the brain. Strokes may be of two types: hemorrhagic (in which the artery actually
ruptures or leaks) or ischemic (in which the artery is blocked by debris or progressive
narrowing and no blood can go through it). Ischemic strokes are by far the more
common and are a byproduct of atherosclerosis and other disorders of blood vessels.
The medical treatment of stroke has been revolutionized in the past five years by the
introduction of therapy with tPA (tissue plasminogen activator). This is a “clot busting
drug” which is used to clean out the debris blocking the artery. Although this agent may
be effective if used early (i.e., within three hours of the onset of the stroke), its delayed
use can be associated with catastrophic brain hemorrhages. Moreover, the three-hour
time window is too tight for many patients with stroke. Thus the need to develop anti-
stroke agents is a continuing challenge.
A conceptual approach which has been pursued in the development of stroke thera-
pies is based upon rescue of the ischemic brain using neuroprotectant drugs. This
approach has been based upon the notion that the reduced supply of blood (and hence
the supply of oxygen and glucose) to the brain leads to depolarization of cell mem-
branes and subsequently to the release of glutamate; this stimulates the NMDA and
AMPA receptors, causing an increase in intracellular calcium which in turn promotes
lipolysis and proteolysis, thereby producing irreversible brain cell damage. The role of
a neuroprotectant drug would be to interrupt this neurotoxic biochemical cascade. The
majority of drugs developed to fulfill this role as a neuroprotectant have targeted gluta-
mate and glutamate receptors: competitive NMDA antagonists (e.g., selfotel,4.222),
NMDA polyamine site antagonists (e.g., eliprodil (4.215), ifenprodil (4.223), NMDA
glycine site antagonists (e.g., gavestinel,4.224), NMDA Mg site antagonists (e.g.,
magnesium sulphate), other NMDA antagonists (e.g., cerestat,4.225), inhibition of
glutamate release (e.g., lamotrigine), and AMPA antagonists (e.g., NBQX). The major-
ity of these drugs worked (and worked impressively at times) in rodent models of stroke
in which an artery was tied off by a ligature, thus producing a stroke. However, these
successes in animal models did not translate into successful drugs for human stroke.
These various neuroprotectant agents, targeting glutamatergic processes, have failed in
human trials due to insufficient efficacy. Clearly human stroke has a complicated bio-
chemistry which is poorly understood and which does not respond to a straightforward
NEUROTRANSMITTERS AND THEIR RECEPTORS 287