The heterogeneous temporal evolution of focal ischemic neuronal damage in the rat.

Male Fisher rats (n = 61) underwent permanent focal cerebral ischemia induced by left middle cerebral artery (MCA) occlusion, in conjunction with ipsilateral common carotid artery ligation. The experiments were terminated at time points ranging from immediately following occlusion to 30 days post MCA occlusion. A coronal histological section, in close proximity to the site of the arterial occlusion, was taken from each brain and divided into six areas encompassing the affected cortex and caudate putamen. Each area was analyzed for ischemic damage according to a grading scale that reflects changes in neuronal morphology. Differential neuronal counts were also made on a 0.5-mm2 field in each of the six areas. The areas closest to the occluded vessel showed accelerated ischemic damage between 8 and 12 h after occlusion, leaving open the possibility that before 8 h, therapeutic intervention may be effective. After 12 h, changes in these areas progressed to complete necrosis and eventual cavitation with a complete loss of neurons after 10 days. The areas more peripheral to the occluded vessel exhibited mild ischemic damage, with an apparent reversal of damage grading at later time points and no loss of neurons. This reversal of ischemic damage in the peripheral areas is suggestive of a histological equivalent of the penumbra.

Temporal evolution of ischemic damage in rat brain measured by proton nuclear magnetic resonance imaging.

We studied the effect of focal cerebral ischemia on the "state" of brain water using proton nuclear magnetic resonance imaging. Focal cerebral ischemia was induced in five halothane-anesthetized rats via tandem occlusion of the left common carotid artery and the left middle cerebral artery. The proton transverse relaxation time, the proton density, and the water diffusion coefficient were measured at various times from the same region of brain tissue from 1.5 to 168 hours after occlusion. Early measurements indicated significant changes in the transverse relaxation time (p = 0.004) and water diffusion coefficient (p = 0.002) of ischemic brain tissue compared with a homologous region from the contralateral hemisphere. However, the transverse relaxation time, proton density, and water diffusion coefficient in ischemic brain tissue showed different temporal evolutions over the study period. Diffusion coefficient weighting was superior to relaxation time and proton density weighting for the visualization of early cerebral ischemia. Our data suggest that nuclear magnetic resonance imaging is sensitive in detecting changes in proton-associated parameters during early cerebral ischemia and confirm significant changes (p less than or equal to 0.01) in the temporal evolution of transverse relaxation times, proton densities, and diffusion coefficients following middle cerebral artery occlusion.

Comparison of phenytoin with noncompetitive N-methyl-D-aspartate antagonists in a model of focal brain ischemia in rat.

Recent in vitro and in vivo experiments have suggested that excitatory amino acid antagonists, particularly those active at the N-methyl-D-aspartate receptor subtype, are effective in ameliorating ischemic injury due to their antiexcitotoxic activity. However, these drugs are also potent and effective in vivo anticonvulsants. The present experiments compared the noncompetitive N-methyl-D-aspartate antagonists phencyclidine and MK-801 with the anticonvulsant phenytoin in a model of focal brain ischemia. Fisher F-344 rats were subjected to tandem occlusion of the middle cerebral and ipsilateral common carotid arteries under halothane anesthesia. Compounds were administered intravenously 30 minutes and 24 hours after arterial occlusion; infarct size was assessed at 48 hours after occlusion. Phencyclidine had no effect on infarct volume at 1 mg/kg, significantly reduced (by 36%) infarct volume at 3 mg/kg, and produced a nonsignificant 26% decrease at 10 mg/kg. The more potent and selective noncompetitive antagonist MK-801 reduced (by 32%) infarct volume significantly at 0.1 mg/kg, produced a nonsignificant 23% decrease at 0.3 mg/kg, and had no effect at 0.5 mg/kg. Phenytoin, which is not a glutamate antagonist, reduced the infarct volume by 45% at 28 mg/kg. A single dose of phenytoin (28 mg/kg) administered 30 minutes after occlusion was neuroprotective, but delaying drug administration for more than 2 hours was ineffective. These data suggest that blockade of the N-methyl-D-aspartate receptor is effective in reducing the infarct size after focal cerebral ischemia. The neuroprotective activity of phenytoin suggests that this may be related to the common anticonvulsant action.