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

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Abstract

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.

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Abbreviations

ADMA:

Asymmetric dimethylarginine (N G, N G-dimethyl-l-arginine)

AGAT:

Arginine:glycine amidinotransferase

AQP:

Aquaporin

CNS:

Central nervous system

CSF:

Cerebrospinal fluids

GC–MS:

Gas chromatography–mass spectrometry

GC–MS/MS:

Gas chromatography–tandem mass spectrometry

hArg:

Homoarginine

HC:

Healthy controls

MS:

Multiple sclerosis

NMO:

Neuromyelitis optica

NO:

Nitric oxide

NOS:

Nitric oxide synthase

OND:

Other neurologic diseases

RRMS:

Relapsing–remitting multiple sclerosis

SDMA:

Symmetric dimethylarginine (N G, N G′-dimethyl-l-arginine)

SPMS:

Secondary progressive multiple sclerosis

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Conflict of interest

The authors declare that they have no conflict of interest related to the present research.

Ethical standard

The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in an approval by the Ethics Committee of the Ruhr-University Bochum (Bochum, Germany).

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Authors and Affiliations

  1. Department of Neurology, St. Josef-Hospital, Ruhr-University, 44791, Bochum, Germany

    Aiden Haghikia & Ralf Gold

  2. Centre of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany

    Arslan Arinc Kayacelebi, Bibiana Beckmann, Erik Hanff & Dimitrios Tsikas

  3. Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

    Arash Haghikia

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  1. Aiden Haghikia
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  2. Arslan Arinc Kayacelebi
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  3. Bibiana Beckmann
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  4. Erik Hanff
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  5. Ralf Gold
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  6. Arash Haghikia
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  7. Dimitrios Tsikas
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Correspondence to Aiden Haghikia.

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Haghikia, A., Kayacelebi, A.A., Beckmann, B. et al. Serum and cerebrospinal fluid concentrations of homoarginine, arginine, asymmetric and symmetric dimethylarginine, nitrite and nitrate in patients with multiple sclerosis and neuromyelitis optica. Amino Acids 47, 1837–1845 (2015). https://doi.org/10.1007/s00726-015-2015-0

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