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Inhibition of gp91(phox) contributes towards normobaric hyperoxia afforded neuroprotection in focal cerebral ischemia.

ABSTRACT: Oxygen therapy is a promising treatment strategy for ischemic stroke. One potential safety concern with oxygen therapy, however, is the possibility of increased generation of reactive oxygen species (ROS), which could exacerbate ischemic brain injury. Our previous study indicated that normobaric hyperoxia (NBO, 95% O(2) with 5% CO(2)) treatment during ischemia salvaged ischemic brain tissue and significantly reduced ROS generation in transient experimental stroke. In this follow-up study, we tested the hypothesis that suppression of NADPH oxidase is an important mechanism for NBO-induced reduction of ROS generation in focal cerebral ischemia. Male Sprague-Dawley rats were given NBO (95% O(2)) or normoxia (21% O(2)) during 90-min filament occlusion of the middle cerebral artery, followed by 22.5-hour reperfusion. NBO treatment increased the tissue oxygen partial pressure (pO(2)) level in the ischemic penumbra close to the pre-ischemic value, as measured by electronic paramagnetic resonance (EPR), and led to a 30.2% reduction in magnetic resonance imaging (MRI) apparent diffusion coefficients (ADC) lesion volume. Real time PCR and western blot analyses showed that the mRNA and protein expression of NADPH oxidase catalytic subunit gp91(phox) were upregulated in the ischemic brain, which was significantly inhibited by NBO. As a consequence of gp91(phox) inhibition, NBO treatment reduced NADPH oxidase activity in the ischemic brain. Our results suggest that NBO treatment given during ischemia reduces ROS generation via inhibiting NADPH oxidase, which may serve as an important mechanism underlying NBO's neuroprotection in acute ischemic stroke.

SUBMITTER: Tang X

PROVIDER: S-EPMC3073844 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Inhibition of gp91(phox) contributes towards normobaric hyperoxia afforded neuroprotection in focal cerebral ischemia.

Tang Xiangqi X Liu Ke Jian KJ Ramu Jaivijay J Chen Qingquan Q Li Ting T Liu Wenlan W

Brain research 20100611

Oxygen therapy is a promising treatment strategy for ischemic stroke. One potential safety concern with oxygen therapy, however, is the possibility of increased generation of reactive oxygen species (ROS), which could exacerbate ischemic brain injury. Our previous study indicated that normobaric hyperoxia (NBO, 95% O(2) with 5% CO(2)) treatment during ischemia salvaged ischemic brain tissue and significantly reduced ROS generation in transient experimental stroke. In this follow-up study, we tes ...[more]

PMID: 20547141

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Project description:Background and purposeAquaporin-4(AQP4) is an abundant water channel protein in brain that regulates water transport to maintain homeostasis. Cerebral edema resulting from AQP4 over expression is considered to be one of the major determinants for progressive neuronal insult during cerebral ischemia. Although, both upregulation and downregulation of AQP4 expression is associated with brain pathology, over expression of AQP4 is one of the chief contributors of water imbalance in brain during ischemic pathology. We have found that Piroxicam binds to AQP4 with optimal binding energy value. Thus, we hypothesized that Piroxicam is neuroprotective in the rodent cerebral ischemic model by mitigating cerebral edema via AQP4 regulation.MethodsRats were treated with Piroxicam OR placebo at 30 min prior, 2 h post and 4 h post 60 minutes of MCAO followed by 24 hour reperfusion. Rats were evaluated for neurological deficits and motor function just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, RT-PCR and western blot experiments.ResultsPiroxicam pretreatment thirty minutes prior to ischemia and four hour post reperfusion afforded neuroprotection as evident through significant reduction in cerebral infarct volume, improvement in motor behavior, neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde were also found to be significantly reduced in ischemic brain regions in treated animals. This neuroprotection was found to be associated with inhibition of acid mediated rise in intracellular calcium levels and also downregulated AQP4 expression.ConclusionsFindings of the present study provide significant evidence that Piroxicam acts as a potent AQP4 regulator and renders neuroprotection in focal cerebral ischemia. Piroxicam could be clinically exploited for the treatment of brain stroke along with other anti-stroke therapeutics in future.

Project description:Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke, and avoids the complications of general hypothermia. However, the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown. In this study, we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein, a key factor in the mitochondrial fission system, during focal cerebral ischemia/reperfusion injury. Sprague-Dawley rats were divided into four groups. In the sham group, the carotid arteries were exposed only. In the other three groups, middle cerebral artery occlusion was performed using the intraluminal filament technique. After 2 hours of occlusion, the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group. Saline, at 4°C and 37°C, were perfused through the carotid artery in the hypothermia and normothermia groups, respectively, followed by restoration of blood flow. Neurological function was assessed with the Zea Longa 5-point scoring method. Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining, and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. Fis1 and cytosolic cytochrome c levels were assessed by western blot assay. Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. Mitochondrial ultrastructure was evaluated by transmission electron microscopy. Compared with the sham group, apoptosis, Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups. These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group. These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis, thereby ameliorating focal cerebral ischemia/reperfusion injury in rats. Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No. 2019008).

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Inhibition of gp91(phox) contributes towards normobaric hyperoxia afforded neuroprotection in focal cerebral ischemia.

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Inhibition of gp91(phox) contributes towards normobaric hyperoxia afforded neuroprotection in focal cerebral ischemia.

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