Differential sensitivity of oligodendrocytes and motor neurons to reactive nitrogen species: implications for multiple sclerosis

Abstract

Depending on its concentration, nitric oxide (NO) has beneficial or toxic effects. In pathological conditions, NO reacts with superoxide to form peroxynitrite, which nitrates proteins forming nitrotyrosine residues (3NY), leading to loss of protein function, perturbation of signal transduction, and cell death. 3NY immunoreactivity is present in many CNS diseases, particularly multiple sclerosis. Here, using the high flux NO donor, spermine‐NONOate, we report that oligodendrocytes are resistant to NO, while motor neurons are NO sensitive. Motor neuron sensitivity correlates with the NO‐dependent formation of 3NY, which is significantly more pronounced in motor neurons when compared with oligodendrocytes, suggesting peroxynitrite as the toxic molecule. The heme‐metabolizing enzyme, heme‐oxygenase‐1 (HO1), is necessary for oligodendrocyte NO resistance, as demonstrated by loss of resistance after HO1 inhibition. Resistance is reinstated by peroxynitrite scavenging with uric acid further implicating peroxynitrite as responsible for NO sensitivity. Most importantly, differential sensitivity to NO is also present in cultures of primary oligodendrocytes and motor neurons. Finally, motor neurons cocultured with oligodendrocytes, or oligodendrocyte‐conditioned media, become resistant to NO toxicity. Preliminary studies suggest oligodendrocytes release a soluble factor that protects motor neurons. Our findings challenge the current paradigm that oligodendrocytes are the exclusive target of multiple sclerosis pathology.

Modulatory effect of celastrol on Th1/Th2 cytokines profile, TLR2 and CD3+ T-lymphocyte expression in a relapsing–remitting model of multiple sclerosis in rats

“…Activation of TLR2 has been reported to induce TNF-α synthesis that contribute to inhibition of adult neural progenitor cell (NPCs) proliferation (Covacu et al, 2009), an effect was mediated via myeloid differentiation primary response gene (88), MyD88-dependent pathway that ultimately allowing NF-κB to diffuse into the cell nucleus, activate transcription, and induce inflammatory cytokines (Kawai and Akira, 2010). In addition, TNF-α as a major Th1 cytokine has been found to induce immune cell iNOS in vitro through transcriptional modulating effect (Napoli and Neumann, 2010) and reciprocally nitric oxide (NO) also induces the production of TNF-α (Bishop et al 2009;Henderson et al 2009). The present results showed significant increase in levels of NF-κB and nitrites in tissues of brain and spinal cord in rats with EAE þvehicle compared to the normal rats.…”

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

“…Related studies have been reported dealing with AO protection [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124]. Sensitivity of motor neurons to reactive nitrogen species has implications for MS [125]. Additional evidence suggests a central role for OS in MS [126].…”

Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis

“…OLs are found to be resistant to nitric oxide, but more susceptible to the toxicity of peroxynitrite (Jack et al, 2007;Bishop et al, 2009). However, the mechanisms underlying the action of nitric oxide and peroxynitrite in OLs are unclear.…”