Neuroprotective effects of the antioxidant LY231617 and NO synthase inhibitors in global cerebral ischaemia.
Recent studies have shown that the novel antioxidant LY231617 protects against ischaemia-induced neuronal damage in rat models of global cerebral ischaemia. In the present studies we have examined the effects of LY231617 in the gerbil model of global cerebral ischaemia. We also examined the effects of four nitric oxide synthase inhibitors (3-bromo-7-nitroindazole, N(G)-nitro-L-arginine methyl ester, aminoguanidine and S-methylisothiourea sulphate) in this model. LY231617 (50 mg/kg p.o. or 30 mg/kg i.p.) was administered either 30 min prior to occlusion or immediately post-occlusion followed by three further doses at 4, 24 and 48 h after the initial dose. 3-Bromo-7-nitroindazole was administered at 40 mg/kg i.p. immediately after occlusion followed by 20 mg/kg i.p. at 3, 6, 24 and 48 h, N(G)-nitro-L-arginine methyl ester was administered at 10 mg/kg i.p. immediately after occlusion followed by 5 mg/kg i.p. at 3, 6, 24 and 48 h. Aminoguanidine was administered at 80 mg/kg i.p. immediately after occlusion followed by 40 mg/kg i.p. at 3, 6, 24 and 48 h and S-methylisothiourea sulphate was administered at 10 mg/kg i.p. immediately, 3, 6, 24 and 48 h after occlusion. We also examined the effects of aminoguanidine administered at 80 mg/kg i.p. immediately after occlusion followed by 40 mg/kg i.p. at 3, 6, 24, 48, 72 and 96 h and S-methylisothiourea sulphate administered at 10 mg/kg i.p. immediately, 3, 6, 24, 48, 72 and 96 h after occlusion. Control animals were either sham operated or subjected to 5 min bilateral carotid occlusion. Extensive neuronal death was observed in the CA1 layer of the hippocampus in 5-min bilateral carotid artery occluded animals 5 days after surgery. LY231617 provided significant neuroprotection against the ischaemia-induced brain damage when administration was initiated before or after occlusion (P < 0.05). The neuronal NO synthase inhibitors, 3-bromo-7-nitroindazole and a general NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester also provided significant neuroprotection (P < 0.05). In contrast aminoguanidine and S-methylisothiourea sulphate (two inducible NO synthase inhibitors) failed to protect against the ischaemia-induced brain damage. These results indicate that free radicals and nitric oxide are involved in ischaemia-induced brain damage following global cerebral ischaemia. Antioxidants such as LY231617 or neuronal NO synthase inhibitors can prevent the ischaemia-induced neurodegeneration and may be useful as anti-ischaemic agents.
O'Neill
M J
MJ
Lilly Research Centre Limited, Erl Wood Manor, Surrey, UK. oneill_michael_j@lilly.com
Hicks
C
C
Ward
M
M
Panetta
J A
JA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy*; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D004195:Disease Models, Animal; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D019001:Nitric Oxide Synthase / Q000187:drug effects*
D000975:Antioxidants; D002084:Butylated Hydroxytoluene; C081064:LY 231617; D019001:Nitric Oxide Synthase