MK 801: A Possible Neuroprotective Agent by Poststroke Depression?

To the Editor: Stroke is the third leading cause of death and adult morbidity in developed countries. 1 Many deleterious cellular pathways have been proposed to explain the molecular pathogenesis of this clinically devastating disease. 2 Interest in the role of neurotransmitters in the pathogenesis of ischemic stroke resulted in studies establishing that the release of glutamate and its excitotoxic actions through the N -methyl- D -aspartic acid (NMDA) receptors are significant in the development of ischemic neuronal damage. 2

It is widely known that the occurrence of poststroke mood disorders, especially depression, is one of the most frequent complications of stroke. 3 It affects approximately 20% to 40% of all patients and the definitive treatment includes various antidepressant agents. 3 Interestingly, the evidence regarding antidepressant activity of NMDA receptor antagonists (especially MK 801) is rapidly replicating. 4, 5 In light of these findings, we wanted to evaluate whether this novel antidepressant agent also has a neuroprotective effect by cerebral ischemia.

To examine this matter, we evaluated the neuroprotective effect of MK 801 (dizocilpine), a noncompetitive NMDA receptor antagonist, after transient focal cerebral ischemia, a relevant model for the thrombolyzed stroke in humans.

Anesthetized Wistar rats (330–370 g) were submitted to transient thread occlusion of the middle cerebral artery using an intraluminal filament technique. 6 The rectal temperature was maintained between 36.5°C and 37.0°C using a feedback-controlled heating system. The cerebral blood flow, measured by laser Doppler flowmetry, was reduced to ∼15% of preischemic control levels immediately after thread insertion in all animal groups. MK 801 or vehicle was applied intraperitoneally (3 mg/kg) just after transient ischemia. Twenty-four hours after reperfusion, the area of infarction was measured by toluidine blue staining. This study was interesting with regard to poststroke depression by which a mood stabilizer with neuroprotective properties would be preferable.

MK 801 showed a significant neuroprotection (p<0.05, analysis of variance followed by least significant difference tests) after transient focal cerebral ischemia (73.12±23.2 versus 23.12+21.1) ( Figure 1 ). In summary, this study indicates that even with a serious brain injury, MK 801 could exert a significant neuroprotective effect. However, further experiments to evaluate the long-term clinical reflections of such neuroprotective effects of MK 801 in poststroke depression patients via MRI and spectroscopy studies, would be logical future steps in the field of psychiatric research.