Abdul Hafiz Mohmmad, Calabrese Vittorio, Calvani Menotti, Butterfield D Allan
Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, 40506, USA.
J Neurosci Res. 2006 Aug 1;84(2):398-408. doi: 10.1002/jnr.20877.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by senile plaques and neurofibrillary tangles in brain. Amyloid-beta peptide, particularly the 42-amino-acid peptide (Abeta(1-42)), is a principal component of senile plaques and is thought to be central to the pathogenesis of the disease. The AD brain is under significant oxidative stress, and Abeta(1-42) peptide is known to cause oxidative stress in vitro and in vivo. Acetyl-L-carnitine (ALCAR) is an endogenous mitochondrial membrane compound that helps to maintain mitochondrial bioenergetics and lowers the increased oxidative stress associated with aging. Glutathione (GSH) is an important endogenous antioxidant, and its levels have been shown to decrease with aging. Administration of ALCAR increases cellular levels of GSH in rat astrocytes. In the current study, we investigated whether ALCAR plays a protective role in cortical neuronal cells against Abeta(1-42)-mediated oxidative stress and neurotoxicity. Decreased cell survival in neuronal cultures treated with Abeta(1-42) correlated with an increase in protein oxidation (protein carbonyl, 3-nitrotyrosine) and lipid peroxidation (4-hydroxy-2-nonenal) formation. Pretreatment of primary cortical neuronal cultures with ALCAR significantly attenuated Abeta(1-42)-induced cytotoxicity, protein oxidation, lipid peroxidation, and apoptosis in a dose-dependent manner. Addition of ALCAR to neurons also led to an elevated cellular GSH and heat shock proteins (HSPs) levels compared with untreated control cells. Our results suggest that ALCAR exerts protective effects against Abeta(1-42) toxicity and oxidative stress in part by up-regulating the levels of GSH and HSPs. This evidence supports the pharmacological potential of acetyl carnitine in the management of Abeta(1-42)-induced oxidative stress and neurotoxicity. Therefore, ALCAR may be useful as a possible therapeutic strategy for patients with AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为记忆和认知丧失，以及大脑中出现老年斑和神经原纤维缠结。β-淀粉样肽，尤其是42个氨基酸的肽（Aβ(1-42)），是老年斑的主要成分，被认为是该疾病发病机制的核心。AD大脑处于显著的氧化应激状态，已知Aβ(1-42)肽在体外和体内均可引起氧化应激。乙酰-L-肉碱（ALCAR）是一种内源性线粒体膜化合物，有助于维持线粒体生物能量，并降低与衰老相关的氧化应激增加。谷胱甘肽（GSH）是一种重要的内源性抗氧化剂，其水平已显示会随衰老而降低。给予ALCAR可增加大鼠星形胶质细胞中GSH的细胞水平。在本研究中，我们调查了ALCAR是否对皮质神经元细胞免受Aβ(1-42)介导的氧化应激和神经毒性发挥保护作用。用Aβ(1-42)处理的神经元培养物中细胞存活率降低与蛋白质氧化（蛋白质羰基、3-硝基酪氨酸）和脂质过氧化（4-羟基-2-壬烯醛）形成增加相关。用ALCAR预处理原代皮质神经元培养物可显著减轻Aβ(1-42)诱导的细胞毒性、蛋白质氧化、脂质过氧化和凋亡，且呈剂量依赖性。与未处理的对照细胞相比，向神经元中添加ALCAR还导致细胞GSH和热休克蛋白（HSPs）水平升高。我们的结果表明，ALCAR部分通过上调GSH和HSPs水平对Aβ(1-42)毒性和氧化应激发挥保护作用。这一证据支持了乙酰肉碱在管理Aβ(1-42)诱导的氧化应激和神经毒性方面的药理学潜力。因此，ALCAR可能作为AD患者的一种潜在治疗策略。
