Brown Ian R
Center for the Neurobiology of Stress, University of Toronto at Scarborough, 1265 Military Trail, Toronto, Ontario, Canada M1C 1A4.
Ann N Y Acad Sci. 2007 Oct;1113:147-58. doi: 10.1196/annals.1391.032. Epub 2007 Jul 26.
Manipulation of the cellular stress response offers strategies to protect brain cells from damage induced by ischemia and neurodegenerative diseases. Overexpression of Hsp70 reduced ischemic injury in the mammalian brain. Investigation of the domains within Hsp70 that confers ischemic neuroprotection revealed the importance of the carboxyl-terminal domain. Arimoclomol, a coinducer of heat shock proteins, delayed progression of amyotrophic lateral sclerosis (ALS) in a mouse model in which motor neurons in the spinal cord and motor cortex degenerate. Celastrol, a promising candidate as an agent to counter neurodegenerative diseases, induced expression of a set of Hsps in differentiated neurons grown in tissue culture. Heat shock "preconditioning" protected the nervous system at the functional level of the synapse and selective overexpression of Hsp70 enhanced the level of synaptic protection. Following hyperthermia, constitutively expressed Hsc70 increased in synapse-rich areas of the brain where it associates with Hsp40 to form a complex that can refold denatured proteins. Stress tolerance in neurons is not solely dependent on their own Hsps but can be supplemented by Hsps from adjacent glial cells. Hence, application of exogenous Hsps at neural injury sites is an effective strategy to maintain neuronal viability.
调控细胞应激反应为保护脑细胞免受缺血和神经退行性疾病所致损伤提供了策略。热休克蛋白70（Hsp70）的过表达可减轻哺乳动物脑缺血损伤。对Hsp70中赋予缺血性神经保护作用的结构域进行研究发现，其羧基末端结构域很重要。阿利克仑莫，一种热休克蛋白的共诱导剂，在脊髓和运动皮质运动神经元发生退化的小鼠模型中延缓了肌萎缩侧索硬化症（ALS）的进展。雷公藤红素，作为一种对抗神经退行性疾病的有前景的候选药物，可诱导组织培养中分化神经元表达一组热休克蛋白。热休克“预处理”在突触功能水平保护神经系统，而Hsp70的选择性过表达则增强了突触保护水平。热疗后，组成型表达的热休克同源蛋白70（Hsc70）在富含突触的脑区增加，在那里它与热休克蛋白40（Hsp40）结合形成一个能使变性蛋白重新折叠的复合体。神经元的应激耐受性不仅取决于其自身的热休克蛋白，还可由相邻神经胶质细胞的热休克蛋白补充。因此，在神经损伤部位应用外源性热休克蛋白是维持神经元活力的有效策略。
