Synergistic neuroprotective effects by combining an NMDA or AMPA receptor antagonist with nitric oxide synthase inhibitors in global cerebral ischaemia

We have investigated the neuroprotective effects of combining an NMDA or AM PA receptor antagonist with a nitric oxide synthase (NOS) inhibitor in the gerbil model of global cerebral ischaemia. Ischaemia was induced by occlusi on of the common carotid arteries for 5 min. (5R,10S)-(+)-5-methyl-10,11-di hydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801, 2.5 mg/kg i.p.) or (3S ,4aR,6R,8aR)-6-[2-(1(2) H-tetrazole-5-yl)]decahydroisoquinoline-3-carboxyli c acid (LY293558, 20 mg/kg i.p.) and 7-nitroindazole (25 mg/kg i.p.) or N-[ 4-(2-{[(3-chlorophenyl)methyl]amino}ethyl) phenyl]-2-thiophenecarboximidami de dihydrochloride (ARL17477, 25 mg/kg i.p.) were administered alone or in combination (i.e., MK-801 with 7-nitroindazole or ARL17477 or LY293558 with 7-nitroindazole or ARL17477). In the present studies, both MK-801 and LY29 3558 provided significant degree of neuroprotection, while 7-nitroindazole and ARL17477 also provided some neuroprotection, which failed to reach sign ificance in every case. However, the combination of MK-801 with 7-nitroinda zole or ARL17477 provided 21% or 44% greater protection than the total prot ection or either alone. Likewise, the combination of LY293558 with 7-nitroi ndazole or ARL17477 provided 14.5% and 35% greater protection than total pr otection of either compound alone. These results indicate that several path ways contribute to ischaemic cell death and combining excitatory amino anta gonists and NOS inhibitors provides greater protection than either alone. T herefore, combination therapy should be considered as an approach for treat ing ischaemic conditions. (C) 1999 Elsevier Science B.V. All rights reserve d.