Inhibition of Nitric Oxide Synthase Initiates Relapsing Remitting Experimental Autoimmune Encephalomyelitis in Rats, Yet Nitric Oxide Appears to be Essential for Clinical Expression of Disease

Abstract

Myelin basic protein-CFA-induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic disease from which animals recover. In this model, spontaneous relapses do not occur and rats develop a resistance to further active reinduction of disease. Previously, we reported that oral administration of the NO synthase inhibitor N-methyl-l-arginine acetate (l-NMA) to recovered rats precipitated a second episode of disease in 100% of animals. Further studies now show that this second clinical episode is actually a chronic relapsing disease that persists for months. This occurs only in rats that have recovered from actively induced EAE and not in rats recovered from passively induced EAE, suggesting the need for a peripheral Ag depot to induce secondary disease. We have also determined that clinical signs of EAE in l-NMA-treated recovered rats do not appear until l-NMA treatment has stopped. This is despite the fact that, at the same time point, CNS inflammatory lesions in symptomless animals receiving l-NMA are qualitatively and quantitatively similar to those with severe disease symptoms from whom l-NMA treatment has been withdrawn. The latter animals have significantly higher levels of reactive nitrogen intermediates in the cerebrospinal fluid than the former group. This study examines the mechanism of reinduction of disease by l-NMA treatment, and the findings suggest a dual role for NO in regulation of pathology in EAE that is dependent on site and timing of NO production.

An investigation of NOS2A promoter polymorphisms in Australian multiple sclerosis patients

“…48,49 Several studies have therefore proposed a dual role for NO, showing that iNOS activity is destructive in the acute phase of disease but protective in the progressive phase. 50,51 The dual effects of NO in disease pathogenesis are well demonstrated in NOS2A knockout mice infected with Toxoplasma gondi. 52 During acute infection, knockout mice survived because of the removal of an intense inflammatory response that killed most normal mice.…”

Exposure to a Dysfunctional Glucocorticoid Receptor from Early Embryonic Life Programs the Resistance to Experimental Autoimmune Encephalomyelitis Via Nitric Oxide-Induced Immunosuppression

“…Although different events, including alteration of cytokine production, changes in T cell sensitivity to proapoptotic signals, and/or the production of suppressor molecules (20,21), may participate in the immunosuppression of Tg mice, the final common pathway appears to be macrophage activation of iNOS/NO, as demonstrated by studies ex vivo and in vitro, using NOS inhibitors, NO scavengers, or NO donors. In addition, the ability of L-NIL treatment in vivo to sharply increase MOG-reactive LNC and spleen cell proliferation and revert the EAE resistance of GR-deficient mice further supports the participation of iNOS/NO in counteracting MOG reactive cell expansion during the early induction phase of EAE (46,55). Several endogenous and exogenous molecules can induce (LPS, IFN-␥, TNF-␣, and IL-1␤) or repress (TGF-␣, IL-4, IL-8, IL-10, corticosteroids, and estrogens) iNOS activity.…”

“…In contrast, peritoneal exudate from IFN-␥ ϩ/ϩ -resistant mice produced high levels of NO and down-regulated Ag-driven cell proliferation of IFN ␥ Ϫ/Ϫ mice (46). The down-regulatory effect of NO in primary EAE has been previously suggested to involve inhibition of T cell proliferation as well as inhibition of cell adhesion and migration (55). Such modulation may be dependent on the known functions of iNOS/NO, such as suppression of cytokine production, scavenging of superoxide, and/or apoptosis of macrophages or (encephalitogenic) T cells (20,21).…”

Antioxidants and polyunsaturated fatty acids in multiple sclerosis

“…It was proposed that the mechanism of EAE inhibition in iron-deficient mice involves the delivery and metabolism of iron for optimal CD4 þ T-cell development (Grant et al, 2003). Some investigators have shown iNOS inhibition as well as NO scavenging to suppress EAE (Cross et al, 1994;Zhao et al, 1996;Hooper et al, 1997;Jolivalt et al, 2003), whereas others have shown iNOS inhibition (O'Brien et al, 1999(O'Brien et al, , 2001 or NO donor (Xu et al, 2001) to aggravate or ameliorate EAE, thus not clarifying the exact role for NO .…”