Inhibition of intracellular proton-sensitive Ca^(2+)-permeable TRPV3 channels protects against ischemic brain injury

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 Ca^(2+)-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.

Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia-reperfusion injury

Systematic administration of anti-inflammatory cytokine interleukin 4(IL-4)has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown.Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-repertusion(I/R)injury.In multi-electrode array(MEA)recordings,IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons.IL-4 mRNA and protein expressions are upregulated after I/R injury.Genetic deletion of 11-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation(OGD)injury in cortical neurons.Conversely,supplemental IL-4 protects 11-4-/-cortical neurons against OGD injury.Mechanistically,cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4-/-mice.Furthermore,upregulation of Nav1.1 channel,and downregulations of KCa3.1 channel and a6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4-/-mice.Taken together,our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury,thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.