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

Bourgognon, Julie-Myrtille; Spiers, Jereme G.; Robinson, Sue W.; Scheiblich, Hannah; Glynn, Paul; Ortori, Catharine; Bradley, Sophie J.; Tobin, Andrew B.; Steinert, Joern R.

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


Authors

Julie-Myrtille Bourgognon

Jereme G. Spiers

Sue W. Robinson

Hannah Scheiblich

Paul Glynn

Catharine Ortori

Sophie J. Bradley

Andrew B. Tobin



Abstract

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.

Citation

Bourgognon, J., Spiers, J. G., Robinson, S. W., Scheiblich, H., Glynn, P., Ortori, C., …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, 118(10), Article e2009579118. https://doi.org/10.1073/pnas.2009579118

Journal Article Type Article
Acceptance Date Jan 22, 2021
Online Publication Date Mar 2, 2021
Publication Date Mar 9, 2021
Deposit Date Mar 19, 2021
Publicly Available Date Mar 29, 2024
Journal Proceedings of the National Academy of Sciences
Print ISSN 0027-8424
Electronic ISSN 1091-6490
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 118
Issue 10
Article Number e2009579118
DOI https://doi.org/10.1073/pnas.2009579118
Keywords neurodegeneration, nitric oxide, neuroinflammation, glycation, prion aggregation
Public URL https://nottingham-repository.worktribe.com/output/5402736
Publisher URL https://www.pnas.org/content/118/10/e2009579118

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