Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia.
Department of Medical Biochemistry, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia.
Cell Mol Neurobiol. 2017 Nov;37(8):1417-1431. doi: 10.1007/s10571-017-0473-5. Epub 2017 Feb 16.
Increased level of homocysteine (hHcy) in plasma is an accompanying phenomenon of many diseases, including a brain stroke. This study determines whether hyperhomocysteinemia (which is a risk factor of brain ischemia) itself or in combination with ischemic preconditioning affects the ischemia-induced neurodegenerative changes, generation of reactive oxygen species (ROS), lipoperoxidation, protein oxidation, and activity of antioxidant enzymes in the rat brain cortex. The hHcy was induced by subcutaneous administration of homocysteine (0.45 μmol/g body weight) twice a day in 8 h intervals for 14 days. Rats were preconditioned by 5 min ischemia. Two days later, 15 min of global forebrain ischemia was induced by four vessel's occlusion. The study demonstrates that in the cerebral cortex, hHcy alone induces progressive neuronal cell death and morphological changes. Neuronal damage was associated with the pro-oxidative effect of hHcy, which leads to increased ROS formation, peroxidation of lipids and oxidative alterations of cortical proteins. Ischemic reperfusion injury activates degeneration processes and de-regulates redox balance which is aggravated under hHcy conditions and leads to the augmented lipoperoxidation and protein oxidation. If combined with hHcy, ischemic preconditioning could preserve the neuronal tissue from lethal ischemic effect and initiates suppression of lipoperoxidation, protein oxidation, and alterations of redox enzymes with the most significant effect observed after prolonged reperfusion. Increased prevalence of hyperhomocysteinemia in the Western population and crucial role of elevated Hcy level in the pathogenesis of neuronal disorders makes this amino acid as an interesting target for future research. Understanding the multiple etiological mechanisms and recognition of the co-morbid risk factors that lead to the ischemic/reperfusion injury and ischemic tolerance is therefore important for developing therapeutic strategies in human brain stroke associated with the elevated level of Hcy.
血浆同型半胱氨酸（hHcy）水平升高是许多疾病的伴随现象，包括脑中风。本研究旨在确定高同型半胱氨酸血症（脑缺血的危险因素）本身或与缺血预处理联合作用是否会影响缺血诱导的神经退行性变化、活性氧（ROS）的产生、脂质过氧化、蛋白质氧化以及大脑皮质中抗氧化酶的活性。hHcy 通过每天两次皮下注射同型半胱氨酸（0.45μmol/g 体重），8 小时间隔 14 天诱导。大鼠通过 5 分钟的缺血预处理。两天后，通过四血管闭塞诱导 15 分钟全脑缺血。研究表明，在大脑皮质中，hHcy 单独诱导进行性神经元细胞死亡和形态变化。神经元损伤与 hHcy 的促氧化作用有关，导致 ROS 形成增加、脂质过氧化和皮质蛋白的氧化改变。缺血再灌注损伤激活变性过程并使氧化还原平衡失调，这种失调在 hHcy 条件下加剧，并导致脂质过氧化和蛋白质氧化增加。如果与 hHcy 联合使用，缺血预处理可以保护神经元组织免受致命的缺血作用，并启动脂质过氧化、蛋白质氧化和氧化还原酶改变的抑制作用，在延长再灌注后观察到最显著的效果。西方人群中高同型半胱氨酸血症的高发率和 Hcy 水平升高在神经元疾病发病机制中的关键作用使这种氨基酸成为未来研究的一个有趣目标。因此，理解导致缺血/再灌注损伤和缺血耐受的多种病因机制和共病风险因素对于开发与 Hcy 水平升高相关的人类脑中风的治疗策略非常重要。
