Failure to enhance thrombolytic therapy by neuroprotection with memantine in a model of embolic stroke

Background: To combine neuroprotective drugs with recanalizing therapy seems to be an excellent rationale to improve stroke therapy and outcome. However, experimental data employing an embolic stroke model with suboptimal reperfusion rates – as present after thrombolysis in human stroke patients – are not available. We hypothetized that the combined use of tissue plasminogen activator (t-PA) and memantine (NMDA receptor antagonist) could extend the therapeutic window of thrombolytic therapy.

Methods: Animals were submitted to MCA clot embolism and treated with t-PA at 1.5-h (n=20) or 3.5-h (n=17) postocclusion (i.a. 5mg/kg). Control rats (n=8) neither received t-PA nor memantine after occlusion. In both treatment groups, rats were randomly assigned to additional neuroprotective therapy or saline injection. The verum animals received i.p. 10mg/kg memantine at the time when thrombolysis was initiated. Cerebral blood flow (CBF) was continuously monitored by using laser-Doppler flowmetry. Experiments were terminated after 6 hrs by perfusion fixation. Cresyl violet stained brain sections were used to determine lesion volumes, both for complete infarction and scattered neuronal injury.

Results: In control experiments, no reperfusion was detected. In 35% of t-PA treated rats, a lasting normalization of CBF could be observed. Treatment with memantine did not influence infarct volumes whether combined with early or late thrombolysis. Pooled animals with successful reperfusion after t-PA treatment had smaller infarcts (n=13, 71±9 mm3, mean±SEM) than non-reperfused animals (n=24, 118±10 mm3, p<0.05). There was a significant reverse correlation between total ischemic injury volume and mean CBF after onset of t-PA treatment (r=-0.405, p<0.001).

Conclusions: In a rat model of thromboembolic MCA occlusion, the combined treatment of t-PA and memantine did not improve the effect of recanalization whether applied early or late. However, successful recanalization by t-PA lead to reduced infarct volumes also if applied at 3.5-h postocclusion. These findings may help to explain why so many clinical stroke trials have failed that had tested neuroprotective drugs in humans.