Neuroprotective Effects of Carvedilol, a New Antihypertensive Agent, in Cultured Rat Cerebellar Neurons and in Gerbil Global Brain Ischemia
Neuroprotective Effects of Carvedilol, a New Antihypertensive Agent, in Cultured Rat Cerebellar Neurons and in Gerbil Global Brain Ischemia
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新型抗高血压药物卡维地洛对培养大鼠小脑神经元和沙鼠全脑缺血的神经保护作用
DOI：
10.1161/01.str.23.11.1630
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发表时间：
1992
期刊：
影响因子：
8.3
通讯作者：
G. Feuerstein
中科院分区：
文献类型：
--
作者：
P. G. Lysko;K. Lysko;T. Yue;C. Webb;J. Gu;G. Feuerstein
背景与目的：自由基的产生介导了兴奋性氨基酸谷氨酸引起的部分缺血性神经元损伤。卡维地洛是一种新型的多效降压药，在猪心和大鼠脑组织匀浆中显示出清除自由基和抑制脂质过氧化作用。因此，我们研究了卡维地洛对培养的小脑神经元和脑缺血沙土鼠海马CA 1区神经元的保护作用。研究方法：神经保护机制进行了研究，在体外缺血模型培养的大鼠小脑颗粒细胞神经元暴露于谷氨酸或氧自由基产生系统。通过测定硫代巴比妥酸反应物的形成，研究卡维地洛对脂质过氧化的预防作用。在全脑缺血再灌注6分钟后7天，通过直接神经元计数检测沙土鼠CA 1神经元存活。结果如下：卡维地洛以剂量依赖性方式保护培养的神经元免受谷氨酸介导的兴奋性毒性（抑制浓度[IC 50] =1.1 μM）以及20分钟氧化攻击（IC 50 =5 μM）。通过在卡维地洛存在下生长神经元24小时，抗氧化挑战的IC 50降低至1.3 μM。在10 μM时，卡维地洛抑制暴露于两种不同自由基产生系统的神经元中50%和73%的脂质过氧化（n=4，p< 0.001）。通过每天两次皮下注射3 mg/kg卡维地洛分别进行4天和3天的预处理和后处理，实现了沙土鼠CA 1海马神经元的52%（n=22，p=0.009 vs载体）的神经保护。结论：卡维地洛在体外和体内神经损伤模型中都提供了神经保护作用，其中氧自由基可能发挥重要作用。因此，卡维地洛可能通过其抗高血压作用和抗氧化特性降低脑缺血和中风的风险。
Background and Purpose: Free radical generation mediates part of the ischemic neuronal damage caused by the excitatory amino acid glutamate. Carvedilol, a novel multiple-action antihypertensive agent, has been shown to scavenge free radicals and inhibit lipid peroxidation in swine heart and rat brain homogenates. Therefore, we studied the neuroprotective effect of carvedilol on cultured cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. Methods: Neuroprotective mechanisms were studied using an in vitro ischemia model of cultured rat cerebellar granule cell neurons exposed to either glutamate or oxygen free radical-generating systems. Prevention of lipid peroxidation by carvedilol was studied by measuring the formation of thiobarbituric acid-reactive substance. Gerbil CA1 neuron survival was examined by direct neuronal count 7 days after 6 minutes of global ischemia with reperfusion. Results: Carvedilol protected cultured neurons in a dose-dependent manner against glutamate-mediated excitotoxicity (inhibitory concentration [IC50] =1.1 μM) as well as against a 20-minute oxidative challenge (IC50=5 μM). The IC50 against the oxidative challenge was lowered to 1.3 μM by growing neurons for 24 hours in the presence of carvedilol. At 10 μM carvedilol inhibited lipid peroxidation 50% and 73% (n=4, p< 0.001) in neurons exposed to two different free radical-generating systems. Neuroprotection of 52% (n=22, p=0.009 versus vehicle) of gerbil CA1 hippocampal neurons was achieved by pretreatment and posttreatment with subcutaneous injection of 3 nig/kg carvedilol twice a day for 4 and 3 days, respectively. Conclusions: Carvedilol provided neuroprotection in both in vitro and in vivo models of neuroinjury, where oxygen radicals are likely to play an important role. Therefore, carvedilol may reduce the risk of cerebral ischemia and stroke by virtue of both its antihypertensive action and its antioxidative properties.
影响因子：
4.1
作者：
KONTOS, HA;WEI, EP
通讯作者：
WEI, EP
抗氧化剂可防止神经元细胞系中谷氨酸诱导的细胞毒性。
DOI：
--
发表时间：
1989
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Miyamoto,M;Murphy,TH;Schnaar,RL;Coyle,JT
通讯作者：
Coyle,JT