AMPA receptors: a better target for ischaemic brain damage?

Abstract

The excitatory transmitter glutamate accumulates in the interstitial space of brain tissue following ischaemic insult, and facilitates neuronal cell death via excessive stimulation of glutamate receptors. Pre-clinical data suggest that glutamate blockers might be effective for preventing neurodegeneration following brain ischaemia. The prevalent assumption used to be that damage to neurons is mediated mainly following excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors. However, NMDA-receptor blockade did not effectively reduce ischaemic brain damage in several animal models. Another glutamate receptor subtype, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor, is more closely associated with neuronal cell death following ischaemic stroke. The study by Schielke et al.1 Schielke G.P. et al. The neuroprotective effect of the novel AMPA receptor antagonist PD152247 (PNQX) in temporary focal ischaemia in the rat. Stroke. 1999; 30: 1472-1477 Crossref PubMed Scopus (23) Google Scholar shows that 1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido [3,4-f]quinoxaline-2,3-dione (PNQX), a potent and selective AMPA receptor antagonist, reduced ischaemic brain damage following temporary focal ischaemia in the rat. Temporary ischaemia was induced by occluding the middle cerebral artery and both carotid arteries for 3 h. Brain lesion volume, determined by haematoxylin and eosin staining after three days, was reduced by half in rats receiving PNQX within 30 min of the insult 1 Schielke G.P. et al. The neuroprotective effect of the novel AMPA receptor antagonist PD152247 (PNQX) in temporary focal ischaemia in the rat. Stroke. 1999; 30: 1472-1477 Crossref PubMed Scopus (23) Google Scholar .