Administration of an Acidic Sphingomyelinase (ASMase) Inhibitor, Imipramine, Reduces Hypoglycemia-Induced Hippocampal Neuronal Death.
Administration of an Acidic Sphingomyelinase (ASMase) Inhibitor, Imipramine, Reduces Hypoglycemia-Induced Hippocampal Neuronal Death.
复制标题
给药酸性鞘磷脂酶（ASMase）抑制剂，丙咪嗪，减少了低血糖诱导的海马神经元死亡。
作者：
Kho AR;Choi BY;Lee SH;Hong DK;Kang BS;Lee SH;Suh SW
严重低血糖（低于35 mg/dL）最常见于持续注射胰岛素的糖尿病患者。为了快速停止低血糖状态，本研究进行了葡萄糖再灌注，这可以诱导低血糖后的继发性神经元死亡级联。酸性鞘磷脂酶（ASMase）将鞘磷脂水解成神经酰胺和磷胆碱。ASMase活性可受细胞中阳离子、pH、氧化还原、脂质和其他蛋白质的影响，低血糖时这些因素有许多变化。因此，我们预计ASMase在低血糖后被过度激活。神经酰胺可引起自由基产生、过度炎症、钙调节失调和溶酶体损伤，导致神经元凋亡和坏死。丙咪嗪主要用于治疗抑郁症和某些焦虑症，尤其被称为ASMase抑制剂。我们推测丙咪嗪可能通过抑制低血糖后ASMase降低神经酰胺，从而减少海马神经元死亡。在本研究中，我们证实给药丙咪嗪可显著降低低血糖诱导的神经元死亡并改善认知功能。因此，我们认为丙咪嗪可能是预防低血糖诱导的神经元死亡的一种有前途的治疗工具。
Severe hypoglycemia (below 35 mg/dL) appears most often in diabetes patients who continuously inject insulin. To rapidly cease the hypoglycemic state in this study, glucose reperfusion was conducted, which can induce a secondary neuronal death cascade following hypoglycemia. Acid sphingomyelinase (ASMase) hydrolyzes sphingomyelin into ceramide and phosphorylcholine. ASMase activity can be influenced by cations, pH, redox, lipids, and other proteins in the cells, and there are many changes in these factors in hypoglycemia. Thus, we expect that ASMase is activated excessively after hypoglycemia. Ceramide is known to cause free radical production, excessive inflammation, calcium dysregulation, and lysosomal injury, resulting in apoptosis and the necrosis of neurons. Imipramine is mainly used in the treatment of depression and certain anxiety disorders, and it is particularly known as an ASMase inhibitor. We hypothesized that imipramine could decrease hippocampal neuronal death by reducing ceramide via the inhibition of ASMase after hypoglycemia. In the present study, we confirmed that the administration of imipramine significantly reduced hypoglycemia-induced neuronal death and improved cognitive function. Therefore, we suggest that imipramine may be a promising therapeutic tool for preventing hypoglycemia-induced neuronal death.