Keller J N, Mattson M P
Biology Department, University of Kentucky, Lexington 40536, USA.
Rev Neurosci. 1998;9(2):105-16. doi: 10.1515/revneuro.1998.9.2.105.
Free radicals are known to occur as natural by-products under physiological conditions and have been implicated in the neuronal loss observed in a variety of neuropathological conditions including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and ischemia. Oxyradical-induced cytotoxicity arises from both chronic and acute increases in reactive oxygen species which give rise to subsequent lipid peroxidation (LP). By reacting with polyunsaturated fatty acids in the the various cellular membranes, oxyradicals such as hydroxyl (OH.) and peroxynitrite (ONOO) give rise to a variety of lipid peroxidation products (LPP), including 4-hydroxynonenal (HNE) and malondialdehyde (MD). Once formed, these peroxidation metabolites have been demonstrated to have relatively long half-lives within cells (minutes to hours), allowing for multiple interactions with cellular components. Emerging data suggest that LP and LPP may underlie the neuronal alterations and neurotoxicity observed in numerous neurodegenerative conditions. Data supporting this involvement include the detection of LP and formation of LPP in a variety of neuropathological conditions including AD, ALS, PD, and ischemia. Secondly, direct application of LPP, either in vivo or in vitro, has been shown to be cytotoxic and mimic neuronal alterations observed in neuropathological conditions. Furthermore, prevention of LP and subsequent LPP formation have been demonstrated to be neuroprotective in a variety of neurodegenerative paradigms. Additionally, LP and LPP have been implicated in the modulation of a wide array of activities within the central nervous system including long term potentiation, neurite outgrowth, and proliferation. Understanding the mechanism(s) and involvement of LP in these processes will greatly enhance the understanding of oxyradical and ion homeostasis in neurophysiological and neuropathological conditions. The focus of this review is to describe the process by which lipid peroxidation occurs and establish a framework for its involvement in the central nervous system.
已知自由基作为生理条件下的天然副产物而产生，并与在包括阿尔茨海默病（AD）、肌萎缩侧索硬化症（ALS）、帕金森病（PD）和缺血在内的多种神经病理状况中观察到的神经元损失有关。氧自由基诱导的细胞毒性源于活性氧的慢性和急性增加，这会导致随后的脂质过氧化（LP）。通过与各种细胞膜中的多不饱和脂肪酸反应，诸如羟基（OH·）和过氧亚硝酸盐（ONOO）等氧自由基会产生多种脂质过氧化产物（LPP），包括4-羟基壬烯醛（HNE）和丙二醛（MD）。一旦形成，这些过氧化代谢产物已被证明在细胞内具有相对较长的半衰期（数分钟至数小时），从而允许与细胞成分进行多种相互作用。新出现的数据表明，LP和LPP可能是在众多神经退行性疾病中观察到的神经元改变和神经毒性的基础。支持这种参与的数据包括在包括AD、ALS、PD和缺血在内的多种神经病理状况中检测到LP和LPP的形成。其次，无论是在体内还是体外直接应用LPP，都已显示具有细胞毒性，并模拟在神经病理状况中观察到的神经元改变。此外，在各种神经退行性范例中，预防LP和随后的LPP形成已被证明具有神经保护作用。此外，LP和LPP还与中枢神经系统内的一系列广泛活动的调节有关，包括长期增强、神经突生长和增殖。了解LP在这些过程中的机制和参与情况将极大地增进对神经生理和神经病理状况中氧自由基和离子稳态的理解。本综述的重点是描述脂质过氧化发生的过程，并建立其在中枢神经系统中参与情况的框架。
