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Post-stroke inhibition of induced NADPH Oxidase type 4 prevents oxidative stress and neurodegeneration
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نویسنده
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kleinschnitz c. ,grund h. ,wingler k. ,armitage m.e. ,jones e. ,mittal m. ,barit d. ,schwarz t. ,geis c. ,kraft p. ,barthel k. ,schuhmann m.k. ,herrmann a.m. ,meuth s.g. ,stoll g. ,meurer s. ,schrewe a. ,becker l. ,gailus-durner v. ,fuchs h. ,klopstock t. ,de angelis m.h. ,jandeleit-dahm k. ,shah a.m. ,weissmann n. ,schmidt h.h.h.w.
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منبع
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plos biology - 2010 - دوره : 8 - شماره : 9
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چکیده
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Ischemic stroke is the second leading cause of death worldwide. only one moderately effective therapy exists,albeit with contraindications that exclude 90% of the patients. this medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. thus,there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. one such candidate mechanism is oxidative stress. however,antioxidant approaches have failed in clinical trials,and the significant sources of oxidative stress in stroke are unknown. we here identify nadph oxidase type 4 (nox4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. upon ischemia,nox4 was induced in human and mouse brain. mice deficient in nox4 (nox4-/-) of either sex,but not those deficient for nox1 or nox2,were largely protected from oxidative stress,blood-brain-barrier leakage,and neuronal apoptosis,after both transient and permanent cerebral ischemia. this effect was independent of age,as elderly mice were equally protected. restoration of oxidative stress reversed the stroke-protective phenotype in nox4-/- mice. application of the only validated low-molecular-weight pharmacological nadph oxidase inhibitor,vas2870,several hours after ischemia was as protective as deleting nox4. the extent of neuroprotection was exceptional,resulting in significantly improved long-term neurological functions and reduced mortality. nox4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. © 2010 kleinschnitz et al.
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آدرس
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neurologische klinik und poliklinik,universität würzburg,würzburg, Germany, rudolf-buchheim-institut für pharmakologie and medizinische klinik,justus-liebig-universität,gießen, Germany, rudolf-buchheim-institut für pharmakologie and medizinische klinik,justus-liebig-universität,gießen,germany,department of pharmacology,centre for vascular health,monash university,melbourne,australia,department of pharmacology and toxicology,cardiovascular research institute maastricht (carim),maastricht university,netherlands,national stroke research institute,florey neuroscience institutes,melbourne, Australia, department of pharmacology,centre for vascular health,monash university,melbourne,australia,national stroke research institute,florey neuroscience institutes,melbourne, Australia, department of pharmacology,centre for vascular health,monash university,melbourne, Australia, rudolf-buchheim-institut für pharmakologie and medizinische klinik,justus-liebig-universität,gießen, Germany, baker idi heart and diabetes institute,juvenile diabetes research foundation (jdrf),international center for diabetic complications research,melbourne, Australia, neurologische klinik und poliklinik,universität würzburg,würzburg, Germany, neurologische klinik und poliklinik,universität würzburg,würzburg, Germany, neurologische klinik und poliklinik,universität würzburg,würzburg, Germany, abteilung neurologie,georg-august universität göttingen,göttingen, Germany, neurologische klinik und poliklinik,universität würzburg,würzburg,germany,universitätsklinik münster,klinik und poliklinik für neurologie-entzündliche,erkrankungen des nervensystems und neuroonkologie,münster, Germany, neurologische klinik und poliklinik,universität würzburg,würzburg,germany,universitätsklinik münster,klinik und poliklinik für neurologie-entzündliche,erkrankungen des nervensystems und neuroonkologie,münster, Germany, neurologische klinik und poliklinik,universität würzburg,würzburg,germany,universitätsklinik münster,klinik und poliklinik für neurologie-entzündliche,erkrankungen des nervensystems und neuroonkologie,münster, Germany, neurologische klinik und poliklinik,universität würzburg,würzburg, Germany, department of pharmacology,centre for vascular health,monash university,melbourne, Australia, institute of experimental genetics,helmholtz zentrum münchen,german research center for environmental health,münchen, Germany, institute of experimental genetics,helmholtz zentrum münchen,german research center for environmental health,münchen,germany,friedrich-baur-institut an der neurologischen klinik,klinikum der ludwig-maximilians-universität münchen,münchen, Germany, institute of experimental genetics,helmholtz zentrum münchen,german research center for environmental health,münchen, Germany, institute of experimental genetics,helmholtz zentrum münchen,german research center for environmental health,münchen, Germany, friedrich-baur-institut an der neurologischen klinik,klinikum der ludwig-maximilians-universität münchen,münchen, Germany, institute of experimental genetics,helmholtz zentrum münchen,german research center for environmental health,münchen,germany,lehrstuhl für experimentelle genetik,technische universität münchen,freising-weihenstephan, Germany, baker idi heart and diabetes institute,juvenile diabetes research foundation (jdrf),international center for diabetic complications research,melbourne, Australia, king's college london school of medicine,the james black centre,cardiovascular division,london, United Kingdom, rudolf-buchheim-institut für pharmakologie and medizinische klinik,justus-liebig-universität,gießen, Germany, rudolf-buchheim-institut für pharmakologie and medizinische klinik,justus-liebig-universität,gießen,germany,department of pharmacology,centre for vascular health,monash university,melbourne,australia,department of pharmacology and toxicology,cardiovascular research institute maastricht (carim),maastricht university,netherlands,national stroke research institute,florey neuroscience institutes,melbourne, Australia
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Authors
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