There is unmet need for effective stroke therapies. Numerous neuroprotection attempts for acute cerebral ischemia have failed and there is growing interest in developing therapies that widen the treatment initiation window and promote functional recovery through increasing synaptic plasticity. The p38α mitogen-activated protein kinase is an already proven target for acute experimental stroke intervention and was hypothesized to also contribute to neuroinflammation-mediated impairment of recovery during the subacute phase. Neflamapimod, an orally bioavailable, brain-penetrant, potent and selective small molecule p38α inhibitor was evaluated as a subacute phase stroke treatment to promote recovery in this research study. Neflamapimod administration at two clinically relevant dose levels was initiated outside of the previously characterized neuroprotection window of less than 24 hours after stroke for p38α inhibitors to rats after transient middle cerebral artery occlusion. Continuous administration of neflamapimod, starting at 48 hours after reperfusion, significantly improved behavioral outcomes assessed by the modified neurological severity score at four- and six-weeks post stroke in a dose-dependent manner. Neflamapimod also demonstrated beneficial effects on additional measures of sensory and motor function and resulted in a dose-related increase in the terminal brain-derived neurotrophic factor protein level in both the injured and uninjured brain hemisphere. Variable interleukin-1β levels were detected in the injured brain hemisphere at study termination in a subset of the animals within every test group, implying ongoing, chronic inflammation, however, no clear neflamapimod effect on interleukin-1β production was observable. The dose-related in vivo efficacy of neflamapimod offers the possibility of both expanding the window for initiation of therapy after stroke and for improving recovery after a completed stroke. Since neflamapimod is already in mid-stage clinical trials for Alzheimer’s disease and related dementias, the current results make it especially attractive for evaluation in a proof-of- concept clinical trial as therapeutic to promote recovery after ischemic stroke.

中文翻译：

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在大鼠短暂性脑缺血引起的中风后的亚急性期连续施用p38α抑制剂neflamapimod可以促进剂量依赖性功能恢复，并伴随脑BDNF蛋白水平升高

有效的中风疗法没有得到满足。用于急性脑缺血的许多神经保护尝试均失败了，并且人们对开发能够扩大治疗起始窗口并通过增加突触可塑性促进功能恢复的疗法的兴趣日益浓厚。p38α丝裂原激活的蛋白激酶已经被证明是急性实验性卒中干预的靶标，据推测在亚急性期也可导致神经炎症介导的恢复受损。在本研究中，Neflamapimod是一种口服生物可利用的，脑渗透剂，有效且选择性的小分子p38α抑制剂，被评估为亚急性阶段性卒中治疗，以促进其恢复。在短暂的大脑中动脉闭塞后，p38α抑制剂在卒中后不到24小时之前，在先前表征的神经保护窗外开始以两种临床相关剂量的Neflamapimod给药。从再灌注后48小时开始，连续服用neflamapimod可以显着改善行为结果，该结果通过卒中后四周和六周的神经系统严重程度评分得到了改善，并且呈剂量依赖性。Neflamapimod还显示出对其他感觉和运动功能指标的有益作用，并导致受伤和未受伤的大脑半球的终末脑源性神经营养因子蛋白水平呈剂量相关增加。在每个试验组的一部分动物中，研究结束时在受伤的脑半球中检测到了可变的白介素-1β水平，这表明正在进行的慢性炎症，但是，未观察到明确的奈弗拉莫德对白介素-1β产生的影响。剂量相关尼莫拉莫德的体内疗效提供了扩大中风后开始治疗的窗口以及改善中风后恢复的可能性。由于奈非拉莫德已经在阿尔茨海默氏病和相关痴呆的中期临床试验中，因此目前的结果使其在概念验证性临床试验中作为吸引缺血性卒中后恢复的治疗药物特别有吸引力。