1 h after SE was terminated and then injected once daily for 3 d. The doses of GSK1016790A and HC-067047 were chosen as reported previously [21,22]. Control mice were administered an equal volume of vehicle.…”

Section: Drug Treatmentmentioning

confidence: 99%

“…Kv1.2 was signi cantly downregulated in autosomal dominant lateral temporal epilepsy [20]. In recent studies, the involvement of TRPV4 in the pathogenesis of epilepsy has been reported [21,22]. TRPV4 expression was found to be increased by pilocarpine-induced status epilepticus (PISE) [21].…”

Section: Introductionmentioning

confidence: 99%

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Effect of transient receptor potential vanilloid 4 activation on the delayed rectifier potassium current in the hippocampal pyramidal neurons and Kv subunit expression in the hippocampi of mice

Zhou

et al. 2020

Preprint

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Activation of transient receptor potential vanilloid 4 (TRPV4) can increase hippocampal neuronal excitability. Recent studies have reported that TRPV4 may be involved in the pathogenesis of epilepsy. Voltage-gated potassium channels (VGPCs) play an important role in regulating neuronal excitability and abnormal VGPCs expression or function is related to epilepsy. Activation of TRPV4 can modulate ion channels, but whether activation of it could modulate VGPCs in hippocampal neurons remains unknown. Here we examined the effect of TRPV4 activation on the delayed rectifier potassium current (IK) in the hippocampal pyramidal neurons and on the Kv subunits expression. We also explored the role of TRPV4 in changes in Kv subunits expression in mice following pilocarpine-induced status epilepticus (PISE). Application of TRPV4 agonists, GSK1016790A and 5,6-EET, markedly reduced IK in the hippocampal pyramidal neurons, shifted the voltage-dependent inactivation curve to the hyperpolarization direction, and had no effect on the voltage-dependent activation curve. GSK1016790A- and 5,6-EET-induced inhibition of IK was blocked by TRPV4 specific antagonists, HC-067047 and RN1734. GSK1016790A-induced inhibition of IK was markedly attenuated by calcium/calmodulin-dependent kinase II (CaMKII) antagonist, but was not affected by protein kinase C or protein kinase A antagonists. Application of GSK1016790A for up to 1 h did not change the hippocampal protein levels of Kv1.1, Kv1.2, or Kv2.1. Intracerebroventricular injection of GSK1016790A for 3 d reduced the hippocampal protein levels of Kv1.2 and Kv2.1, leaving that of Kv1.1 unchanged. Kv1.2 and Kv2.1 protein levels were reduced markedly in hippocampi on day 3 post PISE, which was significantly reversed by HC-067047. We conclude that activation of TRPV4 inhibits IK in the hippocampal pyramidal neurons, possibly by activating CaMKII. Persistent activation of TRPV4 decreased Kv1.2 and Kv2.1 expression, which may be associated with the decrease in Kv1.2 and Kv2.1 expression following PISE.

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TRPV4: A trigger of pathological RhoA activation in neurological disease

2022

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Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface-localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease. Supporting this hypothesis is our recent work demonstrating direct physical and bidirectional functional interactions of TRPV4 with RhoA, which can lead to activation of RhoA and reorganization of the actin cytoskeleton.Furthermore, a confluence of evidence implicates TRPV4 and/or RhoA in pathological responses triggered by a range of acute neurological insults ranging from stroke to traumatic injury. While initiated by a variety of insults, TRPV4-RhoA signaling may represent a common pathway that disrupts axonal regeneration and blood-brain barrier integrity. These insights also suggest that TRPV4 inhibition may represent a safe, feasible, and precise therapeutic strategy for limiting pathological TRPV4-RhoA activation in a range of neurological diseases.

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TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice

Cited by 110 publications

References 43 publications

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

Effect of transient receptor potential vanilloid 4 activation on the delayed rectifier potassium current in the hippocampal pyramidal neurons and Kv subunit expression in the hippocampi of mice

TRPV4: A trigger of pathological RhoA activation in neurological disease

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