Although various neuroprotective and
fibrinolytic drugs are currently under evaluation in the acute stages of
ischaemic stroke, their therapeutic potential is likely to be limited by unwanted side effects and a narrow time window of opportunity for intervention.
Proteolytic enzymes are involved in the catabolism of
peptide neurotransmitters and structural cellular
proteins in normal brain and have been implicated in the pathogenesis of
neurodegenerative disorders. We hypothesised that activation of these
enzymes might also play a crucial role in effecting ischaemic neuronal injury, thereby providing a potential site for therapeutic intervention in human
stroke. Focal cerebral ischaemia was induced by
thermocoagulation of the left middle cerebral artery in aged (30 month) male Wistar rats who were pre-treated with saline or the competitive
N-methyl-D-Aspartate antagonist
D-CPP-ene, which has been shown to be neuroprotective in young animal models of
stroke. Major
protease activities were analysed in the left (ischaemic) and right (non-ischaemic) hemispheres, following tissue homogenisation. Data have been analysed using Mann-Whitney tests and are presented as means +/- standard errors.
Enzyme activity decreased in ischaemic brain; for example, the mean activity of
dipeptidyl aminopeptidase I was 23 +/- 3 and 43 +/- 6 nmol substrate/hour/ml brain extract in the left and right hemispheres respectively (n = 10, p < 0.05). Ischaemic neuronal injury is not effected by the early activation of
proteolytic enzymes and
protease inhibitors are therefore unlikely to be of benefit in human
stroke.