Post-ischemic administration of nimodipine following focal cerebral ischemic-reperfusion injury in rats alleviated excitotoxicity, neurobehavioural alterations and partially the bioenergetics
Post-ischemic administration of nimodipine following focal cerebral ischemic-reperfusion injury in rats alleviated excitotoxicity, neurobehavioural alterations and partially the bioenergetics
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DOI：
10.1016/j.ijdevneu.2010.08.001
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发表时间：
2011-02-01
影响因子：
1.8
通讯作者：
Ramanathan, Muthiah
中科院分区：
文献类型：
--
作者：
Babu, Chidambaram Saravana;Ramanathan, Muthiah
本研究的重点是通过同时测量兴奋毒性、生物能量学和神经行为学范式，探讨尼莫地平（NM）治疗的大脑中动脉闭塞（缺血2 h）-再灌注（再灌注70 h）大鼠中钙的时间意义。进一步确定了脑卒中钙通道拮抗剂的适宜治疗时间窗。NM（5 mg/kg，i.p.）在缺血前（诱导缺血前30分钟）、缺血中（MCA闭塞后1小时）和缺血后（再灌注开始后3小时）状态下给药。就兴奋性毒性（谷氨酸、谷氨酰胺合成酶）而言，神经保护的程度。测量和比较脑卒中患者的生物能量学（ATP、NAD（+））和神经行为学（神经功能评分和旷场探索行为），以确定脑卒中NM的治疗时间窗。发现在溶剂处理组（IR组）中大脑中动脉闭塞-再灌注（MCAO/R）升高谷氨酸、谷氨酰胺合成酶水平并降低Na（+）K（+）ATP酶活性。还观察到生物能量学如ATP和NAD（+）水平的显著降低。此外，IR组表现出严重的氧化应激（脂质过氧化、蛋白质羰基含量、亚硝酸盐/硝酸盐水平增加，超氧化物歧化酶和谷胱甘肽水平降低），伴随沿着焦虑行为、神经功能缺损和神经元损伤，以及CA 1海马区核质比降低。缺血后NM给药显著逆转了兴奋性毒性、神经行为和组织病理学改变，但仅部分恢复了MCAO/R大鼠的生物能量学水平，这些发现通过缺血后NM和缺血前美金刚（MN）给药的联合治疗（CT）得到进一步证实，因为MN在缺血前给药中显示出保护作用（Babu和Ramanathan，2009）。NM未能阻止缺血前和缺血期间的神经变性，提示缺血再灌注（IR）的初始阶段损伤可能通过其他机制介导，如谷氨酸能过度刺激或谷氨酸转运体的反向操作。从目前的研究中可以得出结论，钙在缺血后状态中起着至关重要的作用，钙拮抗剂的合适治疗时间窗是缺血后状态。(C)2010 ISDN。由爱思唯尔有限公司出版。保留所有权利。
The present study focuses on the temporal calcium significance in middle cerebral artery occluded (2 h ischemia)-reperfused (70 h reperfusion) rats treated with nimodipine (NM) through concurrent measurements of excitotoxicity, bioenergetics and neurobehavioural paradigms. Further, the suitable therapeutic time window of calcium channel antagonism in stroke was also ascertained. NM (5 mg/kg, i.p.) was administered at pre (30 min before the induction of ischemia), during (1 h following occlusion of MCA) and post-ischemic (3 h after begin of reperfusion) states. The magnitude of neuroprotection in terms of excitotoxicity (glutamate, glutamine synthetase. Na(+)K(+)ATPase), bioenergetics (ATP, NAD(+)) and neurobehavioural paradigms (neurological score and open field exploratory behaviour) were measured and compared to ensure the therapeutic time-window of NM in stroke. Middle cerebral artery occlusion-reperfusion (MCAO/R) was found to elevate glutamate, glutamine synthetase levels and deplete Na(+)K(+)ATPase activity in the vehicle treated group (IR group). Significant decrease in bioenergetics such as ATP and NAD(+) levels was also observed. Further, IR group demonstrated grievous oxidative stress (increase in lipid peroxidation, protein carbonyl content, nitrite/nitrate levels and decrease in superoxide dismutase and glutathione levels) along with anxiogenic behaviour, neurological deficits and neuronal damage and decreased nuclear to cytoplasm ratio in CA1 hippocampal region. Post-ischemic NM administration reversed the excitotoxicity, neurobehavioural and histopathological alterations significantly, but it restored bioenergetics level in MCAO/R rats only partially.These findings were further confirmed with the combination treatment (CT) of post-ischemic NM and pre-ischemic memantine (MN) administration, since MN showed protective effect in the pre-ischemic administration (Babu and Ramanathan, 2009). The failure of NM to forefend the neurodegeneration on pre- and during-ischemic administration suggests that the initial phase damages in ischemic-reperfusion (IR) might be mediated through other mechanism(s) such as glutamergic overstimulation or reverse operation of glutamate transporters. From the present study, it is concluded that calcium plays a crucial role in post-ischemic status and the suitable therapeutic time window of calcium antagonism is the post-ischemic state. (C) 2010 ISDN. Published by Elsevier Ltd. All rights reserved.