Serum and cerebrospinal fluid concentrations of homoarginine, arginine, asymmetric and symmetric dimethylarginine, nitrite and nitrate in patients with multiple sclerosis and neuromyelitis optica.

The pathogenic hallmarks of multiple sclerosis (MS) and neuromyelitis optica (NMO) are cellular and humoral inflammatory infiltrates and subsequent demyelination, or astrocytic cell death in NMO, respectively. These processes are accompanied by disruption of the blood-brain barrier as regularly observed by gadolinium enhancement on magnetic resonance imaging. The role of the L-arginine/nitric oxide (NO) pathway in the pathophysiology of neuroinflammatory diseases, such as MS and NMO, remains unclear. In the present study, we measured the concentrations of the nitric oxide (NO) metabolites nitrate and nitrite, the endogenous substrates of NO synthase (NOS) L-arginine (Arg) and L-homoarginine (hArg), and asymmetric dimethylarginine (ADMA), the endogenous inhibitor of NOS activity, in the serum and cerebrospinal fluid (CSF) of patients with MS, NMO or other neurologic diseases (OND). MS (551 ± 23 nM, P = 0.004) and NMO (608 ± 51 nM, P = 0.006) patients have higher ADMA concentrations in serum than healthy controls (HC; 430 ± 24 nM). For MS, this finding was confirmed in CSF (685 ± 100 nM in relapsing-remitting multiple sclerosis, RRMS; 597 ± 51 nM in secondary progressive multiple sclerosis, SPMS) compared with OND (514 ± 37 nM; P = 0.003). Serum concentrations of Arg (61.1 ± 9.7 vs. 63.6 ± 4.9 µM, P = 0.760), hArg (2.62 ± 0.26 vs. 2.52 ± 0.23 µM, P = 0.891), nitrate (38.1 ± 2.2 vs. 38.1 ± 3.0 µM) and nitrite (1.37 ± 0.09 vs. 1.55 ± 0.03 µM) did not differ between MS and OND. Also, CSF concentrations of hArg (0.685 ± 0.100 µM in RRMS, 0.597 ± 0.051 µM in SPMS, 0.514 ± 0.037 µM in OND), nitrate (11.3 ± 0.6 vs. 10.5 ± 0.3 µM) and nitrite (2.84 ± 0.32 vs. 2.41 ± 0.11 µM) did not differ between the groups. In NMO patients, however, serum Arg (117 ± 11 vs. 64 ± 4.9 µM, P = 0.004), nitrate (29 ± 2.1 vs. 38 ± 3 µM, P = 0.03), and nitrite (1.09 ± 0.02 vs. 1.55 ± 0.033 µM, P < 0.0001) were significantly different as compared to OND. Symmetric dimethylarginine (SDMA) concentration did not differ in serum between MS and HC (779 ± 43 vs. 755 ± 58 nM, P = 0.681) or in CSF between MS and OND patients (237 ± 11 vs. 230 ± 17 nM, P = 0.217). Our study suggests a potential role for ADMA and Arg in neuroinflammatory diseases with diverse functions in MS and NMO. Higher ADMA synthesis may explain reduced NO availability in NMO. hArg and SDMA seem not to play an important role in MS and NMO.

Guanidino compound analysis as a complementary diagnostic parameter for hyperargininemia: follow-up of guanidino compound levels during therapy.

The aim of this collaborative study was to investigate whether guanidino compound analyses in the biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange chromatographic system with a fluorescence detection method. The serum arginine, homoarginine, alpha-keto-delta-guanidino-valeric acid, argininic acid, and N-alpha-acetylarginine levels of all the hyperargininemic patients are higher than the normal range. Similar increases were seen for the urinary excretion of alpha-keto-delta-guanidinovaleric acid and argininic acid. Untreated hyperargininemic patients have the highest guanidino compound levels in cerebrospinal fluid. However, even under therapy, the arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid, and argininic acid levels in cerebrospinal fluid are still increased. Protein restriction alone is not sufficient to normalize the hyperargininemia, but protein restriction together with supplementation of essential amino acids with or without sodium benzoate decreases further the arginine levels. However, whereas the argininemia can be normalized, the catabolites of arginine are still increased. We conclude that the urinary amino acid levels may remain normal in hyperargininemia, whereas consistent increases of the guanidino compounds are observed. Thus, guanidino compound analyses can be used as a complementary biochemical diagnostic parameter for hyperargininemia. Although the argininemia can be normalized by therapy, the levels of the catabolites of arginine are still elevated.