During
cerebral ischemia, there is excessive activity of
excitatory amino acids, especially
glutamate. Activation of
glutamate receptors leads to a marked increase in intracellular
calcium, which in turn leads to activation of intracellular
enzymes and neuronal death--the so-called excitotoxic cascade. The
calcium antagonist
nimodipine, which acts at
L-type calcium channels, was tested for a putative
neuroprotectant effect in patients with
acute ischemic stroke, but no beneficial effect was demonstrated.
Glutamate receptors are attractive targets for
neuroprotectant drugs because
glutamate plays a central role in the excitotoxic cascade. Clinical trials of
NMDA (
N-methyl-D-aspartate) antagonists have been disappointing, however, and psychiatric side effects seem to be a general problem with this class of
drug. Another strategy proposed for interfering with
NMDA receptor function is the infusion of
magnesium. The
NMDA receptor is normally blocked by
magnesium ions and will only respond to
glutamate when this
magnesium-induced block is removed on depolarization. A large clinical trial to investigate possible neuroprotection by
magnesium is underway. The
NMDA receptor also has a
glycine-binding site and a
polyamine-binding site, and the
cation channel will only open in response to
glutamate if
glycine and
polyamines are already bound to these obligatory modulatory sites.
Gavestinel is selective for the
glycine-binding site, and
eliprodil for the
polyamine site, but large international clinical trials have failed to find any beneficial effects in patients with
acute ischemic stroke. Neurotoxic
free radicals are also generated during
cerebral ischemia. Laboratory
stroke models suggest that
free radical scavengers might be effective
neuroprotectants. One of these,
NXY-059, was effective in several animal studies, and preliminary studies in human subjects show that plasma concentrations that are neuroprotective in animal models can be achieved and are well tolerated.
Lubeluzole interferes with the
glutamate-induced neuronal damage mediated through the formation of
nitric oxide. However, a meta-analysis of all clinical trials of
lubeluzole was unable to detect a
neuroprotectant effect of the
drug. There is now some evidence that, in addition to
necrosis, some neurons die as a result of apoptosis after
cerebral ischemia. Several drugs that interfere with the apoptosis cascade, for example,
caspase inhibitors, are under investigation.
Clomethiazole ('ZENDRA'; a trademark, the property of the AstraZeneca group of companies) is also undergoing a second large clinical trial in patients with major
ischemic strokes. This
drug's mechanism of action is not completely clear, but it is known to activate a nonbenzodiazepine site on the
GABA(A) (
gamma-aminobutyric acid) receptor. This causes increased
chloride conductance and hyperpolarization. In vitro
clomethiazole inhibits
ischemia-induced
glutamate efflux from cerebral neurons. The first large controlled trial showed it to be well tolerated and suggested a clinically significant effect in patients with deficits of a major
stroke.