Pharmacological intervention of the ischemic penumbra in rats: A study by proton magnetic resonance imaging

The temporal evolution and the pharmacological intervention of focal cerebral ischemia were studied in a rat model of permanent or temporary middle cerebral artery (MCA) occlusion. Multiple pathological events and cerebral hemodynamics were followed for up to one week on individual rats after the occlusion of MCA, using multimodal magnetic resonance imaging techniques. Diffusion-weighted images and T2-weighted spin echo images were used to detect the cytotoxic lesion and vasogenic edema following the onset of ischemia. An assessment of cerebral tissue perfusion status was obtained by a MR contrast-enhanced plasma volume imaging, and by dynamic MR imaging producing relative vascular mean transit time and cerebral blood flow maps. Correlation of ischemic lesions with the cerebral perfusion level VII allowed the identification of a region of ischemic core, where early ischemic damage was seen, and a region of ischemic penumbra, where the onset of ischemic damages were delayed. Quantitative analysis showed that ischemic damage occurred in region where cerebral blood flow (CBF) level was lower than 32% of the contralateral hemisphere. MK801, an non-competitive NMDA receptor antagonist given at a dose of 0.5 mg/kg intravenously 30 minutes before MCA occlusion, significantly reduced the ischemic damage in the ischemic penumbra in the MCA permanent occlusion model. In the reperfusion group, MK801 pretreatment confined the final ischemic damage within the ischemic core. Compared to the saline control, ischemic damage in the MK801 group only occurred in region with more severe perfusion deficit, suggesting MK801 treatment decreased tissue vulnerability to ischemic insult. MK801 reduced both cytotoxic lesion and vasogenic edema to a similar extent. MK801 did not cause a significant change in CBF or brain temperature. This study demonstrated that MRI can be used to define the ischemic core and the ischemic penumbra. The NMDA receptor antagonist MK801 mainly protected the ischemic penumbra from infarction. The neuroprotective effect of MK801 is not mediated by improving CBF or inducing hypothermia.