Inhibition of intracellular proton-sensitive Ca2+-permeable TRPV3 channels protects against ischemic brain injury.
10.1016/j.apsb.2022.01.001
- Author:
Xiaoling CHEN
1
;
Jingliang ZHANG
1
;
KeWei WANG
2
Author Information
1. Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
2. Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266021, China.
- Publication Type:Journal Article
- Keywords:
Acidosis;
Ca2+ influx;
Cerebral ischemia/reperfusion injury;
Excitotoxicity;
Forsythoside B;
Neural excitability;
OGD;
TRP;
TRPV3;
tMACO
- From:
Acta Pharmaceutica Sinica B
2022;12(5):2330-2347
- CountryChina
- Language:English
-
Abstract:
Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-d-aspartate (NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca2+-permeable transient receptor potential vanilloid 3 (TRPV3) channel protects against cerebral ischemia/reperfusion (I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion (tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.
