Kovalska M, Kovalska L, Tothova B, Mahmood S, Adamkov M, Lehotsky J
Institute of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia.
Clinic of Stomatology and Maxillofacial Surgery, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia.
J Physiol Pharmacol. 2015 Dec;66(6):887-97.
Epidemiological studies show positive relationship between mild-to-moderate hyperhomocysteinemia (hHcy) and the risk of cerebrovascular diseases. The study determines whether hyperhomocysteinemia (risk factor of brain ischemia) alone or in combination with the ischemic preconditioning (IPC) affects the ischemia-induced neurodegenerative changes and imbalance in MAPK/p-ERK1/2 and MAPK/p-p38 expression in the rat brains. hHcy was induced by subcutaneous administration of homocysteine (0.45 μmol/g body weight) twice a day at 8 h intervals for 14 days. Rats were preconditioned by 5 min ischemia and 2 days later, 15 min of global forebrain ischemia was induced by four vessel occlusion. We observed that hHcy alone significantly increased neurodegeneration by Fluoro-Jade C and TUNEL possitive cells in hippocampus as well as in cortex. We found elevated level of MAPK/p-ERK and decreased level of MAPK/p-p38 after pre-ischemic challenge by Western blot and fluorescent immunohistochemistry. In conclusion, preconditioning even if combined with hHcy could preserve the neuronal tissue from lethal ischemic effect. This study provides evidence for the interplay and tight integration between ERK and p38 MAPKs signalling mechanisms in response to the hHcy and also if in association with brain ischemia/IPC challenge in the rat brain.
流行病学研究表明，轻度至中度高同型半胱氨酸血症（hHcy）与脑血管疾病风险之间存在正相关关系。本研究旨在确定高同型半胱氨酸血症（脑缺血的危险因素）单独或与缺血预处理（IPC）联合使用是否会影响大鼠脑内缺血诱导的神经退行性变化以及丝裂原活化蛋白激酶/磷酸化细胞外信号调节激酶1/2（MAPK/p-ERK1/2）和丝裂原活化蛋白激酶/磷酸化p38（MAPK/p-p38）表达的失衡。通过每天两次皮下注射同型半胱氨酸（0.45 μmol/g体重），间隔8小时，持续14天来诱导hHcy。对大鼠进行5分钟的缺血预处理，2天后，通过四动脉闭塞诱导15分钟的全脑缺血。我们观察到，单独的hHcy显著增加了海马体和皮质中Fluoro-Jade C阳性细胞和TUNEL阳性细胞的神经退行性变。通过蛋白质免疫印迹法和荧光免疫组织化学法，我们发现在缺血预处理后，MAPK/p-ERK水平升高，MAPK/p-p38水平降低。总之，即使与hHcy联合使用，预处理也能保护神经元组织免受致命性缺血影响。本研究为大鼠脑中ERK和p38丝裂原活化蛋白激酶信号传导机制在应对hHcy以及与脑缺血/IPC挑战相关时的相互作用和紧密整合提供了证据。
