6-cyano-7-nitroquinoxaline-2-3-dione and Nervous-System-Diseases

There is conflicting evidence regarding the impact of glucocorticoid exposure on hypoxic ischemic brain injury. We examined the effects of timing, duration, and concentration of dexamethasone on neuronal injury following in vitro oxygen glucose deprivation (OGD). Dissociated embryonic rat basal forebrain cells were cultured and either preincubated with dexamethasone for 72 h or continuously exposed prior to, during, and after OGD. Injury was assessed by morphology rating and cholineacetyltransferase (ChAT) activity at Day 13 in vitro, 2 days after OGD. Preincubation with nanomolar concentrations of dexamethasone resulted in a dose-dependent exaggeration of injury. Combined glutamate receptor antagonist application negated this deleterious effect, suggesting that dexamethasone may increase glutamate release, decrease uptake, or upregulate glutamate receptor expression. Continuous application of a narrow concentration range of dexamethasone (100 nM and 1 microM) prior to, during, and after insult protected neurons. Dose, timing, and duration of glucocorticoid administration may each be critical variables influencing outcome of hypoxic ischemic brain insult.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cell Death; Cell Hypoxia; Choline O-Acetyltransferase; Dexamethasone; Excitatory Amino Acid Antagonists; Fetus; Glucose; L-Lactate Dehydrogenase; Nervous System Diseases; Neuroprotective Agents; Neurotoxins; Prosencephalon; Rats; Rats, Sprague-Dawley

Neurotoxicity of glutamate in conjunction with subcritical hypoxia was determined in vitro using hippocampal neurons obtained from 18-day-old rat fetuses. Neurons were plated at a low density and maintained for 3 days in a chemically defined medium without glutamate. When glutamate + was added after subcritical hypoxic stress, a low dose of glutamate, even at 10 microM, could cause significant neuronal loss in the following 24 h. The observed neurotoxicity to low glutamate dose (10-100 microM) could completely be prevented by 5 microM of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). This protective effect of CNQX was more potent than that of MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate). The mechanism by which glutamate is transformed from a neurotransmitter to a neurotoxin is discussed.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamates; Glutamic Acid; Hippocampus; Hypoxia; Nervous System Diseases; Neurons; Pregnancy; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, AMPA; Receptors, Kainic Acid; Receptors, Neurotransmitter