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Effects of a novel NMDA antagonist on experimental stroke rapidly and quantitatively assessed by diffusion-weighted
1Department of Neurology, Medical Center of Central Massachusetts, Worcester 01605.
Abstract:
We employed diffusion-weighted MRI (DWI) to identify regions of focal brain ischemia during the first 3 hours after permanent occlusion of the middle cerebral artery in rats. Using DWI as early as 30 minutes after the onset of ischemia, it was possible to identify the areas of brain destined to progress to infarction over the next 24 hours in untreated animals, as demonstrated by postmortem evaluation. DWI studies revealed the cerebroprotective effects of a noncompetitive N-methyl-D-aspartate receptor antagonist, CNS 1102, administered 15 minutes postocclusion, both on the cortical and caudoputaminal regions during the initial 3 hours of ischemia. Although the treatment effect lessened over the next 21 hours in a few animals with lower plasma drug levels at 3 hours, postmortem studies demonstrated a 66% reduction in the total volume of infarcted tissue with the treatment and confirmed the DWI results. T2-weighted MRI obtained at similar times revealed little or no abnormality. These results suggest that DWI provides a sensitive in vivo measure of focal cerebral ischemic injury and can assess the beneficial effects of cytoprotective therapy. DWI may be useful in the early evaluation of human stroke patients and in monitoring the effects of cerebroprotective therapies in the clinical setting.
Insights
Diffusion-weighted MRI (DWI) detects early brain ischemia and infarction in rats. DWI also shows the protective effects of N-methyl-D-aspartate receptor antagonists against stroke, aiding stroke evaluation.
Area of Science:
- Neuroscience
- Radiology
- Pharmacology
Background:
- Focal cerebral ischemia, such as middle cerebral artery occlusion, leads to brain infarction.
- Early detection of ischemic brain regions is crucial for timely intervention.
- Assessing the efficacy of neuroprotective agents requires sensitive imaging techniques.
Purpose of the Study:
- To evaluate diffusion-weighted MRI (DWI) for detecting early focal cerebral ischemia.
- To assess the cerebroprotective effects of a novel N-methyl-D-aspartate receptor antagonist (CNS 1102).
- To correlate in vivo DWI findings with postmortem infarct volumes.
Main Methods:
- Permanent middle cerebral artery occlusion was induced in rats.
- Diffusion-weighted MRI (DWI) was performed at various time points post-occlusion.
- Animals received either vehicle or CNS 1102 (a noncompetitive N-methyl-D-aspartate receptor antagonist) 15 minutes postocclusion.
- T2-weighted MRI was also acquired for comparison.
- Postmortem histological analysis was conducted to determine infarct volume.
Main Results:
- DWI identified ischemic regions as early as 30 minutes after middle cerebral artery occlusion.
- DWI revealed significant cerebroprotection in cortical and caudoputaminal areas with CNS 1102 treatment.
- Postmortem studies confirmed a 66% reduction in infarct volume in treated animals compared to controls.
- T2-weighted MRI showed minimal abnormalities, highlighting DWI's sensitivity.
Conclusions:
- DWI is a sensitive in vivo tool for detecting focal cerebral ischemic injury.
- DWI can effectively monitor the beneficial effects of cytoprotective therapies like CNS 1102.
- DWI holds potential for early human stroke evaluation and therapy monitoring.