Cerebrospinal fluid levels of nitric oxide metabolites predict response to methylprednisolone treatment in multiple sclerosis and optic neuritis

Object. Decreased availability of nitric oxide (NO) has been proposed to evoke delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). Asymmetric dimethyl-l-arginine (ADMA) inhibits endothelial NO synthase (eNOS) and, therefore, may be responsible for decreased NO availability in cases of cerebral vasospasm. The goal of this study was to determine whether ADMA levels are associated with cerebral vasospasm in a primate model of SAH. Methods. Twenty-two cynomolgus monkeys (six control animals and 16 with SAH) were used in this study. The levels of ADMA, l-arginine, l-citrulline, nitrites, and nitrates in cerebrospinal fluid (CSF) and serum were determined on Days 0, 7, 14, and 21 following onset of SAH. Cerebral arteriography was performed to assess the degree of vasospasm. Western blot analyses of the right and left middle cerebral arteries (MCAs) were performed to assess the expression of eNOS, type I protein—arginine methyl transferase (PRMT1) and dimethylarginine dimethylaminohydrolase (DDAH2). Cerebrospinal fluid levels of ADMA remained unchanged in the control group (six animals) and in animals with SAH that did not have vasospasm (five animals; p = 0.17), but the levels increased in animals with vasospasm (11 animals) on Day 7 post-SAH (p < 0.01) and decreased on Days 14 through 21 (p < 0.05). Cerebrospinal fluid levels of ADMA correlated directly with the degree of vasospasm (correlation coefficient = 0.7, p = 0.0001; 95% confidence interval: 0.43–0.83). Levels of nitrite and nitrate as well as those of l-citrulline in CSF were decreased in animals with vasospasm. Furthermore, DDAH2 expression was attenuated in the right spastic MCA on Day 7 post-SAH, whereas eNOS and PRMT1 expression remained unchanged. Conclusions. Changes in the CSF levels of ADMA are associated with the development and resolution of vasospasm found on arteriograms after SAH. The results indicate that endogenous inhibition of eNOS by ADMA may be involved in the development of delayed cerebral vasospasm. Inhibition of ADMA production may provide a new therapeutic approach for cerebral vasospasm after SAH.

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

Multiple Sclerosis Journal ◽

10.1177/135245859800400107 ◽

1998 ◽

Vol 4 (1) ◽

pp. 27-30 ◽

Cited By ~ 19

Author(s):

G Giovannoni

Keyword(s):

Nitric Oxide ◽

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Blood Brain Barrier ◽

Neurological Diseases ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Nitric Oxide Metabolites ◽

Nitrate And Nitrite

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.

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