Abstract
Extracellular acidification in the brain has been observed in ischemia; however, the physiological and pathophysiological implications of the pH reduction remain largely unknown. Here, we analyzed the roles of proton-sensing G protein-coupled receptors, including T-cell death-associated gene 8 (TDAG8), ovarian cancer G protein-coupled receptor 1 (OGR1), and G protein-coupled receptor 4 (GPR4) in a mouse ischemia reperfusion model. Cerebral infarction and dysfunctional behavior with transient middle cerebral artery occlusion (tMCAO) and subsequent reperfusion were exacerbated by the deficiency of TDAG8, whereas no significant effect was observed with the deficiency of OGR1 or GPR4. We confirmed that the pH of the predicted infarction region was 6.5. TDAG8 mRNA was observed in Iba1-positive microglia in the mouse brain. The tMCAO increased the mRNA expression of tumor necrosis factor-α in the ipsilateral cerebral hemisphere and evoked morphological changes in microglia in an evolving cerebral injury. These tMCAO-induced actions were significantly enhanced by the TDAG8 deficiency. Administration of minocycline, which is known to inhibit microglial activation, improved the cerebral infarction and dysfunctional behavior induced by tMCAO in the TDAG8-deficient mouse. Thus, acidic pH/TDAG8 protects against cerebral infarction caused by tMCAO, at least due to the mechanism involving the inhibition of microglial functions.
Highlights
Extracellular acidification in the brain has been observed in ischemia; the physiological and pathophysiological implications of the pH reduction remain largely unknown
Among protonsensing G proteincoupled receptors (GPCRs), T-cell death-associated gene 8 (TDAG8) expression in the ipsilateral hemisphere was significantly higher than in the contralateral hemisphere, which was associated with an increase in the mRNA expression of Iba[1] and glial fibrillary acidic protein (GFAP), after the induction of transient middle cerebral artery occlusion (tMCAO) for 0.5 h and subsequent reperfusion for 24 h
In addition to ion channels, the brain expresses an abundant level of proton-sensing GPCRs, including TDAG8, ovarian cancer G protein-coupled receptor 1 (OGR1), and G protein-coupled receptor 4 (GPR4), which sense an acidic pH of higher than 6 5,6
Summary
Extracellular acidification in the brain has been observed in ischemia; the physiological and pathophysiological implications of the pH reduction remain largely unknown. The tMCAO increased the mRNA expression of tumor necrosis factor-α in the ipsilateral cerebral hemisphere and evoked morphological changes in microglia in an evolving cerebral injury. These tMCAO-induced actions were significantly enhanced by the TDAG8 deficiency. IL-1 and TNF-α are known to play a causal role in their n eurodegeneration[17,18,24,25,26,27,28,29,30,31] These results suggest the possibility that microglial TDAG8 in response to ischemic acidification might be involved in brain strokes. GPR4 and OGR1 are expressed in cortical neurons isolated from mouse embryo and N1E115 neuronal c ells[6,16,32,33] and are potential receptors to regulate cellular events in response to brain acidosis
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