A phenothiazine derivative reduces rat brain damage after global or focal ischemia.

Abstract

Background and Purpose:We previously reported that 2-(10//-phenothiazin-2-yloxy)-yV,/V-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<0.05). In the transient focal stroke model, the compound reduced cortical infarct volume from 130.1+10.3 mm 3 for control rats to 95.2±24.5 mm 3 for treated rats (p<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. (Stroke 1992;23:1287-1291

Intrinsic and Extrinsic Limitations to the Design and Optimization of Inhibitors of Lipid Peroxidation and Associated Cell Death

“…This is underscored by the structure–reactivity–potency data provided above, which clearly show that the PNX scaffold can tolerate varied substitution with little impact on its excellent antiferroptotic potency. It should also be pointed out that related phenothiazine compounds are well established as blood–brain barrier permeable therapeutics, , (and indeed have been shown to mitigate post-ischemia and post-TBI brain damage in animal models) ,− a feature which, if held in common, will greatly enable their development as therapeutics for neurodegeneration.…”

Cellular Prion Protein Is Essential for Myocardial Regeneration but Not the Recovery of Left Ventricular Function from Apical Ballooning

“…5-Bromodeoxycytidine is deaminated to form BrdU, which was used in the present study for the purpose of detecting cell proliferation. The dosages of BrdU and Stelazine to be used in the present study were based on our [ 30 ] and previous [ 31 ] studies.…”

“…), especially when we took the PrP C as a potential role of tissue regeneration and improvement of the heart function into consideration. Second, the use of the Stelazine dosage in mice was only based on the previous report [ 31 ] without a stepwise increase in the concentration. Accordingly, the result of this study did not provide adequate information regarding the optimal dosage of Stelazine on improving the LVEF.…”

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

“…The neuroprotective effect of phenothiazine and some of its derivatives have been explored since 1990s (Yu et al , 1992a; Yu et al , 1992b). The protective action of phenothiazine derivatives have been demonstrated in models of ischemic stroke (Yu et al , 1992a) and PD (Mocko et al , 2010). On the other hand, the protective action of MB was discovered more recently.…”