Neuronal nitric oxide synthase plays a key role in CNS demyelination.
Nitric oxide (NO) is a small, short-lived molecule released from a variety of cells that is implicated in a multitude of biological processes. In pathological conditions, overproduction of NO may lead to the generation of highly reactive species, such as peroxynitrite and stable nitrosothiols, that may cause irreversible cell damage. Accordingly, several studies have suggested that NO may be involved in the pathogenesis of various neuroinflammatory/degenerative diseases. Increased concentrations of NO in the CNS in such cases are usually attributed to an increase in the inducible isoform of NO synthase (iNOS) usually produced by inflammatory cells. However, recent reports have suggested that the constitutive isoforms of NOS, neuronal (nNOS) and endothelial (eNOS), can also play a role. Here we examined the role that the constitutive isoforms of NOS might play in the cuprizone-induced model of demyelination/remyelination. Our results demonstrate that demyelination was greatly prevented in mice lacking nNOS. Protection was associated with a dramatic increase in mature oligodendrocyte survival and a decrease in apoptosis. Moreover, nNOS-/- mice did not respond to cuprizone with the extensive recruitment of microglia/macrophages and astrocytes, which is a typical feature in wild-type mice. Although demyelinating less, nNOS-/- mice exhibited a delay in remyelination. In eNOS-/- mice, demyelination progressed to the same extent as in wild type, but they showed a slight delay in spontaneous remyelination. In conclusion, this study highlights the importance of considering the source of NO when assessing its role in neuroinflammation/degeneration and emphasizes the differing pathological effects driven by the different NOS isoforms.
Liñares
David
D
Neurosciences Research Unit, Australian National University Medical School, Canberra Hospital, Australian Capital Territory 2601, Australia. david.linares@anu.edu.au
Taconis
Maaike
M
Maña
Paula
P
Correcha
Manuel
M
Fordham
Sue
S
Staykova
Maria
M
Willenborg
David O
DO
D000818:Animals; D002493:Central Nervous System Diseases / Q000201:enzymology* / Q000473:pathology; D003711:Demyelinating Diseases / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism / Q000502:physiology
D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III