Diabetes is a chronic metabolic disease and cerebral ischemia is a serious complication of diabetes. Anti-diabetic therapy mitigates this complication but increases the risk of exposure to recurrent hypoglycemia (RH). We showed previously that RH exposure increases ischemic brain damage in insulin-treated diabetic (ITD) rats. The present study evaluated the hypothesis that increased intra-ischemic acidosis in RH-exposed ITD rats leads to pronounced post-ischemic hypoperfusion via activation of acid-sensing (proton-gated) ion channels (ASICs). Streptozotocin-diabetic rats treated with insulin were considered ITD rats. ITD rats were exposed to RH for 5 days and were randomized into Psalmotoxin1 (PcTx1, ASIC1a inhibitor), APETx2 (ASIC3 inhibitor), or vehicle groups. Transient global cerebral ischemia was induced overnight after RH. Cerebral blood flow was measured using laser Doppler flowmetry. Ischemic brain injury in hippocampus was evaluated using histopathology. Post-ischemic hypoperfusion in RH-exposed rats was of greater extent than that in control rats. Inhibition of ASICs prevented RH-induced increase in the extent of post-ischemic hypoperfusion and ischemic brain injury. Since ASIC activation-induced store-operated calcium entry (SOCE) plays a role in vascular tone, next we tested if acidosis activates SOCE via activating ASICs in vascular smooth muscle cells (VSMCs). We observed that SOCE in VSMCs at lower pH is ASIC3 dependent. The results show the role of ASIC in post-ischemic hypoperfusion and increased ischemic damage in RH-exposed ITD rats. Understanding the pathways mediating exacerbated ischemic brain injury in RH-exposed ITD rats may help lower diabetic aggravation of ischemic brain damage.

中文翻译：

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酸敏感离子通道的阻断减弱了经治疗的糖尿病大鼠缺血性脑损伤的复发性低血糖诱导的增强作用。

糖尿病是一种慢性代谢性疾病，脑缺血是糖尿病的严重并发症。抗糖尿病治疗可减轻这种并发症，但会增加暴露于复发性低血糖 (RH) 的风险。我们之前表明，RH 暴露会增加胰岛素治疗的糖尿病 (ITD) 大鼠的缺血性脑损伤。本研究评估了这样的假设，即 RH 暴露的 ITD 大鼠缺血性酸中毒增加会通过激活酸敏感（质子门控）离子通道 (ASICs) 导致明显的缺血后低灌注。用胰岛素治疗的链脲佐菌素糖尿病大鼠被认为是 ITD 大鼠。ITD 大鼠暴露于 RH 5 天，并被随机分为 Psalmotoxin1（PcTx1，ASIC1a 抑制剂）、APETx2（ASIC3 抑制剂）或载体组。RH 后一夜之间诱发短暂性全脑缺血。使用激光多普勒血流仪测量脑血流量。使用组织病理学评估海马缺血性脑损伤。暴露于 RH 的大鼠的缺血后灌注不足程度大于对照大鼠。抑制 ASIC 可防止 RH 诱导的缺血后低灌注和缺血性脑损伤程度的增加。由于 ASIC 激活诱导的储存操作钙进入 (SOCE) 在血管张力中起作用，接下来我们测试酸中毒是否通过激活血管平滑肌细胞 (VSMC) 中的 ASIC 来激活 SOCE。我们观察到 VSMC 中较低 pH 值的 SOCE 依赖于 ASIC3。结果显示 ASIC 在 RH 暴露的 ITD 大鼠缺血后灌注不足和缺血性损伤增加中的作用。