During cerebral ischaemia, glutamate is released in supraphysiological amounts 
and is toxic to brain tissue. This excitotoxicity is mediated by several 
glutamate receptor subtypes, including the ionotropic N-methyl-D-aspartate 
(NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) 
receptors. Clinical trials of drugs that block the NMDA receptor in acute 
ischaemic stroke have been disappointing. No improvement in clinical outcome of 
stroke has been seen with competitive NMDA antagonists (selfotel) and 
non-competitive NMDA antagonists (dextrorphan, GV150526, aptiganel and 
eliprodil). The AMPA receptor differs in important ways from the NMDA receptor. 
It is the principal mediator of fast excitatory neurotransmission. This 
ligand-gated cation channel is primarily permeable to sodium rather than 
calcium. It is found in grey and white matter. It is expressed by 
oligodendrocytes. This distribution may provide neuroprotection for both grey 
and white matter. In a variety of animal models, reduction in infarct volume 
with AMPA blockade has been demonstrated. AMPA antagonists also show benefit in 
spinal cord ischaemia and trauma. The clinical development of safe and effective 
AMPA blockers has been hampered by poor water solubility and associated renal 
toxicity. A novel, highly water-soluble, competitive AMPA receptor antagonist, 
YM872 
([2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic 
acid monohydrate; Yamanouchi), has been identified. Phase I clinical trial data 
indicate that this agent can be safely administered in young and elderly 
subjects. Sedation and other CNS associated adverse events determine the ceiling 
dose and become more problematic with infusion times exceeding 24 h. Phase II 
studies of YM872 in acute ischaemic stroke are ongoing.