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 i s thought to be responsible for much of the neuronal death that occurs following focal hypoxia-ischemia in the central nervous system, Our l aboratory has identified endogenous sulfated steroids that potentiate or inhibit NMDA-induced currents, Here we report that 3 alpha-ol-5 bet a-pregnan-20-one hemisuccinate (3 alpha 5 beta HS), a synthetic homolo gue of naturally occurring pregnanolone sulfate, inhibits NMDA-induced currents and cell death in primary cultures of rat hippocampal neuron s, 3 alpha beta PHS exhibits sedative, anticonvulsant, and analgesic p roperties consistent with an action at NMDA-type glutamate receptors, Intravenous administration of 3 alpha 5 beta HS to rats (at a nonsedat ing dose) following focal cerebral ischemia induced by middle cerebral artery occlusion significantly reduces cortical and subcortical infar ct size, The in vitro and in vivo neuroprotective effects of 3 alpha 5 beta HS demonstrate that this steroid represents a new class of poten tially useful therapeutic agents for the treatment of stroke and certa in neurodegenerative diseases that involve over activation of NMDA rec eptors.