6-(1h-imidazol-1-yl)-7-nitro-2-3(1h-4h)-quinoxalinedione and selfotel

An in vitro model of ischemia was developed and characterized using the acute rat hippocampal slice preparation. Neuroprotective concentrations of several competitive and noncompetitive glutamate subtype-selective antagonists (CGS-19755, MK-801, YM90K and GYKI-52466) were initially determined in anoxia-enhanced agonist-induced excitotoxicity experiments. Concentrations which proved to be effective in these studies were subsequently tested for their effectiveness against an ischemic episode. Ischemia was defined as a 30-min exposure to aglycemic media ending in 5 min of concurrent anoxia, a protocol which was arrived at by empirically determining the effect of various hypoglycemic and anoxic insults on the ability of hippocampal slices to retain their electrophysiological viability. Exposure to such an ischemic episode resulted in a loss of viability by most slices, an effect which was strongly dependent on extracellular calcium. AMPA antagonists applied alone produced no neuroprotective effect in the present model of in vitro ischemia, while NMDA antagonists applied alone had a modest neuroprotective effect. In contrast, the coapplication of 10 microM MK-801 and 300 microM GYKI-52466, noncompetitive NMDA and AMPA receptor antagonists, respectively, resulted in almost complete neuroprotection. This protection was comparable to that obtained by withholding extracellular calcium, indicating that the toxic effects of glutamate receptor overstimulation can be accounted for solely by calcium influx. The effect of this combination treatment on the survival rate of hippocampal slices was synergistic, that is greater than the sum of the effects of the individual compounds. The results indicate that neuroprotection against acute ischemic insults may require a combination therapy approach.

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Brain Ischemia; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hypoxia; Male; Neuroprotective Agents; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

In this study, we examined the acute anticonvulsant spectrum of (1) dizocilpine (0.03-3 mg/kg), CGS 19755 (1-10 mg/kg), and 7-chlorokynurenic acid (1-100 nmol) (NMDA receptor/ionophore complex antagonists); (2) muscimol (0.1-10 nmol; direct GABA(A) agonist); (3) YM90K (3-10 mg/kg; AMPA receptor antagonist); and (4) diazepam (2 and 5 mg/kg) and carbamazepine (5 and 20 mg/kg), two standard anticonvulsants, using the partially-kindled hippocampal model for epileptic seizures in freely moving rats. The anticonvulsant effect of these compounds were assessed by determining (1) the afterdischarge (AD), which is indicative of the severity of the seizure and related to seizure maintenance, and (2) the pulse number threshold (PNT), which is indicative of the seizure threshold or initiation. In addition, ataxia, a measure of CNS dysfunction, was assessed for each compound. Overall, our results indicated that the anticonvulsant compounds examined could be classified into three categories based on effects on the AD and PNT: (1) elevation of PNT (carbamazepine, dizocilpine, CGS 19755 and 7-chlorokynurenic acid); (2) reduction of AD (diazepam and muscimol); and (3) mixed action, i.e., increased PNT and decreased AD (YM90K). Behavioral data indicated that all compounds, except carbamazepine, produced a dose- or concentration-dependent ataxia. Overall, our results suggest that NMDA receptors play a role in seizure initiation, whereas the GABA(A) receptors appear to be involved in seizure maintenance and AMPA receptors may be involved in both phenomena.

Topics: Animals; Anticonvulsants; Ataxia; Carbamazepine; Diazepam; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; GABA Agonists; Hippocampus; Kynurenic Acid; Male; Muscimol; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Seizures

The interaction of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist YM90K with the competitive N-methyl-D-aspartate (NMDA) antagonist CGS19755 or with the NMDA channel blocker MK801 on the spatial memory of rats was examined by the 4-arm-baited radial maze task. When administered alone, these drugs had no effect on the spatial memory. The combination of YM90K and MK801 synergistically disrupted working and reference memories, whereas the combination of YM90K and CGS19755 had no effect. These results indicate that the blockade of the AMPA receptor and NMDA channels produces a synergistic impairment of spatial memory and suggest that interaction between the AMPA and NMDA receptors plays a role in cognitive function.

Topics: Animals; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

The effects of the N-methyl-D-aspartate (NMDA) receptor antagonists CGS19755 and MK801 and the 2-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist YM90K on spatial working memory were investigated by using a delay-interposed radial-arm maze (RAM) task in rats. CGS19755 and MK801, at the largest dose that had no effect on the performance in the nondelayed RAM task, significantly decreased the initial correct response after the 5-min delay in the delay-interposed RAM task. In contrast, YM90K had no effect on the initial correct response and arm reentries in both the delay-interposed and nondelayed RAM task. CGS19755, MK801 and YM90K, at all doses tested, did not alter the running time in either the delayed or the nondelayed RAM tasks. These results suggest that spatial working memory can be impaired by a blockade of NMDA receptor function and that such impairment is particularly sensitive to delay interposition. The lack of effect of the AMPA receptor antagonist provides additional evidence of the importance of the NMDA subtype of the glutamate receptors in cognitive processes.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory, Short-Term; Pipecolic Acids; Psychomotor Performance; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Space Perception