Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease

被引:38
作者
Bourgognon, Julie-Myrtille [1 ]
Spiers, Jereme G. [2 ]
Robinson, Sue W. [3 ]
Scheiblich, Hannah [4 ]
Glynn, Paul [3 ]
Ortori, Catharine [5 ]
Bradley, Sophie J. [6 ]
Tobin, Andrew B. [6 ]
Steinert, Joern R. [7 ]
机构
[1] Univ Glasgow, Ctr Immunobiol, Glasgow G12 8TA, Lanark, Scotland
[2] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem & Genet, Melbourne, Vic 3083, Australia
[3] Univ Leicester, Med Res Council, Toxicol Unit, Leicester LE1 9HN, Leics, England
[4] Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat Neurol, D-53127 Bonn, Germany
[5] Univ Nottingham, Sch Pharm, Nottingham NG7 2RD, England
[6] Univ Glasgow, Ctr Translat Pharmacol Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland
[7] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Nottingham NG7 2UH, England
基金
英国医学研究理事会;
关键词
neurodegeneration; nitric oxide; neuroinflammation; glycation; prion aggregation; S-NITROSYLATION; ALZHEIMER-DISEASE; END-PRODUCTS; NONENZYMATIC GLYCATION; OXIDATIVE STRESS; SYNTHASE; NEURODEGENERATION; PROTEIN; NITROTYROSINATION; EXPRESSION;
D O I
10.1073/pnas.2009579118
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Several neurodegenerative diseases associated with protein mis-folding (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 electro-physiological 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.
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页数:11
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