Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-D-aspartate receptor

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 3 alpha-ol-5 beta-pregnan-20-one hemisuccinate (3 alpha 5 beta HS), a synthetic homologue of naturally occurring pregnanolone sulfate, inhibits NMDA-induced currents and cell death in primary cultures of rat hippocampal neurons, 3 alpha beta PHS exhibits sedative, anticonvulsant, and analgesic properties consistent with an action at NMDA-type glutamate receptors, Intravenous administration of 3 alpha 5 beta HS 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 3 alpha 5 beta HS 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.