Glucose and NADPH oxidase drive neuronal superoxide formation in stroke.
ABSTRACT Hyperglycemia has been recognized for decades to be an exacerbating factor in ischemic stroke, but the mechanism of this effect remains unresolved. Here, we evaluated superoxide production by neuronal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a possible link between glucose metabolism and neuronal death in ischemia-reperfusion.
Superoxide production was measured by the ethidium method in cultured neurons treated with oxygen-glucose deprivation and in mice treated with forebrain ischemia-reperfusion. The role of NADPH oxidase was examined using genetic disruption of its p47(phox) subunit and with the pharmacological inhibitor apocynin.
In neuron cultures, postischemic superoxide production and cell death were completely prevented by removing glucose from the medium, by inactivating NADPH oxidase, or by inhibiting the hexose monophosphate shunt that generates NADPH from glucose. In murine stroke, neuronal superoxide production and death were decreased by the glucose antimetabolite 2-deoxyglucose and increased by high blood glucose concentrations. Inactivating NADPH oxidase with either apocynin or deletion of the p47(phox) subunit blocked neuronal superoxide production and negated the deleterious effects of hyperglycemia.
These findings identify glucose as the requisite electron donor for reperfusion-induced neuronal superoxide production and establish a previously unrecognized mechanism by which hyperglycemia can exacerbate ischemic brain injury.
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ABSTRACT: The purpose of this study is to determine clinical factors associated with complications of drug-induced seizures. This prospective observational study was conducted at an American Association of Poison Control Centers-certified regional poison control center (PCC) over a 1-year period. All consecutive cases reported to a PCC involving seizures were forwarded to investigators, who obtained standardized information including the specific drug or medication exposure, dose, reason for exposure, vital signs, laboratory data, treatment, and outcome. Patients were monitored by daily telephone follow-up until death or discharge. Subjects were excluded if the seizure was deemed to be unrelated to exposure. Odds ratios were used to analyze variables for associations with admission to the hospital for >72 h, endotracheal intubation, status epilepticus, anoxic brain injury, or death. One hundred twenty-one cases met inclusion criteria. Sixty-three (52%) were male, and the mean age was 30 (SD14) years. Common exposures included: antidepressants (33%), stimulants (15%), and anticholinergics (10%). One hundred and three (85%) of the exposures were intentional, of which 74 were suicide attempts and 16 were drug abuse or misuse. Forty-nine (40%) patients required endotracheal intubation, 12(10%) had status epilepticus, 50(41%) were hospitalized for more than 72 h, and one patient died. Median hospital stay was 3 days. Variables significantly associated with complications included stimulant exposure (odds ratios, OR=11 [95% confidence intervals (CI) 1.9-52]), suicide attempt (OR=2.2 [95% CI 1.02-4.7]), initial hypotension (OR=11.2 [95% CI 1.4-89.3]), admission glucose >130 mg/dL (OR=5.4 [95% CI 1.6-18.1]), and admission HCO(3) <20 mEq/L (OR=4.0 [95% CI 1.4-11.3]). Significant clinical factors associated with complications of drug-related seizures include stimulant exposure, suicide attempt, initial hypotension, and admission acidosis or hyperglycemia.Journal of medical toxicology: official journal of the American College of Medical Toxicology 03/2011; 7(1):16-23.
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ABSTRACT: Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions.Molecular Neurodegeneration 01/2011; 6(1):11. · 4.28 Impact Factor
Article: Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea.[show abstract] [hide abstract]
ABSTRACT: In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Excessive NADPH oxidase activity may play a role in IH-induced CNS dysfunction. The effect of IH during light period on two forms of spatial learning in the water maze and well as markers of oxidative stress was assessed in mice lacking NADPH oxidase activity (gp91phox(_/Y)) and wild-type littermates. On a standard place training task, gp91phox(_/Y) displayed normal learning, and were protected from the spatial learning deficits observed in wild-type littermates exposed to IH. Moreover, anxiety levels were increased in wild-type mice exposed to IH as compared to room air (RA) controls, while no changes emerged in gp91phox(_/Y) mice. Additionally, wild-type mice, but not gp91phox(_/Y) mice had significantly elevated levels of NADPH oxidase expression and activity, as well as MDA and 8-OHDG in cortical and hippocampal lysates following IH exposures. The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by excessive NADPH oxidase activity, and thus pharmacological agents targeting NADPH oxidase may provide a therapeutic strategy in sleep-disordered breathing.PLoS ONE 01/2011; 6(5):e19847. · 4.09 Impact Factor