A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice
A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice
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DOI：
10.1096/fj.11-201822
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发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
Yu, Shan P.
中科院分区：
文献类型：
--
作者：
Choi, Ko-Eun;Hall, Casey L.;Yu, Shan P.
来自临床前和临床研究的令人信服的证据表明，亚低温对缺血性中风具有神经保护作用。然而，目前的物理降温方法阻碍了低温治疗的临床应用，这种方法在临床情况下通常效率低下且不切实际。在这份报告中，我们证明了新型神经降压素受体1(NTR1)激动剂ABS-201在成年小鼠局灶性脑缺血模型中药物诱导低温(PIH)的可能性。ABS-201(1.5-2.5 mg/kg，ip)以剂量依赖的方式在15-30分钟内将身体和大脑的温度降低2-5摄氏度，而不会引起颤抖或改变生理参数。卒中后24小时，无论是卒中诱导后立即开始，还是在延迟30-60分钟后，PIH治疗都能使脑梗塞体积缩小30%-40%。与卒中对照组相比，ABS-201治疗增加了bcl2的表达，减少了caspase-3的激活，减少了梗死周边区域的TUNEL阳性细胞，并抑制了自噬细胞的死亡。使用ABS-201的妊高征组可改善卒中后21d的感觉运动功能的恢复。这些结果表明，以ABS-201为代表的神经降压素类似物诱导的妊高征是治疗缺血性卒中的有希望的候选药物，也可能用于其他缺血或创伤的治疗。崔凯娥、霍尔、孙俊民、魏力、穆罕默德、O.、Dix、T.A.、Yu、S.P.一种新的药物诱导的小鼠局灶性脑缺血后亚低温卒中疗法。FASE B J.26,2799-2810(2012)。Www.fasebj.org
Compelling evidence from preclinical and clinical studies has shown that mild to moderate hypothermia is neuroprotective against ischemic stroke. Clinical applications of hypothermia therapy, however, have been hindered by current methods of physical cooling, which is generally inefficient and impractical in clinical situations. In this report, we demonstrate the potential of pharmacologically induced hypothermia (PIH) by the novel neurotensin receptor 1 (NTR1) agonist ABS-201 in a focal ischemic model of adult mice. ABS-201 (1.5-2.5 mg/kg, i.p.) reduces body and brain temperature by 2-5 degrees C in 15-30 min in a dose-dependent manner without causing shivering or altering physiological parameters. Infarct volumes at 24 h after stroke are reduced by similar to 30-40% when PIH therapy is initiated either immediately after stroke induction or after 30-60 min delay. ABS-201 treatment increases bcl-2 expression, decreases caspase-3 activation, and TUNEL-positive cells in the peri-infarct region, and suppresses autophagic cell death compared to stroke controls. The PIH therapy using ABS-201 improves recovery of sensorimotor function as tested 21 d after stroke. These results suggest that PIH induced by neurotensin analogs represented by ABS-201 are promising candidates for treatment of ischemic stroke and possibly for other ischemic or traumatic injuries. Choi, K.-E., Hall, C. L., Sun, J.-M., Wei, L., Mohamad, O., Dix, T. A., Yu, S. P. A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice. FASEB J. 26, 2799-2810 (2012). www.fasebj.org