Weaver C E, Marek P, Park-Chung M, Tam S W, Farb D H
Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, 80 East Concord Street, Boston, MA 02118, USA.
Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10450-4. doi: 10.1073/pnas.94.19.10450.
Release of the excitatory neurotransmitter glutamate and the excessive stimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors is thought to be responsible for much of the neuronal death that occurs following focal hypoxia-ischemia in the central nervous system. Our laboratory has identified endogenous sulfated steroids that potentiate or inhibit NMDA-induced currents. Here we report that 3alpha-ol-5beta-pregnan-20-one hemisuccinate (3alpha5betaHS), a synthetic homologue of naturally occurring pregnanolone sulfate, inhibits NMDA-induced currents and cell death in primary cultures of rat hippocampal neurons. 3alpha5betaHS exhibits sedative, anticonvulsant, and analgesic properties consistent with an action at NMDA-type glutamate receptors. Intravenous administration of 3alpha5betaHS to rats (at a nonsedating dose) following focal cerebral ischemia induced by middle cerebral artery occlusion significantly reduces cortical and subcortical infarct size. The in vitro and in vivo neuroprotective effects of 3alpha5betaHS demonstrate that this steroid represents a new class of potentially useful therapeutic agents for the treatment of stroke and certain neurodegenerative diseases that involve over activation of NMDA receptors.
兴奋性神经递质谷氨酸的释放以及N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体的过度刺激被认为是中枢神经系统局灶性缺氧缺血后发生的许多神经元死亡的原因。我们实验室已经鉴定出能增强或抑制NMDA诱导电流的内源性硫酸化甾体。在此我们报告，3α-羟基-5β-孕烷-20-酮半琥珀酸酯（3α5βHS），一种天然存在的硫酸孕烷醇酮的合成类似物，可抑制大鼠海马神经元原代培养物中NMDA诱导的电流和细胞死亡。3α5βHS表现出与作用于NMDA型谷氨酸受体一致的镇静、抗惊厥和镇痛特性。在大脑中动脉闭塞诱导的局灶性脑缺血后，以非镇静剂量给大鼠静脉注射3α5βHS可显著减小皮质和皮质下梗死灶的大小。3α5βHS的体外和体内神经保护作用表明，这种甾体代表了一类新型的潜在有用的治疗药物，可用于治疗中风和某些涉及NMDA受体过度激活的神经退行性疾病。
