Activation of acid-sensing ion channel 1a (ASIC1a) plays a major role in mediating acidosis-induced neuronal injury following a stroke. Therefore, the inhibition of ASIC1a is a potential therapeutic avenue for the treatment of stroke. Venom-peptide Hi1a, a selective and highly potent ASIC1a inhibitor, reduces the infarct size and functional deficits when injected into the brain after stroke in rodents. However, its efficacy when administered using a clinically relevant route of administration remains to be established. Therefore, the current investigation aims to examine the efficacy of systemically administered Hi1a, using two different models of stroke in different species. Mice were subjected to the filament model of middle cerebral artery occlusion (MCAO) and treated with Hi1a systemically using either a single- or multiple-dosing regimen. 24 h poststroke, mice underwent functional testing, and the brain infarct size was assessed. Rats were subjected to endothelin-1 (ET-1)-induced MCAO and treated with Hi1a intravenously 2 h poststroke. Rats underwent functional tests prior to and for 3 days poststroke, when infarct volume was assessed. Mice receiving Hi1a did not show any improvements in functional outcomes, despite a trend toward reduced infarct size. This trend for reduced infarct size in mice was consistent regardless of the dosing regimen. There was also a trend toward lower infarct size in rats treated with Hi1a. More specifically, Hi1a reduced the amount of damage occurring within the somatosensory cortex, which was associated with an improved sensorimotor function in Hi1a-treated rats. Thus, this study suggests that Hi1a or more brain-permeable ASIC1a inhibitors are a potential stroke treatment.

中文翻译：

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Hi1a 可改善内皮素 1 诱发的大鼠中风后的感觉运动缺陷，但不会改善细丝诱发的小鼠中风后的功能结果

酸敏感离子通道 1a (ASIC1a) 的激活在介导中风后酸中毒引起的神经元损伤中发挥着重要作用。因此，抑制ASIC1a是治疗中风的潜在治疗途径。毒液肽 Hi1a 是一种选择性且高效的 ASIC1a 抑制剂，在啮齿动物中风后注射到大脑中可减少梗死面积和功能缺陷。然而，当使用临床相关的给药途径给药时其功效仍有待确定。因此，当前的研究旨在使用不同物种的两种不同中风模型来检查系统施用 Hi1a 的功效。小鼠接受大脑中动脉闭塞 (MCAO) 的细丝模型，并使用单剂量或多剂量方案全身接受 Hi1a 治疗。中风后 24 小时，对小鼠进行功能测试，并评估脑梗塞面积。大鼠接受内皮素 1 (ET-1) 诱导的 MCAO，并在中风后 2 小时静脉注射 Hi1a 治疗。大鼠在中风前和中风后 3 天接受功能测试，评估梗塞体积。尽管梗塞面积有缩小的趋势，但接受 Hi1a 治疗的小鼠并未表现出功能结果的任何改善。无论给药方案如何，小鼠梗塞面积减少的趋势都是一致的。使用 Hi1a 治疗的大鼠还存在梗塞面积减小的趋势。更具体地说，Hi1a 减少了体感皮层内发生的损伤量，这与 Hi1a 治疗大鼠的感觉运动功能改善有关。因此，这项研究表明 Hi1a 或更具脑渗透性的 ASIC1a 抑制剂是一种潜在的中风治疗方法。