NEUROPATHOLOGICAL END-POINTS IN EXPERIMENTAL STROKE PHARMACOTHERAPY - THE IMPORTANCE OF BOTH EARLY AND LATE EVALUATION

This study adresses the issue of endpoint selection in the evaluation of neuroprotective drugs in experimental focal ischaemia. Previous work with the permanent middle cerebral artery (MCA) occlusion model in the rat' has demonstrated that the ischaemic lesion does not acquire its final appearance until at least 28 days after the ictus2. Therefore, the effect of the NMDA receptor blocker MK-801 (dizocilpine maleate) was evaluated both early (3 days) and late (28 days) after MCA occlusion to determine if the previously reported protective effect of a single post-ischaemic dose of MK-801 found in acute experiments remained after 28 days. Mk-801 (0.5 mg/kg, i.v.) or isotonic saline was randomly given to rats 30 min after MCA occlusion. Infarct volume and volume of ipsilateral and contralateral hemispheres were estimated from camera lucida drawings of 8 defined3 coronal histological sections of the brain. As expected, a 40% (p < 0.05) reduction of infarct size was found in MK-801 treated rats after 3 days. In animals evaluated 28 days after MCA occlusion, no significant difference in infarct size, total tissue loss (infarct volume + ipsilateral hemisphere atrophy) or remaining non-infarcted tissue (contralateral hemisphere - total tissue loss) was seen between the MK-801 and placebo treated rats. The results suggest that the single dose treatment with MK-801 postponed the evolution of the infarct, which at 3 days after MCA occlusion is still in progress, possibly by ameliorating oedema formation. It remains to be shown if a multiple dose treatment with NMDA receptor antagonists improves the final neuropathological outcome after experimental stroke. The study illustrates the importance of including a late endpoint when evaluating the efficacy of neuroprotective stroke therapy.