AMPA Antagonist NBQX Research Articles

Administration of quinolic acid in the rat hippocampus induces expression of c- fos and NGFI-A

We have studied the effect of intrahippocampal administration of quinolinic acid (QUIN) on the temporal expression of mRNAs encoding the immediate early genes (IEGs) c- fos and NGFI-A, by in situ hybridization histochemistry. After administration of QUIN to the left hippocampus, expression of mRNA of both IEGs was transiently stimulated. Maximal expression was found between 1 and 3 h. mRNA of both IEGs was simultaneously expressed in the ipsilateral and contralateral sides in the granule cell layer of the dentate gyrus, the pyramidal cell layer of the CA1 and CA3 fields as well as in the cortex. After pretreatment with the non-competitive NMDA antagonist MK-801 (2 mg/kg i.p. − 30 min) the increased expression of both IEGs was partially prevented in the hippocampus and completely in the cortex. No inhibition was observed after treatment with the AMPA antagonist NBQX (30 mg/kg i.p. −15, −5 and +10 min). Additional delayed expression of both IEGs was observed in the ipsilateral hippocampus. This expression was related to cell damage. Twelve h after QUIN administration, c- fos and NGFI-A mRNAs were present in the dentate gyrus. After 4 days, only c- fos mRNA was observed in the dentate gyrus and CA1 field while no NGFI-A mRNA was detected. The present results show that the effect of QUIN is mediated by NMDA and not by AMPA receptors.

Regional cerebral protein synthesis after transient ischemia in the rat: Effect of the AMPA antagonist NBQX

Normothermic rats with 12 min, complete cerebral ischemia were treated with the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxalinedione (NBQX) [10], which prevents CA1 pyramidal neuron loss. Twenty hours after ischemia, cerebral protein synthesis rate (CPSR) was measured autoradiographically using [ 35S]methionine. Ischemia caused a 38% decrease of CPSR in CA1, and postischemic treatment with NBQX caused a 66% decrease in this region. Also treatment with NBQX alone resulted in a decrease (22% in CA1) of the CPSR. Since some evidence exists that the neuroprotective effect of NBQX is related to blockade of the fast AMPA-mediated transmission, the further decrease of the postischemic CPSR in CA1 could be a mere side effect.

MK-801 SELECTIVELY PROTECTS MOUSE ARCUATE NEURONS IN VIVO AGAINST GLUTAMATE TOXICITY

The receptor mediating glutamate toxicity in vivo has not yet been identified. The effects of NMDA antagonist MK-801 and the AMPA antagonist NBQX were studied on glutamate toxicity in the arcuate nucleus of newborn and adult mice. Morphometric methods were used to determine the effects of antagonists on glutamate toxicity. In the developing arcuate, MK-801 abolished glutamate neurotoxicity whereas NBQX has no effect. MK-801, but not NBQX, afforded significant but not complete protection in mature arcuate neurons. The residual toxicity could not be blocked by co-administration of NBQX which paradoxically partially inhibited the protective effect of MK-801. The results show that throughout development, glutamate neurotoxicity in the arcuate nucleus is predominantly mediated by NMDA receptors.

Protection against dendrotoxin-induced clonic seizures in mice by anticonvulsant drugs

Various anticonvulsant drugs were evaluated for their ability to protect against clonic seizures induced in mice by intraventricular injection of the K + channel blocking peptide dendrotoxin (DTX). Phenytoin, the phenytoin-like anticonvulsant carbamazepine and the broad spectrum drug valproate were effective in this model, whereas the GABA-enhancers diazepam and tiagabine, the NMDA antagonists (±)-CPP and (+)-MK-801, the AMPA antagonist NBQX, the antiabsence drug ethosuximide and the Ca 2+ channel antagonist nimodipine were inactive. In contrast to the lack of activity of other NMDA antagonists, phencylclidine and ADCI [(±)-aminocarbonyl-10,11-dihydro-5 H-dibenzo [ a,d]cyclohepten-5,10-imine] were potent antagonists of DTX-induced seizures.

Synergism of the AMPA-antagonist NBQX and the NMDA-antagonist CPP with L-Dopa in models of Parkinson's disease

Degeneration of dopaminergic nigrostriatal neurons in Parkinson's disease results in an overactivity of excitatory glutamatergic projections from the subthalamic nucleus to the output nuclei of the basal ganglia resulting in rigidity and akinesia. In theory pharmacological blockade of these overactive systems should improve parkinsonian symptomatology. The selective AMPA-antagonist NBQX and the competitive NMDA-antagonist CPP are not effective in animal models of Parkinson's disease when given alone but ameliorate parkinsonian symptomatology and stimulate locomotor activity when co-administered with a threshold dose of L-Dopa. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Therefore competitive NMDA and non-NMDA antagonists may offer a new therapeutic strategy for the treatment of Parkinson's disease.