Neuroprotection with NBQX in rat focal cerebral ischemia. Effects on ADC probability distribution functions and diffusion-perfusion relationships.
OBJECTIVE
We have previously shown that treatment with glutamate receptor antagonists after focal ischemia can partially reverse acute lesions measured with diffusion-weighted MRI. The goal of this study was to examine the quantitative nature of these effects of neuroprotection.


METHODS
Rats were subjected to permanent occlusion of the middle cerebral artery under halothane anesthesia and treated with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (30 mg/kg IP; two doses given immediately after ischemia and 1 hour after ischemia) or given injections of saline. Diffusion-weighted MRI scans were performed to map the changes in water diffusivity during the first 3 hours after ischemia. Apparent diffusion coefficients (ADCs) within the ischemic hemisphere were calculated, and ischemic changes were expressed as absolute reductions and as a percentage of contralateral mean values. Relative perfusion deficits in the ischemic hemisphere were assessed with dynamic MRI of transient changes in transverse relaxation rates (delta R2*).


RESULTS
Analysis with ADC probability distribution functions showed that focal ischemia was present with gradients in ADC reductions emanating from the center to the periphery of the lesion. Ischemic evolution in control rats was manifested as a progressive shift of the probability distribution functions over time. NBQX treatment resulted in a reverse shift of these probability functions. By 3 hours after occlusion, probability distribution functions were significantly improved in treated rats (P < .05). Because of the temporal evolution of the probability distribution functions, ADC thresholds that correlated with histological outcomes of infarction changed over time. NBQX did not alter the cerebral perfusion index, measured as delta R2* peak values.


CONCLUSIONS
The results indicate that ADC probability distribution functions can be used to quantitatively evaluate the effects of neuroprotective treatment on the gradients of injury in focal cerebral ischemia. The probability functions also allow for intrasubject comparisons and may therefore be useful for exploring therapeutic windows.
Lo
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EH
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA. eng@cipr.mgh.harvard.edu
Pierce
A R
AR
Mandeville
J B
JB
Rosen
B R
BR
D000818:Animals; D001834:Body Water / Q000378:metabolism*; D001925:Brain Damage, Chronic / Q000517:prevention & control*; D001929:Brain Edema / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D004058:Diffusion; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors
D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline