气候变化领域集成服务门户(CCPortal): Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease

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DOI	10.1073/pnas.2009579118
	Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease
	Bourgognon J.-M.; Spiers J.G.; Robinson S.W.; Scheiblich H.; Glynn P.; Ortori C.; Bradley S.J.; Tobin A.B.; Steinert J.R.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	Several neurodegenerative diseases associated with protein misfolding (Alzheimer’s and Parkinson’s disease) exhibit oxidative and nitrergic stress following initiation of neuroinflammatory pathways. Associated nitric oxide (NO)-mediated posttranslational modifications impact upon protein functions that can exacerbate pathology. Nonenzymatic and irreversible glycation signaling has been implicated as an underlying pathway that promotes protein misfolding, but the direct interactions between both pathways are poorly understood. Here we investigated the therapeutic potential of pharmacologically suppressing neuroinflammatory NO signaling during early disease progression of prion-infected mice. Mice were injected daily with an NO synthase (NOS) inhibitor at early disease stages, hippocampal gene and protein expression levels of oxidative and nitrergic stress markers were analyzed, and electrophysiological characterization of pyramidal CA1 neurons was performed. Increased neuroinflammatory signaling was observed in mice between 6 and 10 wk postinoculation (w.p.i.) with scrapie prion protein. Their hippocampi were characterized by enhanced nitrergic stress associated with a decline in neuronal function by 9 w.p.i. Daily in vivo administration of the NOS inhibitor L-NAME between 6 and 9 w.p.i. at 20 mg/kg prevented the functional degeneration of hippocampal neurons in prion-diseased mice. We further found that this intervention in diseased mice reduced 3-nitrotyrosination of triose-phosphate isomerase, an enzyme involved in the formation of disease-associated glycation. Furthermore, L-NAME application led to a reduced expression of the receptor for advanced glycation end-products and the diminished accumulation of hippocampal prion misfolding. Our data suggest that suppressing neuroinflammatory NO signaling slows functional neurodegeneration and reduces nitrergic and glycation-associated cellular stress. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Glycation; Neurodegeneration; Neuroinflammation; Nitric oxide; Prion aggregation
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180351
作者单位	Centre for Immunobiology, University of Glasgow, Glasgow, G12 8TA, United Kingdom; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3083, Australia; Medical Research Council Toxicology Unit, University of Leicester, Leicester, LE1 9HN, United Kingdom; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn, Bonn, 53127, Germany; School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, United Kingdom; Centre for Translational Pharmacology, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom; School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
推荐引用方式 GB/T 7714	Bourgognon J.-M.,Spiers J.G.,Robinson S.W.,et al. Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease[J],2021,118(10).
APA	Bourgognon J.-M..,Spiers J.G..,Robinson S.W..,Scheiblich H..,Glynn P..,...&Steinert J.R..(2021).Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Bourgognon J.-M.,et al."Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).