2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Cerebrovascular-Disorders

The cytoprotective effects of MK-801 and NBQX, selective N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists, respectively, were compared both singularly and in combination in models of transient severe forebrain and transient focal cerebral ischemia. After 10 minutes of four-vessel occlusion ischemia, the sodium salt of NBQX (30 mg/kg IP) given at the time of reperfusion and, subsequently, 15 and 30 minutes later produced a dramatic reduction in CA1 hippocampal necrosis at 7 days. This effect was not obtained with the intraperitoneal administration of either MK-801 (1 mg/kg x 3) or the combination of both NBQX and MK-801 given at the same time intervals. This effect of intraperitoneal NBQX alone was reproduced in a two-vessel occlusion/hypotension model using this same drug administration. Delayed treatment with both NBQX and GYKI 52466, but neither MK-801 nor the combination of NBQX and MK-801 given after a delay, produced a significant reduction in the mean volume of neocortical infarction after transient focal ischemia. We conclude that the AMPA receptor may play a more important role than the NMDA receptor in both selective ischemic necrosis of hippocampal neurons and in neocortical infarction. AMPA antagonists should be subjected to clinical stroke trials.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anti-Anxiety Agents; Benzodiazepines; Cerebral Infarction; Cerebrovascular Disorders; Dizocilpine Maleate; Drug Administration Schedule; Injections, Intraperitoneal; Male; N-Methylaspartate; Quinoxalines; Rats; Rats, Wistar; Reperfusion

A focal, unilateral thrombotic stroke was produced in the rat sensorimotor cortex. The time course of expression and localization of the immediate early inducible genes: c-fos, c-jun, zif268; nerve growth factor, brain-derived neurotrophic factor and the related tyrosine kinase high-affinity receptor (trkB) messenger RNAs were studied by in situ hybridization. The levels of messenger RNAs for c-fos, zif268, brain-derived neurotrophic factor (but not nerve growth factor) and trkB were consistently increased in cortex ipsilaterally to the lesion, while c-jun messenger RNA content was only slightly increased. The brain-derived neurotrophic factor messenger RNA was increased from 2 to 18 h following the stroke, mainly in cells having a normal morphological appearance. The trkB messenger RNA displayed temporal and spatial increases similar to brain-derived neurotrophic factor messenger RNA. The time course and pattern of expression of immediate early inducible gene and trophic factor messenger RNAs did not clearly support a causal relationship between these two families of factors. The observed messenger RNA increases were greatly attenuated by the non-competitive N-methyl-D-aspartate-sensitive glutamate receptor antagonist (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine , but substantially unaffected by the non-N-methyl-D-aspartate receptor antagonist 2,3-dihydroxy-6-nitrosulphanoylbenzoquinoxaline. The results suggest a major contribution of N-methyl-D-aspartate-sensitive glutamate receptor activation to the transcriptionally directed events subsequent to stroke. Future studies should clarify the contribution of these processes to either the progression of neuronal degeneration or the establishment of protective compensatory responses.

Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Cerebrovascular Disorders; Dizocilpine Maleate; DNA-Binding Proteins; Early Growth Response Protein 1; Gene Expression; Genes, fos; Genes, jun; Immediate-Early Proteins; In Situ Hybridization; Kinetics; Male; Membrane Proteins; Nerve Growth Factors; Nerve Tissue Proteins; Photochemistry; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Proto-Oncogenes; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptor, Ciliary Neurotrophic Factor; RNA, Messenger; Rose Bengal; Time Factors; Transcription Factors

Efficacy and safety of combined alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor blockade and thrombolytic therapy with human recombinant tissue plasminogen activator (TPA) was tested in a rat embolic stroke model. Sixty-three rats were embolized in the right internal carotid territory with a 200 microliters suspension of microclots formed by alternate moving of 150 microliters whole blood and 50 microliters of thrombin between two interconnected syringes for 4 min. Sixteen embolized rats served as controls, and 16 rats were treated with NBQX immediately after embolization. Thirty-one rats were treated with TPA 2 h following embolization, and in 16 of these rats additional NBQX treatments were initiated 90 min following embolization. Hemispheric cerebral blood flow (CBF) was measured by an intraarterial 133Xenon injection method before and after embolization. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after 2 days, evaluated neuropathologically, and infarct volumes were measured. Median CBF was reduced by 70-77% in the affected hemispheres following embolization. Significant recanalization occurred in all groups except those treated with NBQX. TPA-treated rats had significantly better reperfusion compared to controls judged by angiography 3 h following embolization (P = 0.04). NBQX alone and TPA alone caused insignificant reduction in infarct volume but, when combined, total infarct volume was reduced by 77% compared to controls (P = 0.02). Separate measurement of cortical infarct revealed significantly smaller infarcts (P = 0.05) in the combined treatment group compared to the TPA treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Cerebral Angiography; Cerebral Infarction; Cerebrovascular Circulation; Cerebrovascular Disorders; Fibrinolytic Agents; Intracranial Embolism and Thrombosis; Male; Plasminogen Activators; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA