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Diffusion and perfusion magnetic resonance imaging studies to evaluate a noncompetitive N-methyl-D-aspartate
1Department of Neurology, Medical Center of Central Massachusetts, Worcester 01605.
Background And Purpose:
Diffusion magnetic resonance imaging (MRI) can quantitatively detect focal ischemic injury within minutes of onset, and perfusion MRI can evaluate the brain's microcirculation. N-Methyl-D-aspartate (NMDA) antagonists and reperfusion can reduce lesion size in stroke models. We used diffusion and perfusion MRI to evaluate the in vivo effects of a noncompetitive NMDA antagonist, CNS 1102, in a temporary ischemia model.
Methods:
Sixteen Sprague-Dawley rats underwent suture occlusion of the middle cerebral artery. Fifteen minutes after occlusion, animals were randomly assigned to treatment with CNS 1102 (n = 10) or placebo (n = 6), receiving a bolus of 1.13 mg/kg at that time and an infusion of 0.785 mg.kg-1.h-1 for the next 165 minutes. The placebo group received a saline bolus and infusion. Diffusion MRI studies by a spin-echo technique were initiated 30 minutes after occlusion and repeated every 30 minutes for the next 3 hours. Perfusion MRI studies were obtained using echo-planar imaging after injection of superparamagnetic iron oxide particles, immediately before and 15 minutes after withdrawal of the occluder at 3 hours after middle cerebral artery occlusion. At 24 hours, the animals were clinically evaluated (scale of 0 to 5) and electively killed, and the brain was stained with triphenyltetrazolium chloride to evaluate infarct size.
Results:
Diffusion imaging demonstrated markedly reduced ischemic lesion area in the CNS 1102 group during occlusion--10.5 +/- 7.3% (mean +/- SEM) of the ischemic hemisphere (optic chiasm slice) at 30 minutes after occlusion versus 50.0 +/- 2.7% of the hemisphere in controls (P < .02). With reperfusion after 3 hours of temporary ischemia, diffusion imaging documented an additional 29% reduction of the ischemic lesion area in the CNS 1102-treated group (P < .01) compared with the prereperfusion ischemic lesion area, with no change in the placebo group. During occlusion, perfusion imaging demonstrated a relative signal intensity decline of 31.5 +/- 7.7% in controls and 83.4 +/- 7.6% in the CNS 1102 group (P < .005), indicating better perfusion in the latter group. After removal of the occluder, perfusion improved in both groups and was not significantly different. Post mortem infarct volume was 53.8 +/- 20.0 mm3 in the CNS 1102 group and 216.8 +/- 16.1 mm3 in the controls (P < .0001). Clinical outcome at 24 hours was 1.1 +/- 0.4 in the CNS 1102 group and 4.0 +/- 0.5 (scale of 0 to 5) in the controls (P < .005).
Conclusions:
This study demonstrates that CNS 1102 reduces early postischemic injury as documented by diffusion MRI and improves perfusion as documented by perfusion MRI and that reperfusion confers additional reduction of ischemic lesion size.
Insights
The NMDA antagonist CNS 1102 significantly reduced ischemic brain injury and improved perfusion in a rat stroke model. This neuroprotective agent demonstrated reduced lesion size and better clinical outcomes after temporary ischemia.
Area of Science:
- Neuroscience
- Radiology
- Pharmacology
Background:
- Diffusion MRI detects ischemic injury; perfusion MRI assesses brain microcirculation.
- N-Methyl-D-aspartate (NMDA) antagonists and reperfusion show potential in reducing stroke lesion size.
- In vivo evaluation of NMDA antagonists in temporary ischemia models is crucial.
Purpose of the Study:
- To evaluate the in vivo effects of the NMDA antagonist CNS 1102.
- To assess CNS 1102's impact on ischemic injury using diffusion MRI.
- To determine the drug's effect on brain microcirculation via perfusion MRI.
Main Methods:
- Temporary middle cerebral artery occlusion in 16 Sprague-Dawley rats.
- Random assignment to CNS 1102 treatment (n=10) or placebo (n=6).
- Diffusion and perfusion MRI performed during occlusion and reperfusion; infarct size and clinical outcomes assessed at 24 hours.
Main Results:
- CNS 1102 significantly reduced ischemic lesion area by 10.5% vs. 50.0% during occlusion (P < .02).
- Reperfusion led to an additional 29% lesion reduction in the CNS 1102 group (P < .01).
- CNS 1102 improved perfusion (P < .005), reduced infarct volume (P < .0001), and improved clinical outcomes (P < .005).
Conclusions:
- CNS 1102 effectively reduces early postischemic injury, as shown by diffusion MRI.
- Perfusion MRI confirmed improved microcirculation with CNS 1102 treatment.
- Reperfusion provides additional benefits in reducing ischemic lesion size when combined with CNS 1102.