Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice |
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Authors: | Jianya Ma Matthias Endres Michael A Moskowitz |
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Affiliation: | Stroke and Neurovascular Regulation Laboratory, Neurology and Neurosurgery Services, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, U.S.A. |
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Abstract: | - Excitotoxic and apoptotic mechanisms have been implicated in the pathophysiology of cerebral ischaemia. Both MK-801, an NMDA receptor antagonist, or peptide inhibitors of the caspase family (z-VAD.FMK and z-DEVD.FMK), protect mouse brain from ischaemic cell damage. In this study, we examined whether these drugs which act via distinct mechanisms, afford even greater neuroprotection when given in combination following 2 h MCA occlusion (filament model) and 18 h reperfusion.
- Given alone as pretreatment, MK-801 (1, 3 and 5 mg kg−1, but not 0.3 mg kg−1, i.p.) decreased infarct size by 34–75%. When injected 1 h after occlusion and before reperfusion, 3 mg kg−1 reduced injury but not when administered 1 h after reperfusion.
- Pretreatment with a subthreshold dose of MK-801 (0.3 mg kg−1) plus a subthreshold dose of z-VAD.FMK (27 ng) or z-DEVD (80 ng) significantly decreased infarct size by 29 and 30%, respectively, and enhanced neurological function.
- Administering a subthreshold dose of z-VAD.FMK (27 ng) or z-DEVD.FMK (80 ng) as pretreatment extended the time window for MK-801 (3 mg kg−1) by 2 h from 1 h before reperfusion to at least 1 h after reperfusion.
- Pretreating with a subthreshold dose of MK-801 (0.3 mg kg−1) extended the time window for z-DEVD.FMK (480 ng) from 1 h after reperfusion to at least 3 h after reperfusion.
- We conclude that caspase inhibitors which putatively block apoptotic cell death and inhibit cytokine production and the NMDA antagonist MK-801 act synergistically and prolong their respective therapeutic windows in cerebral ischaemia.
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Keywords: | MK-801 NMDA receptor ICE-family caspases focal cerebral ischaemia apoptosis |
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