Inhibition of transient receptor potential vanilloid‐1 confers neuroprotection, reduces tumor necrosis factor‐alpha, and increases IL‐10 in a rat stroke model

Abstract

Stroke is a major cause of mortality and long-term disability in adults. Transient receptor potential vanilloid-1 (TRPV1) plays a crucial role in neuroinflammation. In this study, the effects of TRPV1 agonist (capsaicin) and antagonist (AMG9810) on cerebral ischemia were investigated. Forty male Wistar rats were assigned to the following experimental groups: sham, vehicle) ischemic), AMG9810 (selective TRPV1 antagonist, 0.5 mg/kg; 3 h after stroke), and capsaicin (1 mg/kg; 3 h after stroke). Stroke was induced by permanent middle cerebral artery occlusion and neurological deficits were evaluated 1, 3, and 7 days after stroke. Then, infarct volume, brain edema, body temperature, mRNA expression of TRPV1, and serum concentrations of tumor necrosis factor-alpha (TNF-α) and IL-10 were measured. Compared to the vehicle group, AMG9810 significantly decreased the infarct volume (P < 0.01). Latency for the removal of sticky labels from the forepaw and the hanging time were significantly decreased and increased, respectively, following administration of AMG9810 (P < 0.01 and P < 0.001 vs. vehicle) 3 and 7 days after stroke. Compared to the sham group, the mRNA expression of TRPV1 was significantly increased in vehicle group (P < 0.01). Administration of AMG9810 significantly increased the anti-inflammatory cytokine IL-10 and decreased the inflammatory cytokine TNF-α (P < 0.05). Moreover, our results indicate that AMG9810 might a promising candidate for the hypothermic treatment of stroke. The findings also suggest a key role for AMG9810 in reducing inflammation after stroke and imply that TRPV1 could be a potential target for the treatment of ischemic stroke.

Advancement in research on the role of the transient receptor potential vanilloid channel in cerebral ischemic injury (Review)

“…TRPV1 promotes activation of astrocytes and the release of astrocyte-derived IL-1β, predominantly via the Janus kinase 2-signal transducer and activator of transcription 3 signaling pathway, and activation of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in hypoxic-ischemic encephalopathy (44). Overall, these comprehensive analyses suggest that the expression of TRPV1 is closely associated with the inflammatory response and that regulation of TRPV1 may reduce the inflammation induced by ischemic injury (42).…”

“…Preventing the inflammatory response is therefore another important approach that is essential for protecting the brain. A previous study demonstrated that TRPV1 inhibition decreased levels of TNF-α and IL-10 in plasma, which reduced infarction size, thus conferring a neuroprotective effect (42). Another study revealed that inhibiting TRPV1 exerted neuroprotection in rats with cerebral IR injury, which was partially associated with TRPV1-mediated antioxidant stress and anti-inflammation due to inhibiting p38 MAPK activation (43).…”

TRPV1 Contributes to Cerebral Malaria Severity and Mortality by Regulating Brain Inflammation

“…Brain swelling results from increased vascular leakage and disruption of the blood brain barrier [8, 9]. TRPV1 activation promotes vasodilation and oedema formation [53, 54]. Then, the contribution of TRPV1 to brain oedema formation was assessed in infected mice.…”

“…Interestingly, IFN γ and TNF α have been linked to cerebral malaria progression by acting on brain endothelial cells, thus promoting their activation and/or apoptosis [67, 68]. Recently, the TRPV1 antagonist AMG9810 was found to confer neuroprotection by attenuating TNF α production in a rodent model of stroke [54]. These evidences and the gathered data allow us to suggest that the diminished cytokine generation by TRPV1KO mice contributes to the diminished brain swelling and damage observed in P. berghei ANKA-infected mice, a response that is associated with a greater ability of these mice to produce higher amounts of oxygen/nitrogen-derived oxidant species which in turn may enhance their capacity of killing this parasite.…”

Preclinical Evidence and Mechanism of Xingnaojing Injection for Cerebral Ischemia: A Systematic Review and Meta-Analysis of Animal Studies

“…Oxidative stress is another reaction after cerebral ischemia, and the function of free radical scavenging system in the body decreased during cerebral ischemia. The endogenous antioxidant systems are unbalanced and produced large amounts of free radicals, leading to the peroxidation of lipid, protein and nucleic acid, and the biochemical alteration (SOD ↓, GSH-Px ↓, and MDA↑), and further led to BBB disruption with secondary vasogenic edema, activation of apoptosis, and brain infarction [47, 48]. Therefore, the production and release of oxygen free radicals are the key steps that cause cerebral injury.…”