Cerebrospinal fluid and serum nitric oxide metabolites in patients with multiple sclerosis

Abstract

Nitric oxide is hypothesised to play a role in the immunopathogenesis of multiple sclerosis. Raised cerebrospinal fluid and serum levels of the nitric oxide metabolites nitrate and nitrite have been described in patients with multiple sclerosis. Cerebrospinal fluid and serum nitrate and nitrite were measured in patients with multiple sclerosis, inflammatory and non-inflammatory neurological diseases, and correlated with the albumin quotient, an index of blood-brain-barrier dysfunction. Patients undergoing diagnostic lumbar and vene puncture were prospectively recruited, clinical data were obtained from the hospital records, and the CSF and serum nitrate and nitrite levels were measured by the nitrate reductase and Griess reaction methods. Nitrate and nitrite, were raised in the CSF and serum of patients with multiple sclerosis and other inflammatory neurological diseases compared to patients with non-inflammatory neurological disorders (median nitrate and nitrite: cerebrospinal fluid=10.3 μM vs 15.4 μMvs 6.6 μM, P50.001, and serum=49.0 μM vs 46.4 μM vs 38.8 μM, P=0.02, respectively). CSF nitrate and nitrite levels correlated with the albumin quotient (n=59, r=0.42, P50.001). This study provides further evidence for a role of nitric oxide in the immunopathogenesis of multiple sclerosis and supports a role for nitric oxide as a possible mediator of inflammatory blood-brain-barrier dysfunction.

Keywords

nitric oxide multiple sclerosis blood-brain-barrier

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References

Moncada S , Higgs A. (1993) The L-Arginine-Nitric Oxide Pathway . N Engl J Med 329: 2002-2012 .

Shulka A , Dikshit M , Srimal RC. (1995) Nitric oxide modulates blood-brain-barrier permeability during infections with an inactivated bacterium . Neuroreport 6: 1629-1632 .

Boje KMK. (1996) Inhibition of nitric oxide synthase attenuates blood-brain-barrier disruption during experimental meningitis . Brain Res 720: 75-83 .

Beckman JS et al. (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide . Proc Natl Acad Sci USA 87: 1620-1624 .

Merrill JE et al. (1993) Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide . J Immunol 151: 2132-2141 .

Mitrovic B et al. (1994) Nitric oxide as a potential pathological mechanism in demyelination: its differential effects on primary glial cells in vitro . Neuroscience 61: 575-585 .

Boje KM , Arora K. (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death . Brain Res 587: 250-256 .

Bolanos JP , Heales SJR , Land JM , Clark JB. (1995) Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurones and astrocytes in primary culture . J Neurochem 64: 1965-1972 .

Barker JE et al. (1996) Glutathione protects astrocytes from peroxynitrite mediated mitochondrial damage. Implications for neuronal/astrocytic trafficking and neurodegeneration . Dev Neurosci 18: 391-396 .

10.

Inoue S , Kawanishi S. (1995) Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide . FEBS Lett 371: 86-88 .

11.

Hausladen A , Fridovich I. (1994) Superoxide and peroxynitrite inactive aconitases, but nitric oxide does not . J Biol Chem 269: 29405-29408 .

12.

Mateo RB et al. (1995) Impact of nitric oxide on macrophage glucose metabolism and glyceraldehyde-3- phosphate dehydrogenase activity . Am J Physiol 268: 669-675 .

13.

Roy B , Lepoivre M , Henry Y , Fontecave M. (1995) Inhibition of ribonucleotide reductase by nitric oxide derived from thionitrites: reversible modifications of both subunits . Biochemistry 35: 5411-5418 .

14.

Lee SC , Dickson DW , Liu W , Brosnan CF. (1993) Induction of nitric oxide synthase activity in human astrocytes by interleukin-1-beta and interferon gamma . J Neuroimmunol 46: 19-24 .

15.

Bagasara O et al. (1995) Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis . Proc Natl Acad Sci USA 92: 12041-12045 .

16.

BöL et al. (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains . Ann Neurol 36: 778-786 .

17.

Poser CM et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol 13: 227-231 .

18.

Giovannoni G et al. (1997) Adaptation of the nitric reductase and Griess reaction methods for the measurement of serum nitrate plus nitrite levels . Ann Clin Biochem 34: 193-198 .

19.

Laurell CB. (1972) Electroimmuno assay . Scand J Clin Lab Invest 29: 21-37 .

20.

Lublin FD , Reingold SC. (1996) Defining the clinical course of multiple sclerosis: results of an international survey . Neurology 46: 907-911 .

21.

Johnson AW et al. (1995) Evidence for increased nitric oxide production in multiple sclerosis . J Neurol Neurosurg Psychiatry 58: 107-107 .

22.

Giovannoni G et al. (1996) Raised serum nitrate and nitrite levels in patients with multiple sclerosis . JNeurol Sci (In Press).

23.

Felgenhauer K , Liappis N , Nekic M. (1982) Low molecular solutes and the blood cerebrospinal fluid barrier . Klin Wschr 60: 1385-1392 .

24.

Milstien S et al. (1994) Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases . J Neurochem 63: 1178-1180 .

25.

Hurst RD , Fritz IB. (1996) Nitric oxide-induced pertubations in a cell culture model of the blood-brain barrier . J Cell Physiol 167: 89-94 .

26.

Buster BL , Weintrob AC , Townsend GC , Scheld WM. (1995) Potential role of nitric oxide in the pathophysiology of experimental bacterial meningitis in rats . Infect Immun 63: 3835-3839 .

27.

Sharief MK et al. (1993) Increased levels of circulating ICAM-1 in serum and cerebrospinal fluid of patients with active multiple sclerosis. Correlation with TNF-a and blood-brain barrier damage . J Neuroimmunol 43: 15-22 .