BACKGROUND AND PURPOSE: We previously reported that 2-(10H-phenothiazin-2-yloxy)-N,N-dimethylethanamine hydrochloride is a potent inhibitor of iron-dependent lipid peroxidation in vitro and can protect primary cultures of rat hippocampal neurons from hydrogen peroxide-induced toxicity. Because oxidants may play an important role in mediating postischemic tissue injury, we evaluated this agent in two rat models of transient cerebral ischemia. METHODS: In a model of global forebrain ischemia, 23 male Wistar rats were subjected to 10 minutes of four-vessel occlusion followed by 72 hours of reperfusion. The rats received three intraperitoneal injections of either vehicle (2% aqueous acacia) or test agent (40 mg/kg). In a model of focal stroke, 19 spontaneously hypertensive rats were subjected to 2 hours of tandem middle cerebral and ipsilateral common carotid artery occlusion followed by 24 hours of reperfusion. The rats received three intraperitoneal injections of either vehicle (2% aqueous acacia) or test agent (40 mg/kg). RESULTS: In the global model, the phenothiazine significantly protected the CA1 layer of the hippocampus, with a reduction in mean damage score from 2.1 +/- 0.3 for control rats to 1.0 +/- 0.4 for treated rats (p less than 0.05). In the transient focal stroke model, the compound reduced cortical infarct volume from 130.1 +/- 10.3 mm3 for control rats to 95.2 +/- 24.5 mm3 for treated rats (p less than 0.02). CONCLUSIONS: Although the primary mechanism responsible for the protective effect is unclear at the present time, our study is consistent with the hypothesis that oxidant-mediated lipid peroxidation may be involved in the pathophysiology of postischemic brain injury.
BACKGROUND AND PURPOSE: We previously reported that 2-(10H-phenothiazin-2-yloxy)-N,N-dimethylethanamine hydrochloride is a potent inhibitor of iron-dependent lipid peroxidation in vitro and can protect primary cultures of rat hippocampal neurons from hydrogen peroxide-induced toxicity. Because oxidants may play an important role in mediating postischemic tissue injury, we evaluated this agent in two rat models of transient cerebral ischemia. METHODS: In a model of global forebrain ischemia, 23 male Wistar rats were subjected to 10 minutes of four-vessel occlusion followed by 72 hours of reperfusion. The rats received three intraperitoneal injections of either vehicle (2% aqueous acacia) or test agent (40 mg/kg). In a model of focal stroke, 19 spontaneously hypertensiverats were subjected to 2 hours of tandem middle cerebral and ipsilateral common carotid artery occlusion followed by 24 hours of reperfusion. The rats received three intraperitoneal injections of either vehicle (2% aqueous acacia) or test agent (40 mg/kg). RESULTS: In the global model, the phenothiazine significantly protected the CA1 layer of the hippocampus, with a reduction in mean damage score from 2.1 +/- 0.3 for control rats to 1.0 +/- 0.4 for treated rats (p less than 0.05). In the transient focal stroke model, the compound reduced cortical infarct volume from 130.1 +/- 10.3 mm3 for control rats to 95.2 +/- 24.5 mm3 for treated rats (p less than 0.02). CONCLUSIONS: Although the primary mechanism responsible for the protective effect is unclear at the present time, our study is consistent with the hypothesis that oxidant-mediated lipid peroxidation may be involved in the pathophysiology of postischemic brain injury.
Authors: Shao-Hua Yang; Wenjun Li; Nathalie Sumien; Michael Forster; James W Simpkins; Ran Liu Journal: Prog Neurobiol Date: 2015-11-18 Impact factor: 11.685