2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Infarction--Middle-Cerebral-Artery

We characterized the differential effects of glycine at different levels in the induction of postischemic long-term potentiation, as well as in the neuronal damage induced by focal ischemia.. Whole-cell patch clamp recordings were obtained from rat hippocampal slice preparations. In vitro ischemia and postischemic long-term potentiation were induced by oxygen and glucose deprivation. In vivo ischemia was induced by transient middle cerebral artery occlusion.. In both in vitro and in vivo ischemia models, glycine at low level exerts deleterious effects in postischemic long-term potentiation and ischemic neuronal injury by modulation of the N-methyl-d-aspartate receptor coagonist site; whereas glycine at high level exerts neuroprotective effects by activation of glycine receptor and subsequent differential regulation of N-methyl-d-aspartate receptor subunit components.. Our results provide a molecular basis for the dual roles of glycine in ischemic injury through distinct mechanisms, and they suggest that glycine receptors could be a potential target for clinical treatment of stroke.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain Ischemia; Dose-Response Relationship, Drug; Glucose; Glycine; Hippocampus; Hypoxia, Brain; Infarction, Middle Cerebral Artery; Long-Term Potentiation; Male; Patch-Clamp Techniques; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Stereotaxic Techniques; Viruses

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists have been shown to have neuroprotective effects in stroke models and although clinical trials with some agents are still ongoing, published results have not been favourable. We therefore wished to compare the effects of GYKI 52466, GYKI 53405, EGIS-8332 and EGIS-10608, non-competitive AMPA receptor antagonists with homophthalazine chemical structures, in standard animal stroke models with effects in a neurodegenerative model--excitoxicity in newborn mice. All compounds inhibited the S-AMPA-induced spreading depression in the chicken retina, in vitro, and were potent anticonvulsants against maximal electroshock in mice, in vivo. The AMPA receptor antagonists prevented domoate-induced cell death of motoneurons, in vitro, and reduced infarct size in a dose-dependent manner in the permanent middle cerebral artery occlusion model in mice, in vivo. In newborn mice (P5, histopathology at P10), local injection of the AMPA receptor agonist S-bromo-willardiine at day 5 after birth induced cortical damage and white matter damage, which was reduced in a dose-dependent manner by the AMPA receptor antagonists. EGIS 10608 was a very powerful receptor antagonist of white matter damage. In contrast, GYKI 52466 did not antagonize cortical and white matter damage induced by ibotenic acid. These models allow quantification of the effects of AMPA receptor antagonists in vitro and in vivo.

Topics: Animals; Animals, Newborn; Anticonvulsants; Benzodiazepines; Brain; Brain Ischemia; Cell Survival; Chickens; Cortical Spreading Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Excitatory Amino Acid Antagonists; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred Strains; Motor Neurons; Nerve Degeneration; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Retina; Seizures; Stroke

Although stroke is a major cause of death and disability in the elderly, the inhibitory effects of neuroprotectants in acute stroke have been investigated using experimental cerebral ischemic models of young animals. Recent clinical trials have found that few neuroprotectants are effective. These observations indicate that effects in the clinical setting do not always reflect data from young animals. Thus, we compared the effects of the NMDA receptor antagonist MK-801 and of the AMPA receptor antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinixaline] on ischemic cerebral damage in the photothrombosis model of aged and young rats. MK-801 administered immediately after MCA occlusion significantly (P<0.05) reduced the extent of cerebral damage in young, but not in aged, rats and the effects of NBQX were similar. In separate experiments, we evaluated brain damage after microinjecting NMDA or kainic acid into the cortex using a stereotaxic apparatus. We found no significant differences in focal cerebral damage caused by NMDA between young and aged rats. On the other hand, kainic acid caused all of the aged rats tested to die, but none of the young rats. Our observations indicate that NMDA and AMPA receptor antagonists are less effective in aged, than in young, rats and that cerebral damage by receptor agonists depends on the type of receptor, such as NMDA and AMPA.

Topics: Aging; Animals; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Infarction, Middle Cerebral Artery; Kainic Acid; Male; Nerve Degeneration; Neurons; Neuroprotective Agents; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Telencephalon

Neurons and glia reacting to ischemic injury exhibit delayed expression of heat shock proteins (HSPs). We tested the hypothesis that glutamate receptor antagonists alter neuronal and glial activation during focal cerebral ischemia, as shown by spatio-temporal changes in HSP immunoreactivity. Rats underwent focal ischemia by permanent occlusion of the middle cerebral artery. All animals were pre-treated with NBQX (30 mg kg-1), a competitive antagonist of the AMPA/kainate receptor, or CGS-19755 (10 mg kg-1), a competitive NMDA receptor antagonist, and euthanatized after 6 or 24 h of ischemia to demonstrate regional immunoreactivity of HSP-72 or 32 in brain. Neurons immunolabeled for HSP-72 appeared in the penumbral region adjacent to the infarct at 24 h and increased in number and distribution after pretreatment with NBQX or CGS-19755. Immunolabeling for HSP-32 revealed that pre-treatment with CGS-19755 caused ramified glia to infiltrate the ischemic cortex at 6 h, a pattern that was not seen in ischemic controls until 24 h. Blockade of the NMDA or AMPA/kainate receptor modulates cellular stress responses in both neurons and glia within the developing infarct. We conclude that early, rather than delayed, expression of HSP-32 is a sensitive indicator of glial activation induced specifically by CGS-19755.

Topics: Animals; Brain Ischemia; Excitatory Amino Acid Antagonists; Heat-Shock Proteins; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; HSP72 Heat-Shock Proteins; Infarction, Middle Cerebral Artery; Male; Pipecolic Acids; Quinoxalines; Rats; Rats, Inbred SHR