A pharmacological study on the role of nitric oxide in the pathogenesis of experimental allergic encephalomyelitis
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Objective and Design:
The study examines the effects of nitric oxide synthase (NOS) inhibitors on the development of neurological EAE and the levels of nitrite in the central nervous system (CNS) during established disease.
EAE was induced inmale Lewis rats (200–250 g).
Ras received NG-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg body weight) day 7 to 12 post-inoculation (P.I.), 7-nitroindazole (10 mg/kg) day 7 to 11 P.I. or aminoguanidine (200 or 400 mg/kg) day 1 to 12 P.I.
Neurological symptoms were assessed and CNS cytosol nitrite and protein levels measured. Results were analysed using the Mann Whitney U-test and the Fischer exact probability test.
Symptoms of EAE were associated with a significant elevation in CNS nitrite (P<0.001). Treatment with NOS inhibitors caused a marked reduction in nitrite levels (p<0.00). However, in some experiments, vehicle administration also reduced CNS nitrite content (p<0.05). Although neurological disease was supressed in EAE-sensitised rats receiving L-NAME (2±0.3 vs 3±0.3 mean peak severity ±SEM) and 7-nitroindazole (1±0.3 vs 3±0.3, p<0.01) comparable inhibition was achieved by respective vehicle treatment (p<0.01). In contrast, neither aminoguanidine nor corresponding vehicle altered disease development.
Drug-induced reductions in CNS nitrite levels during EAE are not always associated with a suppression of neurological symptoms, which suggests NO is not of primary importance in disease pathogenesis. In addition, the study emphasises the strict requirement for appropriate controls when assessing the efficacy of drugs on the course of EAE.
Key wordsExperimental allergic encephalomyelitis Nitric oxide Pharmacological manipulation
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- Xie Q, Nathan C. The high-output nitric pathway: role and regulation. J Leuk Biol 1994;56:576–82.Google Scholar
- Brosnan CF, Battistini L, Raine CS, Dickson DW, Casadevall A, Lees SC. Reactive nitrogen intermediates in human neuropathology: An overview. Dev Neurosci 1994;10:152–61.Google Scholar
- MacMicking JD, Willenborg DO, Weidemann MJ, Rockett KA, Cowden WB. Elevated secretion of reactive nitrogen and oxygen intermediates by inflammatory leukocytes in hyperacute experimental autoimmune encephalomyelitis: enhancement by the soluble products of encephalitogenic T cells. J Exp Med 1992;176:303–7.PubMedCrossRefGoogle Scholar
- Scott GS, Lees P, Williams KI, Bolton C. The role of nitric oxide (NO) in neurovascular disruption during the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. J. Physiol 1994;480:P19.Google Scholar
- Förstermann U, Gorsky LD, Pollock JS, Schmidt HHHW, Heller M, Murad F. Regional distribution of EDRF/NO synthesizing enzymes (s) in rat brain. Biochim Biophys Res Commun 1990;168:727–32.Google Scholar
- Bolton C. Recent advances in the pharmacological control of experimental allergic encephalomyelitis (EAE) and the implications for multiple sclerosis (MS) treatment. Multiple Sclerosis: Clin Lan Res 1995;1:143–9.Google Scholar
- Weicker H, Werle E. Interaction between hormones and the immune system. Int J Sports Med 1991;12:S30–7.Google Scholar