Neuroprotective efficacy and therapeutic window of the high-affinity N-methyl-D-aspartate antagonist conantokin-G: In vitro (Primary cerebellar neurons) and in vivo (rat model of transient focal brain ischemia) studies

Conantokin-G (Con-G), a 17-amino-acid peptide derived from marine snails an d a potent N-methyl-D-aspartate (NMDA) antagonist, was evaluated for its ne uroprotective properties in vitro and in vivo. In primary cerebellar neuron s, Con-G was shown to decrease excitotoxic calcium responses to NMDA and to exhibit differential neuroprotection potencies against hypoxia/hypoglycemi a-, NMDA-, glutamate-, or veratridine-induced injury. Using the intralumina l filament method of middle cerebral artery occlusion as an in vivo rat mod el of transient focal brain ischemia, the neuroprotective dose-response eff ect of Con-G administration beginning 30 min postocclusion was evaluated af ter 2 h of ischemia and 22 h of reperfusion. In the core region of injury, an 89% reduction in brain infarction was measured with significant neurolog ical and electroencephalographic recovery at the maximal dose tested (2 nmo l), although mild sedation was noted. Lower doses of Con-G (0.001-0.5 nmol) were significantly neuroprotective without causing sedation. Postinjury ti me course experiments demonstrated a therapeutic window out to at least 4 t o 8 h from the start of the injury, providing a 47% reduction in core injur y. The neuroprotective effect of Con-G (0.5 nmol) was also evaluated after 72 h of injury, where a 54% reduction in core brain infarction was measured . Critically, in both recovery models (i.e., 24 and 72 h), the reduction in brain infarction was associated with significant improvements in neurologi cal and electroencephalographic recovery. These data provide evidence for t he potent and highly efficacious effect of Con-G as a neuroprotective agent , with an excellent therapeutic window for the potential intervention again st ischemic/excitotoxic brain injury.