2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Brain-Damage--Chronic

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.. 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*).. 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.. 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.

Topics: Animals; Body Water; Brain Damage, Chronic; Brain Edema; Brain Ischemia; Cerebral Infarction; Diffusion; Excitatory Amino Acid Antagonists; Magnetic Resonance Imaging; Male; Nerve Tissue Proteins; Neuroprotective Agents; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA

Glutamate receptors are numerous on the ischemia vulnerable CA-1 pyramidal cells. Postischemic use of the AMPA antagonist NBQX has shown up to 80% protection against cell death. Three aspects of this were studied: In the first study, male Wistar rats were given NBQX (30 mg/kg x 3) either 20 hours or immediately (0 h) before 12 min of 4-vessel occlusion with hypotension. After six days of reperfusion comparison with an untreated group showed almost full protection in the 0 h group (4% cell loss, p < 0.001) but only slight protection in the 20 h group (62% cell loss, p < 0.05). After 12 min of ischemia in the present model, eosinophilic CA-1 cells are seen from day 2 on. Since there could be a late, deleterious calcium influx via NMDA receptors, one group of ischemic rats was given MK-801 (5 mg/kg i.p.) 24 hours after ischemia. However, quantitation 6 days later of remaining CA-1 cells showed no protection. In the third study referred here, two groups of ischemic rats were given NBQX (30 mg/kg x 3) immediately after ischemia. The groups survive for six and 21 days, respectively. Counting of CA-1 pyramidal cells showed an equal, significant protection in both groups (approx 20% cell loss).

Topics: Animals; Brain Damage, Chronic; Brain Ischemia; Brain Mapping; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Male; Neurons; Premedication; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

In a model of perinatal hypoxic-ischemic brain damage, we examined the neuroprotective efficacy of posttreatment with the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist NBQX. Unilateral brain damage developed in 95% of rat pups subjected to hypoxia-ischemia with a 27.8 +/- 1.2% weight deficit of the damaged hemisphere. MK-801 in doses of 0.3 and 0.5 mg/kg i.p. reduced the brain damage by 61% (p < 0.001) and 43% (p < 0.001), respectively. A higher dose of MK-801 (0.75 mg/kg) did not offer neuroprotection. Treatment with NBQX (40 mg/kg) reduced the hemispheric lesion by 28% (p < 0.05). In conclusion, posttreatment with both NBQX and low doses of MK-801 reduced perinatal brain damage. The NMDA receptor antagonist offered stronger neuroprotection which is in agreement with a proposed NMDA receptor hyperactivity around postnatal day 7 in rats.

Topics: Animals; Animals, Newborn; Brain Damage, Chronic; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Hypoxia, Brain; Injections, Intraperitoneal; Male; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Severity of Illness Index; Treatment Outcome

Two glutamate antagonists were tested in a rat model of complete, transient cerebral ischemia. Six days after 10 min ischemia the mean loss of hippocampal CA1 pyramidal neurones was 73%. Administration of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) antagonist NBQX (2,3-dihydro-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) reduced the pyramidal neurone loss to 1%, 11% and 15%, when given before, immediately after or 1 h after ischemia, respectively. MK-801 (dizocilpine), a competitive NMDA antagonist gave no protection in this model. We suggest that the AMPA receptor transduction mechanisms are sensitized by ischemia and that the postischemic blockade of the main glutamatergic input to the CA1 cells with NBQX impairs the deleterious effect of "normal" postischemic excitatory transmission.

Topics: Animals; Brain Damage, Chronic; Brain Ischemia; Cell Count; Hippocampus; Male; Nerve Degeneration; Neurons; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter