Therapeutic hypothermia is a potential protective strategy after stroke. The present study evaluated the neurovascular protective potential of pharmacological hypothermia induced by the neurotensin receptor 1 agonist HPI-201 after severe ischemic stroke. Adult C57BL/6 mice were subjected to filament insertion-induced occlusion of the middle cerebral artery (60 min MCAO). HPI-201 was i.p. injected 120 min after the onset of MCAO to initiate and maintain the body temperature at 32-33°C for 6 hrs. The infarct volume, cell death, integrity of the blood brain barrier (BBB) and neurovascular unit (NVU), inflammation, and functional outcomes were evaluated. The hypothermic treatment significantly suppressed the infarct volume and neuronal cell death, accompanied with reduced caspase-3 activation and BAX expression while Bcl-2 increased in the peri-infarct region. The cellular integrity of the BBB and NVU was significantly improved and brain edema was attenuated in HPI-201-treated mice compared to stroke controls. The hypothermic treatment decreased the expression of inflammatory factors including tumor necrosis factor-α (TNF-α), MMP-9, interleukin-1β (IL-1β), the M1 microglia markers IL-12 and inducible nitric oxide synthase (iNOS), while increased the M2 marker arginase-1 (Arg-1). Stroke mice received the hypothermic treatment showed lower neurological severity score (NSS), performed significantly better in functional tests, the mortality rate in the hypothermic group was noticeably lower compared with stroke controls. Taken together, HPI-201 induced pharmacological hypothermia is protective for different neurovascular cells after a severely injured brain, mediated by multiple mechanisms.

中文翻译：

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小鼠短暂性大脑中动脉闭塞严重中风后药理学低温诱导的神经血管保护。

治疗性低温是中风后潜在的保护策略。本研究评估了严重缺血性中风后由神经降压素受体 1 激动剂 HPI-201 诱导的药理学低温的神经血管保护潜力。成年 C57BL/6 小鼠接受长丝插入诱导的大脑中动脉闭塞（60 分钟 MCAO）。HPI-201 在 MCAO 开始后 120 分钟 ip 注射，以启动和维持体温在 32-33°C 6 小时。评估了梗死体积、细胞死亡、血脑屏障 (BBB) 和神经血管单元 (NVU) 的完整性、炎症和功能结果。低温治疗显着抑制了梗死体积和神经元细胞死亡，伴随着 caspase-3 激活和 BAX 表达的减少，而 Bcl-2 在梗塞周围区域增加。与中风对照组相比，HPI-201 治疗小鼠的 BBB 和 NVU 的细胞完整性得到显着改善，脑水肿减轻。低温治疗降低了炎症因子的表达，包括肿瘤坏死因子-α (TNF-α)、MMP-9、白细胞介素-1β (IL-1β)、M1 小胶质细胞标志物 IL-12 和诱导型一氧化氮合酶 (iNOS)，同时增加 M2 标记精氨酸酶-1 (Arg-1)。接受低温治疗的中风小鼠表现出较低的神经严重程度评分 (NSS)，在功能测试中表现明显更好，与中风对照组相比，低温组的死亡率明显较低。综合起来，