Hall E D, Andrus P K, Pazara K E
Upjohn Company, Kalamazoo, MI 49001.
Stroke. 1993 May;24(5):711-5. doi: 10.1161/01.str.24.5.711.
The novel muscarinic cholinergic partial agonist U-80816E was tested in the gerbil brief bilateral carotid occlusion ischemia model based on the rationale that the compound's hypothermic properties might afford effective protection of the selectively vulnerable hippocampal CA1 region.
Male gerbils were subjected to either 10 or 15 minutes of bilateral carotid occlusion, followed by histopathological assessment of the CA1 neuronal survival 7 days later.
In saline-treated animals, 10 minutes of bilateral carotid occlusion resulted in a 30.5% loss of CA1 neurons, whereas a 15-minute insult resulted in a 49.6% loss. Administration of U-80816E (6 mg/kg i.p. 30 minutes before bilateral carotid occlusion and again 2 hours after reperfusion) resulted in a significant protective effect of the CA1 neuronal population with either duration of ischemia; neuronal loss was reduced to 12.6% in the milder model (p < 0.05 versus saline-treated) and 24.9% in the more severe model (p < 0.04 versus saline). However, the 6 mg/kg i.p. dose of U-80816E was found to produce a 1.0 degree C decrease in brain temperature (measured with a tympanic temperature probe) at 10 minutes of ischemia compared with that of saline-treated gerbils. At 10 minutes of reperfusion, after the 10-minute episode of ischemia, the brain temperature of the U-80816E-treated gerbils was 2.2 degrees C lower than that of saline-treated animals. When the U-80816E-treated gerbils were subjected to either 10 or 15 minutes of ischemia but placed in a heated chamber that prevented the hypothermic effects, no cerebroprotection was observed.
These results show that the anti-ischemic efficacy of U-80816E is mediated through its hypothermic properties, thus suggesting the feasibility of pharmacologically induced hypothermia as a cerebroprotective approach.
新型毒蕈碱胆碱能部分激动剂U - 80816E在沙土鼠短暂双侧颈动脉闭塞缺血模型中进行了测试，其依据是该化合物的低温特性可能对选择性易损的海马CA1区提供有效保护。
雄性沙土鼠经历10或15分钟的双侧颈动脉闭塞，7天后对CA1神经元存活情况进行组织病理学评估。
在生理盐水处理的动物中，10分钟的双侧颈动脉闭塞导致CA1神经元损失30.5%，而15分钟的损伤导致49.6%的损失。给予U - 80816E（双侧颈动脉闭塞前30分钟腹腔注射6mg/kg，再灌注后2小时再次注射）对CA1神经元群体产生了显著的保护作用，无论缺血持续时间如何；在较轻的模型中神经元损失减少至12.6%（与生理盐水处理组相比，p < 0.05），在较严重的模型中减少至24.9%（与生理盐水组相比，p < 0.04）。然而，发现腹腔注射6mg/kg剂量的U - 80816E在缺血10分钟时与生理盐水处理的沙土鼠相比，脑温降低了1.0℃（用鼓膜温度探头测量）。在缺血10分钟后的再灌注10分钟时，U - 80816E处理的沙土鼠脑温比生理盐水处理的动物低2.2℃。当U - 80816E处理的沙土鼠经历10或15分钟的缺血但置于加热室中以防止低温效应时，未观察到脑保护作用。
这些结果表明U - 80816E的抗缺血功效是通过其低温特性介导的，从而提示药理学诱导低温作为一种脑保护方法的可行性。
