Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice.
1. 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. 2. 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 I h after reperfusion. 3. 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. 4. 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. 5. 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. 6. 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.
Ma
J
J
Stroke and Neurovascular Regulation Laboratory, Neurology and Neurosurgery Services, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Endres
M
M
Moskowitz
M A
MA
D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013997:Time Factors
D015853:Cysteine Proteinase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate