Neuronal Nitric Oxide Synthase Plays a Key Role in CNS Demyelination

Abstract

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 Ϫ/Ϫ 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 Ϫ/Ϫ mice exhibited a delay in remyelination. In eNOS Ϫ/Ϫ 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.

Identification of a microglia phenotype supportive of remyelination

“…E: Galectin 3 mRNA was gradually upregulated in microglia in the course of demyelination and remyelination, became detectable at the protein level at 5WD (data not shown), and remained upregulated up to 2WR (5WD, 5 weeks of demyelination; 1WR, 1 week of remyelination; 2WR, 2 weeks of remyelination; Tgfb, transforming growth factor beta; Spp1, osteopontin; Iba1, ionized calcium-binding adaptor molecule 1; IB4, isolectin B4; Slpi, antileukoproteinase; Cd11c, integrin alpha-X, a dendritic cell marker; Gal3, galectin-3; calibration bars in our study, both of which have been shown to be indispensable for remyelination to occur (Arnett et al, 2001;Mason et al, 2001). Interestingly, inducible nitric oxide synthase (iNOS) was found to be induced in the cuprizone model in microglia (Arnett et al, 2002;Liñares et al, 2006) and was moderately protective against demyelination (Arnett et al, 2002). Nonetheless, iNOS was not among the genes expressed in our study.…”

Neuronal Nitric Oxide Synthase

“…Previous results demonstrate that demyelination was mainly prevented in mice lacking nNOS. In eNOS -/-mice, demyelination increased to the same level as in wild type, but they showed a slight delay in spontaneous remyelination [50].…”

“…The constitutive NOS make the cuprizone-induced model of demyelination/remyelination [50]. Previous results demonstrate that demyelination was mainly prevented in mice lacking nNOS.…”

The effect of pramiracetam in the myelination of the hippocampus in the BALB/c mouse (Mus musculus)

“…[28] These effects may be attributed to an increase in different isoforms of NOS all of which may lead to detrimental effects. [29] It may thus be inferred from this study that there may be different effects of administration of pramiracetam in different test organisms and may thus need further study to verify whether adverse effects may be seen or not. Furthermore, without conclusive evidence on the effect of pramiracetam, careful use of the nootropic is warranted.…”