Neuroprotective Effects of Pregnanolone Hemisuccinate In Vitro and In Vivo

In contrast to the effects of PREGS, pregnanolone hemisuccinate, an inhibitor of the NMDA-induced current and intracellular Ca2+ accumulation, dose-dependently protects primary cultures of rat hippocampal neurons against NMDA-induced neuronal death, and exhibits potent neuroprotective properties in rats subjected to permanent middle cerebral artery occlusion. Pregnanolone hemisuccinate was administered either 5 or 30 min after MCA occlusion as a 7 mg/kg iv bolus followed by a continuous 7 mg/kg/hr iv infusion. When pregnanolone hemisuccinate was administered beginning 5 min after the onset of ischemia, the volume of cortical and subcortical infarct was reduced by 47% and

26%, respectively. When infusion was delayed until 30 min after the onset of ischemia, the volume of cortical infarct was reduced by 39%, with no reduction apparent in the subcortical region (111). As a therapeutic for the treatment of stroke, it is extremely important that neuroprotective agents be effective when given after the onset of ischemia. The demonstration that pregnanolone hemisuccinate is neuroprotective even when administration is delayed until 30 min after the onset of ischemia indicates that pregnanolone hemisuccinate may be a clinically useful compound for the treatment of stroke.

In addition we have also demonstrated in mice that pregnanolone hemisuccinate prevents NMDA-induced convulsions, and is analgesic in the late phase of formalin-induced pain, an animal model for chronic neuropathic pain (111). These results suggest that in addition to neuroprotection pregnanolone hemisuccinate may potentially be useful in the treatment of seizure and chronic pain.

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