Mechanisms of Ischemic Neuroprotection by Acetyl‐l‐carnitine
Mechanisms of Ischemic Neuroprotection by Acetyl‐l‐carnitine
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DOI：
10.1111/j.1749-6632.2005.tb00021.x
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发表时间：
2005-08
影响因子：
5.2
通讯作者：
S. Zanelli;N. Solenski;R. Rosenthal;G. Fiskum
中科院分区：
文献类型：
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作者：
S. Zanelli;N. Solenski;R. Rosenthal;G. Fiskum
摘要：乙酰- l -肉碱是一种天然存在的物质，当以超生理浓度给药时，在几种全脑和局灶性脑缺血动物模型中具有神经保护作用。通过这些模型和体外急性神经元细胞死亡模型进行的神经化学结果测量，支持了三种主要的作用机制。代谢假说是基于乙酰- l -肉碱的乙酰成分的氧化代谢，这是药物治疗后脑乳酸水平降低和ATP升高的一个简单解释。脑组织和脑脊液中氧化应激标志物（例如蛋白质氧化）的减少支持了抗氧化机制。抑制兴奋性毒性的机制在急性脑损伤和慢性神经退行性疾病中可能非常重要。用大鼠皮层神经元原代培养的新实验表明，乙酰- l -肉碱的存在显著抑制暴露于NMDA（一种兴奋毒性谷氨酸拮抗剂）后的急性和延迟细胞死亡。最后，几种其他的作用机制是可能的，包括乙酰- l -肉碱的神经营养作用和线粒体通透性转变的抑制。虽然乙酰- l -肉碱对神经保护的多种潜在机制限制了最重要作用模式的准确指定，但它们与必须抑制几种脑损伤途径以优化治疗效果的概念是相容的。
Abstract: Acetyl‐l‐carnitine is a naturally occurring substance that, when administered at supraphysiologic concentrations, is neuroprotective in several animal models of global and focal cerebral ischemia. Three primary mechanisms of action are supported by neurochemical outcome measures performed with these models and with in vitro models of acute neuronal cell death. The metabolic hypothesis is based on the oxidative metabolism of the acetyl component of acetyl‐l‐carnitine and is a simple explanation for the reduction in postischemic brain lactate levels and elevation of ATP seen with drug administration. The antioxidant mechanism is supported by reduction of oxidative stress markers, for example, protein oxidation, in both brain tissue and cerebrospinal fluid. The relatively uncharacterized mechanism of inhibiting excitotoxicity could be extremely important in both acute brain injury and chronic neurodegenerative disorders. New experiments performed with primary cultures of rat cortical neurons indicate that the presence of acetyl‐l‐carnitine significantly inhibits both acute and delayed cell death following exposure to NMDA, an excitotoxic glutamate antagonist. Finally, several other mechanisms of action are possible, including a neurotrophic effect of acetyl‐l‐carnitine and inhibition of mitochondrial permeability transition. While the multiple potential mechanisms of neuroprotection by acetyl‐l‐carnitine limit an accurate designation of the most important mode of action, they are compatible with the concept that several brain injury pathways must be inhibited to optimize therapeutic efficacy.