与缺血性卒中相关的脑水肿的进展研究中的最新概念
我们在临床上常常要面对与大面积脑梗塞有关的脑水肿，这是一种主要的致残和致死病因。临床上主要采用渗透疗法来处理与脑梗塞有关的脑水肿。尽管甘露醇是传统中首选的渗透性药物，但高渗的盐溶液(HS)最近也得到了越来越多的关注，在治疗脑损伤的病例中成为一种有效的渗透性试剂。缺血性卒中所致水肿的发病机理异常复杂，还是有些实验揭示了在其形成过程中的一些新的途径，值得注意的是神经胶质细胞膜上水通道的作用，特别是aquaporin?4 (AQP4)，以及与AQP4定位于血管周围有关的dystrophin蛋白复合体中的成分之一α-syntrophin (syn)。神经元介质反应，特别是九肽，精氨酸-抗利尿激素(AVP)也参与了缺血性卒中所致水肿的演变过程。本报告将重点阐述HS溶液对缺血性卒中的疗效及aquaporin-4 和 AVP在缺血性卒中所致水肿发病机理中的复杂的相互作用。
Protein Aggregation after Brain Ischemia
Bingren Hu, Maryann E. Martone, Cindy Liu, Cerebral Vascular Research Center, Department of Neurology (D4-5), University of Maimi School of Medicine, P.O. Box. Miami, FL 33101.
, 百拇医药
(美国)
Brain ischemia causes intra-neuronal accumulation of abnormal protein aggregates. Intracellular protein aggregates are highly toxic to the cells. Abnormal protein aggregates are composed of abnormal proteins that are unfolded, misfolded, abnormally modified such as oxidation or phosphorylation, or damaged by free radicals, protease or other enzymes. Overproduction of abnormal proteins in cell causes protein aggregation. Protein aggregates containing ubiquitinated proteins are commonly observed in neurons of almost all neurodegenerative disorders, and have been considered as a common cause of neuronal degeneration. Recently, we have found severe protein aggregation in hippocampal CA1 neurons after transient forebrain ischemia and in the penumbra neurons after transient focal ischemia. By using ethanolic phosphotungstic acid electron microscopy (EM), ubiquitin immuno-gold EM, high-resolution confocal microscopy and biochemical analysis, we found that protein aggregates were appeared in the neurons at the early stage after transient ischemia. The neurons would die in a delayed manner, days or weeks after ischemia. The protein aggregates were progressively accumulated in the postischemic neurons until their death. However, these aggregates were virtually absent in the neurons that survive the insult. Protein aggregates appeared as clumps of electron dense materials that stained heavily for ubiquitin and were associated with various intracellular membranous structures. High-resolution confocal microscopy further demonstrated that protein aggregates containing ubiquitin immunoreactivity were persistently and progressively accumulated in the postischemic neurons destined to die, but not in neuronal populations that survive after ischemia. On western blots, ubiquitinated proteins were dramatically increased in the brain regions where neurons would die in the delayed manner during the postischemic phase. The ubiquitinated proteins were Triton-insoluble, indicating that they were irreversibly aggregated. We conclude that proteins are severely damaged, ubiquitinated and aggregated in neurons after ischemia. Based on our results, we propose a new hypothesis for ischemic cell death whereby overproduction of unfolded and damaged proteins, and irreversible protein aggregation after ischemia ultimately lead to delayed neuronal death., 百拇医药(Anish Bhardwaj(美国))
Protein Aggregation after Brain Ischemia
Bingren Hu, Maryann E. Martone, Cindy Liu, Cerebral Vascular Research Center, Department of Neurology (D4-5), University of Maimi School of Medicine, P.O. Box. Miami, FL 33101.
, 百拇医药
(美国)
Brain ischemia causes intra-neuronal accumulation of abnormal protein aggregates. Intracellular protein aggregates are highly toxic to the cells. Abnormal protein aggregates are composed of abnormal proteins that are unfolded, misfolded, abnormally modified such as oxidation or phosphorylation, or damaged by free radicals, protease or other enzymes. Overproduction of abnormal proteins in cell causes protein aggregation. Protein aggregates containing ubiquitinated proteins are commonly observed in neurons of almost all neurodegenerative disorders, and have been considered as a common cause of neuronal degeneration. Recently, we have found severe protein aggregation in hippocampal CA1 neurons after transient forebrain ischemia and in the penumbra neurons after transient focal ischemia. By using ethanolic phosphotungstic acid electron microscopy (EM), ubiquitin immuno-gold EM, high-resolution confocal microscopy and biochemical analysis, we found that protein aggregates were appeared in the neurons at the early stage after transient ischemia. The neurons would die in a delayed manner, days or weeks after ischemia. The protein aggregates were progressively accumulated in the postischemic neurons until their death. However, these aggregates were virtually absent in the neurons that survive the insult. Protein aggregates appeared as clumps of electron dense materials that stained heavily for ubiquitin and were associated with various intracellular membranous structures. High-resolution confocal microscopy further demonstrated that protein aggregates containing ubiquitin immunoreactivity were persistently and progressively accumulated in the postischemic neurons destined to die, but not in neuronal populations that survive after ischemia. On western blots, ubiquitinated proteins were dramatically increased in the brain regions where neurons would die in the delayed manner during the postischemic phase. The ubiquitinated proteins were Triton-insoluble, indicating that they were irreversibly aggregated. We conclude that proteins are severely damaged, ubiquitinated and aggregated in neurons after ischemia. Based on our results, we propose a new hypothesis for ischemic cell death whereby overproduction of unfolded and damaged proteins, and irreversible protein aggregation after ischemia ultimately lead to delayed neuronal death., 百拇医药(Anish Bhardwaj(美国))