Publications (2)5.24 Total impact
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Article: Neuroprotective effects of the antioxidant LY231617 and NO synthase inhibitors in global cerebral ischaemia.
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ABSTRACT: 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.Brain Research 07/1997; 760(1-2):170-8. · 2.73 Impact Factor -
Article: Neuroprotective effects of 7-nitroindazole in the gerbil model of global cerebral ischaemia.
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ABSTRACT: To evaluate the role played by nitric oxide in global cerebral ischaemia we examined the effects of 7-nitroindazole and a sodium salt of 7-nitroindazole (inhibitors of neuronal nitric oxide (NO) synthase) and NG-nitro-L-arginine methyl ester (a more general inhibitor of NO synthase) in the gerbil model of cerebral ischaemia. Four experiments were carried out. In the first experiment, animals were either sham-operated, subjected to 5 min bilateral carotid occlusion (BCAO) or administered 7-nitroindazole or NG-nitro-L-arginine methyl ester immediately after occlusion followed by three further doses at 3, 6 and 24 h post-occlusion. In the second experiment, we examined the effects of a sodium salt of 7-nitroindazole, which is more soluble than 7-nitroindazole, using the same protocol. In the third experiment, the effects of the sodium salt of 7-nitroindazole administered at 10 mg/kg at 0, 3, 6, 24, 27, 30, 33, 52, 55, 72, 75 and 78 h post-occlusion or at 0.05 mg/h for 72 h via mini-pumps were evaluated. In separate experiments, we examined the effects of three reference compounds dizocilpine (MK-801), 2, 3-dihydroxy-6-nitro-7-sulphamoyl-benz(F)-quinoxaline (NBQX) and eliprodil using the same model. Extensive neuronal death was observed in the CA1 layer of the hippocampus in 5 min bilateral carotid occluded animals 5 days after surgery. Both 7-nitroindazole and NG-nitro-L-arginine methyl ester provided significant neuroprotection (P < 0.01) against this neuronal death. The sodium salt of 7-nitroindazole showed no protection when administered up to 12 times post-occlusion, but did provide significant (P < 0.01) neuroprotection when administered via mini-pump. The neuroprotection was similar to that provided by MK-801 and eliprodil, but not as good as that observed with NBQX. These results indicate that nitric oxide plays a role in ischaemic cell death and that selective neuronal nitric oxide synthase inhibitors can protect against ischaemic brain damage.European Journal of Pharmacology 09/1996; 310(2-3):115-22. · 2.52 Impact Factor
