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首页> 外文期刊>CNS drug reviews >A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke.
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A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke.

机译：5-HT1A受体激动剂repinotan HCl（BAYx3702）在缺血性中风中的神经保护作用综述。

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Repinotan HCl (repinotan, BAYx3702), a highly selective 5-HT1A receptor agonist with a good record of safety was found to have pronounced neuroprotective effects in experimental models that mimic various aspects of brain injury. Repinotan caused strong, dose-dependent infarct reductions in permanent middle cerebral artery occlusion, transient middle cerebral artery occlusion, and traumatic brain injury paradigms. The specific 5-HT1A receptor antagonist WAY 100635 blocked these effects, indicating that the neuroprotective properties of repinotan are mediated through the 5-HT1A receptor. The proposed neuroprotective mechanisms of repinotan are thought to be the result of neuronal hyperpolarization via the activation of G protein-coupled inwardly rectifying K+ channels upon binding to both pre- and post-synaptic 5-HT1A receptors. Hyperpolarization results in inhibition of neuron firing and reduction of glutamate release. These mechanisms, leading to protection of neurons against overexcitation, could explain the neuroprotective efficacy of repinotan per se, but not necessarily the efficacy by delayed administration. The therapeutic time window of repinotan appeared to be at least 5 h in in vivo animal models, but may be even longer at higher doses of the drug. Experimental studies indicate that repinotan affects various mechanisms involved in the pathogenesis of brain injury. In addition to the direct effect of repinotan on neuronal hyperpolarization and suppression of glutamate release this compound affects the death-inhibiting protein Bcl-2, serotonergic glial growth factor S-100beta and Nerve Growth Factor. It also suppresses the activity of caspase-3 through MAPK and PKCalpha; this effect may contribute to its neuroprotective efficacy. The dose- and time-dependent neuroprotective efficacy of repinotan indicates that the drug is a promising candidate for prevention of secondary brain damage in brain-injured patients suffering from acute ischemic stroke. Unfortunately, however, the first, randomized, double blind, placebo-controlled clinical trial did not demonstrate the efficacy of repinotan in acute ischemic stroke.
机译：在具有良好安全记录的高选择性5-HT1A受体激动剂Repinotan HCl（repinotan，BAYx3702）中，在模拟脑损伤各个方面的实验模型中，具有明显的神经保护作用。 Repinotan导致永久性大脑中动脉闭塞，短暂性大脑中动脉闭塞以及颅脑损伤范例的剂量依赖性强梗塞减少。特异的5-HT1A受体拮抗剂WAY 100635阻断了这些作用，表明雷匹坦类的神经保护特性是通过5-HT1A受体介导的。被认为是雷匹丹坦的拟议神经保护机制是神经元超极化的结果，该神经元超极化是通过与突触前和突触后5-HT1A受体结合而激活G蛋白偶联的内向整流K +通道而实现的。超极化导致神经元放电的抑制和谷氨酸盐释放的减少。这些导致保护神经元免于过度兴奋的机制可以解释雷维坦本身的神经保护功效，但不一定是延迟给药的功效。在体内动物模型中，repinotan的治疗时间窗似乎至少为5小时，但在更高剂量的药物下可能更长。实验研究表明，雷匹诺坦会影响脑损伤发病机制的各种机制。除了视黄醇对神经元超极化和抑制谷氨酸释放的直接作用外，该化合物还影响死亡抑制蛋白Bcl-2，血清素神经胶质生长因子S-100beta和神经生长因子。它还通过MAPK和PKCalpha抑制caspase-3的活性。这种作用可能有助于其神经保护功效。 Repinotan的剂量依赖性和时间依赖性神经保护功效表明，该药物是预防患有急性缺血性中风的脑损伤患者继发性脑损伤的有前途的候选药物。然而，不幸的是，第一项随机，双盲，安慰剂对照的临床试验未证明雷匹坦在急性缺血性中风中的疗效。

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