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 AMPA receptor antagonist with a nitric oxide synthase (NOS) inhibitor in the gerbil model of global cerebral ischaemia. Ischaemia was induced by occlusion of the common carotid arteries for 5 min. (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine (MK-801, 2.5 mg/kg i.p.) or (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroisoq uinoline-3-carboxylic 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-thiophenecarboximidamide 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 LY293558 provided significant degree of neuroprotection, while 7-nitroindazole and ARL17477 also provided some neuroprotection, which failed to reach significance in every case. However, the combination of MK-801 with 7-nitroindazole or ARL17477 provided 21% or 44% greater protection than the total protection or either alone. Likewise, the combination of LY293558 with 7-nitroindazole or ARL17477 provided 14.5% and 35% greater protection than total protection of either compound alone. These results indicate that several pathways contribute to ischaemic cell death and combining excitatory amino antagonists and NOS inhibitors provides greater protection than either alone. Therefore, combination therapy should be considered as an approach for treating ischaemic conditions.
Hicks
C A
CA
Eli Lilly & Company, Lilly Research Centre, Windlesham, Surrey, UK.
Ward
M A
MA
Swettenham
J B
JB
O'Neill
M J
MJ
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002339:Carotid Arteries / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology
C102136:ARL 17477; D000578:Amidines; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007191:Indazoles; D007546:Isoquinolines; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; D016291:Dizocilpine Maleate; C082309:tezampanel; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole