Stroke is a life threatening disease often associated to
the permanent disability of survivors. The disease is triggered by a sudden drop of brain
blood flow, mostly due to an artery occlusion (ischaemic attack). Then, once ischaemia is
established, since the neurones immediately distal the site of the occlusion are without
blood supply, if reperfusion is not restored quickly (the occlusion must be removed within
minutes), these cells begin to die. This event starts the neurodegenerative phase of the
disease which is the ultimate responsible for deaths and for the permanent disabilities.
The rapidly dying brain region immediately distal to the occlusion is called
"core" of the infarct and is surrounded by an at risk zone, with reduced blood
flow, called "penumbra". If blood flow restoration delays too much, also
penumbral cells will slowly die.
Currently there is a good pharmacological coverage of the
vascular side of stroke. The intervention is mainly prophylactic, i.e. focussed on
reduction of risk factors such as hypertension, hypercholesterolemia etc.
For example, chronic treatment of spontaneously
hypertensive stroke prone rats (SHRSPs) with lacidipine, a long-lasting calcium channel
blocking agent, at doses lower than antihypertensive ones, significantly reduces the
mortality and prevents organ damages. This property which is likely due to the antioxidant
activity of lacidipine might enhance stroke prevention during hypertension therapy.
Moreover, current treatment of acute ischaemic stroke is
based upon the use of thrombolytic agents such as urokinase and TPA. This approach is
aimed to the dissolution of obstructive blood clots in the cerebral arteries and it is
effective only when the administration is given early (<3 hrs from the occlusion).
Clearly one of the most important drawback concerns its contraindication in hemorragic
stroke.
The pharmacological approach to the neurodegenerative phase
of stroke is still under clinical evaluation. Based on the cell pathophysiology of the
disease, the most relevant target for a novel neuroprotective compound is the penumbral
area. In fact, due to the fast cell death after ischaemia, the "core" appears
less suitable for intervention mainly because of time constraints (time to make diagnosis,
time to start the treatment etc). Preclinical studies in experimental models of stroke
have shown that cell death in "penumbra" is essentially due to the
overactivation of the central glutamatergic NMDA receptors. Since the regulation of the
NMDA receptor function requires glycine, suitable glycine antagonists can generate novel
neuroprotective drugs. By using GV150526 a potent and selective glycine antagonist,
currently in clinical trials for stroke , it has been shown that the blockade of glycine
receptors results in a strong neuroprotective effect both in animal models of permanent
and of transient MCA occlusion as well as in hemorragic stroke.
As predicted the effect is mostly a preservation from death
of penumbral cells and is detectable even after delayed administration post-occlusion up
to when a significant amount of recoverable tissue is still present. Glycine antagonists
appear to be extremely safe both in animals at neuroprotective doses as well as in man at
doses expected to be effective. At the moment, in view of these features, the glycine
antagonist approach appears to be the most promising of those that are currently under
clinical evaluation as new neuroprotectives for stroke in man.
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