Neuroprotection afforded by a combination of eliprodil and a thrombolytic agent, rt-PA, in a rat thromboembolic stroke model

Abstract

In the present study, we have assessed the efficacy of eliprodil, a neuroprotective agent which blocks both the modulatory polyamine site of the NMDA receptor and neuronal voltage-sensitive calcium channels, alone or in combination with the thrombolytic agent, rt-PA, in a rat embolic stroke model using a neurological score and the volume of the infarct as endpoints. Embolization was induced by intracarotid injection of an arterial blood clot. Eliprodil, administered at the dose of 1 mg/kg, iv. 10 min and 2 h 30 after embolization, reduced the neurological deficit by 54% (P < 0.01) and the total volume of the brain lesion by 49%. Thrombolysis with rt-PA (2.5 mg/kg, as a 30 min iv infusion beginning 1 h after embolization) decreased the neurological deficit by 48% (P < 0.05) and the size of the total infarct by 55% (P < 0.05). Combined therapy greatly improved the degree of neuroprotection as assessed by neurological and histological outcomes (70% (P < 0.001) and 89% (P < 0.01) neuroprotection, respectively). These results demonstrate that the administration of a neuroprotective drug (eliprodil) or a thrombolytic agent (rt-PA) similarly reduce the volume of brain damage and the neurological deficit in a rat embolic stroke model. Combined cytoprotective therapy and thrombolysis markedly improved the degree of neuroprotection and may, thus, represent a valuable approach for the treatment of stroke in humans.