Clomethiazole: mechanisms underlying lasting neuroprotection after hypoxia-ischemia
Clomethiazole: mechanisms underlying lasting neuroprotection after hypoxia-ischemia
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DOI：
10.1096/fj.04-3367fje
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发表时间：
2005-04-01
期刊：
影响因子：
4.8
通讯作者：
Kerr, DS
中科院分区：
文献类型：
--
作者：
Clarkson, AN;Liu, HZ;Kerr, DS
缺氧缺血（HI）后的损伤在皮质和皮质下区域都有观察。本研究我们采用HI的“Levine”大鼠模型（左侧颈动脉结扎+1小时PND-26时的整体缺氧），并使用组织学和电生理学范例来评估氯甲噻唑（CMZ; GABA（A）受体调节剂）的长期神经保护特性。还检查了参与炎症的关键酶，即一氧化氮合酶（NOS）和谷胱甘肽转移酶，以评估不涉及GABA-R激活的潜在CMZ机制。在HI后3天和90天进行评估。广泛的中枢神经系统病变后，HI同侧明显在短期和长期的时间间隔。CMZ治疗后3、90d病灶体积明显缩小（P < 0.01; P < 0.05）。诱发场电位分析用于评估离体海马CA 1神经元活性。闭塞对侧的电生理测量显示，相对于短期-长期对照，HI后神经元功能受损（P < 0.01，3和14天; P < 0.01，90天），CMZ治疗提供了接近完全的保护（P < 0.001，3和14天; P < 0.01，90天）。HI后3d，同侧NOS和NOS活性均显著升高（P < 0.01），NOS活性在HI后90d仍显著升高（P < 0.05）。CMZ可抑制HI诱导的iNOS和NOS活性的升高（P <0.001; P < 0.05）。这些数据提供了CMZ在HI模型中长期功能性神经保护的证据。我们进一步得出结论，在HI的条件下，功能缺陷不限于同侧半球，是由于，至少部分，在NOS和NOS酶的活性的变化。
Damage after hypoxia-ischemia (HI) is observed in both cortical and subcortical regions. In this study. we employed a "Levine" rat model of HI (left carotid ligation + 1 h global hypoxia on PND-26) and used histological and electrophysiological paradigms to assess the long-term neuroprotective properties of clomethiazole (CMZ; a GABA(A) receptor modulator). Key enzymes involved in inflammation, namely nitric oxide synthase (NOS) and arginase, were also examined to assess potential CMZ mechanisms not involving GABA-R activation. Assessments were carried out 3 and 90 days post-HI. Extensive CNS lesions were evident after HI ipsilaterally at both short- and long-term intervals. CMZ significantly decreased the lesion size at 3 and 90 days (P < 0.01; P < 0.05). Evoked field potential analysis were used to assess hippocampal CA1 neuronal acitivity ex vivo. Electrophysiological measurements contralateral to the occlusion revealed impaired neuronal function after HI relative to short- long-term controls (P < 0.01, 3 and 14 days; P < 0.01, 90 days), with CMZ treatment providing near complete protection (P < 0.001 at 3 and 14 days; P < 0.01 at 90 days). Both NOS and arginase activities were significantly increased at 3 days (P < 0.01), with arginase remaining elevated at 90 days post-HI (P < 0.05) ipsilaterally. CMZ suppressed the HI-induced increase in iNOS and arginase activities (P 0.001; P < 0.05). These data provide evidence of long-term functional neuroprotection by CMZ in a model of HI. We further conclude that under conditions of HI, functional deficits are not restricted to the ipsilateral hemisphere and are due, at least in part, to changes in the activity of NOS and arginase.