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Show EDITORIAL Nitric Oxide in Optic Neuritis and Multiple Sclerosis Hideki Chuman, MD, PhD There has been an explosive growth of research on the role of nitric oxide ( NO) in physiological and pathologic processes in the brain. Physiologically, NO functions as a neurotransmitter and a vasodilator for fine local control of cerebral blood flow In pathologic states, NO is induced in response to various inflammatory conditions. In this issue of the Journal ofNeuro- Ophthalmology, Tsoi et al ( 1) report evidence for inducible nitric oxide synthase ( iNOS) and peroxynitrite- mediated damage in optic neuritis ( ON). The article is worth noticing because the optic nerves were obtained from a single patient with clinically isolated ON who died of causes unrelated to ON. Significantly, the patient was in clinical remission and undergoing interferon therapy. The authors compared the immunohistochemical findings in the patient with ON to control normal optic nerves obtained from an eye bank. In the patient with ON, the authors showed localized loss of myelin proteins, myelin breakdown, and the presence of iNOS and nitrotyrosine associated with inflammatory infiltrates on the edges of the nerve and reactive astrocytes. This evidence implicates the role of iNOS in the inflammation and demyelination of ON. Similarly, increased iNOS activity has been demonstrated in astrocytes in demyelinating lesions of postmortem tissues in multiple sclerosis ( MS) ( 2). In addition, a 70% elevation in cerebrospinal nitrite has been reported in living patients with MS ( 3). These reports raise interesting questions in regard to NO and MS. What is the role of NO in MS? We do not know the answer yet. It is likely to be much more complicated than originally thought with a complex interplay between broadly beneficial regulatory effects on the immune system and largely deleterious direct effects on neurologic tissues ( 4). NO can disturb the permeability of the blood- brain barrier ( BBB) and facilitate antibody leakage into lesions ( 5), and it can inhibit T cell activation in the blood and lymphatic tissue, thereby inhibiting T cell- mediated inflammation ( 6). NO may also inhibit the expression of adhesion molecules at the BBB, thereby impairing the recruitment of inflammatory cells into the lesion ( 7), and it may also augment the apoptosis of T lymphocytes in the central nervous system contributing to the termination of the inflammatory reaction ( 8). At the same time, NO produced by iNOS- positive inflammatory cells may cause demyelination by destroying oligodendrocytes and/ or damaging myelin ( 9), and it may also block conduction in demyelinated axons ( 10). Neural function may also be impaired by the effects of NO on synaptic transmission. NO may also directly damage axons and neurons. Might NO inhibition therapy be effective in treating MS or ON? Unfortunately, no clear picture has yet emerged. Some studies have found that aminoguanidine, a partially selective inhibitor of iNOS, inhibits disease expression in a dose- dependent manner ( 11). However, other studies have found that NO inhibition can worsen the inflammation in experimental autoimmune encephalomyelitis ( EAE) ( 12). Some studies have found that inhibition of type IV phosphodiesterase, which increases NO, suppressed inflammation in EAE. ( 13). Administration of uric acid, a scavenger of peroxynitrite, has also been found to be an effective therapy for EAE ( 14). Department of Ophthalmology, Miyazaki Medical College Hospital, Miyazaki, Japan. Address correspondence to Hideki Chuman, MD, PhD, Department of Ophthalmology, Miyazaki Medical College Hospital, 5200 Kihara Kiyotake, Miyazaki, 889- 1692, Japan; E- mail: hchuman@ post. miyazaki- med. ac. jp J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 85 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Editorial These studies involving the NO pathways are preliminary but promising. By showing that NO levels are abnormally high in ON as well as in MS lesions, Tsoi et al ( 1) provide impetus for further study in this area. REFERENCES 1. Tsoi VL, Hill KE, Carlson NG, et al. Immunohistochemical evidence of inducible nitric oxide synthase and nitrotyrosine in a case of clinically isolated optic neuritis J Neuroophthalmol 2006; 26: 87- 94. 2. Bagasra O, Michaels FH, Zheng YM, et al. Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Natl Acad Sci USA 1995; 92: 12041- 5. 3. Johnson AW, Land JM, Thompson EJ, et al. Evidence for increased nitric oxide production in multiple sclerosis. J Neurol Neurosurg Psychiatry 1995; 57: 107. 4. Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol 2002; 1: 232^ U. 5. Mayhan WG. Nitric oxide donor- induced increase in permeability of the blood- brain barrier. Brain Res 2000; 886: 101- 8. 6. Albina JE, Henry WL Jr. Suppression of lymphocyte proliferation through the nitric oxide synthesizing pathway. J Surg Res 1991; 50: 403- 9. 7. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991; 88: 4651- 5. 8. Okuda Y, Sakoda S, Fujimura H, et al. Nitric oxide via an inducible isoform of nitric oxide synthase is a possible factor to eliminate inflammatory cells from the central nervous system of mice with experimental allergic encephalomyelitis. J Neuroimmunol 1997; 73: 107- 16. 9. Mitrovic B, Ignarro LJ, Montestotruque S, et al. Nitric oxide as a potential pathological mechanism in demyelination: its differential effects on primary glial cells in vitro. Neuroscience 1994; 61: 575- 85. 10. Redford EJ, Kapoor R, Smith KJ. Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 1997; 120: 2149- 57. 11. Zhao W, Tilton RG, Corbett JA, et al. Experimental allergic encephalomyelitis in the rat is inhibited by aminoguanidine, an inhibitor of nitric oxide synthase. J Neuroimmunol 1996; 64: 123- 33. 12. Cowden WB, Cullen FA, Staykova MA, et al. Nitric oxide is a potential down regulating molecule in autoimmune disease: inhibition of nitric oxide production renders PVG rats highly susceptible to EAE. J Neuroimmunol 1998; 88: 1- 8. 13. Martinez I, Puerta C, Redondo C, et al. Type IV phosphodiesterase inhibition in experimental allergic encephalomyelitis of Lewis rats: sequential gene expression analysis of cytokines, adhesion molecules and the inducible nitric oxide synthase. J Neurol Sci 1999; 164: 13- 22. 14. Hooper DC, Spitsin S, Kean RB, et al. Uric acid, a natural scavenger of peroxynitrite in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 1998; 95: 675- 80. 86 © 2006 Lippincott Williams & Wilkins |
