Signal transduction via
ionotropic glutamate receptors is found in many life forms, from protozoa to mammals.
Glutamate is the main excitatory
neurotransmitter in the mammalian CNS, were fast postsynaptic depolarisation is induced by the activation of
AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. In addition to their important physiological role, excessive
AMPA receptor stimulation is also a hallmark of excitotoxicity-related diseases, like
ischaemic stroke. Conversely,
AMPA receptor inhibitors were proposed to be useful
neuroprotective drugs. First generation
AMPA receptor blockers were competitive antagonists, like
NBQX, which showed robust neuroprotection in a variety of disease-related animal models. Its clinical use, however, was restricted by the very low solubility, inducing kidney precipitaton in vivo. Second generation competitive antagonists are available, which do not possess this property. None of those, however, up to now is in clinical use. Competitive
AMPA receptor antagonists are not the first choice for
neuroprotective drugs, since due to receptor kinetics they preferently suppress the physiological relevant component of the postsynaptic
glutamate response. Non-competitive blockers, like 2,3-benzodiazepines or the novel
neuroprotectant BIIR 561 should be suited better for the treatment of
stroke. The latter compound is also described as blocker of
voltage-gated sodium channels. Targetting more than one mechanism in the excitotoxicity cascade might be a fruitful approach for the development of
neuroprotective drugs.