Mustafa BİLİCİ, Enver Demirel YILMAZ, Ali Görkem GENÇER, Özge ÜNAL, Yüksel KIVRAK, Mehmet Fatih ÜSTÜNDAĞ

Levels of nitric oxide, asymmetric dimethyl arginine, symmetric dimethyl arginine,and L-arginine in patients with obsessive-compulsive disorder

Background/aim: We aimed to investigate and compare to healthy controls the variations in the levels of nitric oxide (NO), asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), and L-arginine levels in patients with obsessive-compulsive disorder (OCD). Materials and methods: We enrolled 30 patients with OCD and 30 healthy controls in the study consecutively. Diagnostic interviews of all participants were conducted with the Structured Clinical Interview for Axis I Disorders (SCID-I), and sociodemographic data of the participants were recorded. Patients scoring 10 points or more on the Yale Brown Obsessive-Compulsive Scale were enrolled in the study. Results: The NO levels of patients with OCD were increased compared to the control group, but the increase was not statistically significant (P > 0.05). However, patients with OCD had significantly lower levels of ADMA, SDMA, and L-arginine compared with the controls (P < 0.001). Conclusion: We found a significant decrease in ADMA, SDMA, and L-arginine as NO inhibitors between the groups, possibly because of an increase in NO. However, the insignificant increase in NO suggests that ADMA, SDMA, and L-arginine play direct and potentially important roles in OCD biology.

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1. Rasmussen SA, Eisen JL. Clinical features and phenomenology of obsessive compulsive disorder. Psychiat Ann 1989; 19: 67-73.
2. Ersan S, Bakır S, Ersan E, Doğan O. Examination of free radical metabolism and antioxidant defence system elements in patients with obsessivecompulsive disorder. Prog NeuroPsychoph 2006; 30: 1039-1042.
3. Atmaca M, Tezcan E, Kuloglu M, Ustundag B. Plasma nitrate values in patients with obsessive-compulsive disorder. Psychiatry Clin Neurosci 2005; 59: 621-623.
4. Eşsizoğlu A, Yıldırım EA. Nitric oxide in the psychobiology of mental disorders. Dicle Medical Journal 2009; 36: 67-74 (in Turkish with abstract in English).
5. Black MD, Selk DE, Hitchcock JM. On the effect of neonatal nitric oxide synthase inhibition in rats: a potential neurodevelopmental model of schizophrenia. Neuropharmacology 1999; 38: 1299-1306.
6. Crossin KL. Nitric oxide: a versatile second messenger in brain. Trends Biochem Sci 1991; 16: 81-82.
7. Dawson TM, Dawson VL, Snyder SH. A novel neuronal messenger molecule in brain: the free radical, nitric oxide. Ann Neurol 1992; 32: 297-311.
8. Van Amsterdam JG, Opperhuizen A. Nitric oxide and biopterin in depression and stress. Psychiatry Res 1999; 85: 33-38.
9. Hecker M, Sessa WC, Harris HJ, Anggard EE, Vane JR. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine. P Natl Acad Sci USA 1990; 87: 8612-8616.
10. Das I, Khan NS, Hirsch SR. Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production. Neurosci Lett 1996; 215: 209-211.
11. Uzbay IT, Oglesby MW. Nitric oxide and substance dependence. Neurosci Biobehav Rev 2001; 25: 43-52.
12. Yanık M, Vural H, Koçyiğit A, Tutkun H, Zoroğlu SS, Herken H, Savaş HA, Köylü A, Akyol O. Is the arginine-nitric oxide pathway involved in the pathogenesis of schizophrenia? Neuropsychology 2003; 47: 61-65.
13. Dunn RW, Corbett R, Fielding S. Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze. Eur J Pharmacol 1989; 169: 1-10.
14. Zoccali C, Kielstein JT. Asymmetric dimethylarginine: a new player in the pathogenesis of renal disease? Curr Opin Nephrol Hypertens 2006; 15: 314-320.
15. Wanby P, Teerlink T, Brudin L, Brattström L, Nillson I, Palmqvista P, Carlsson M. Asymmetric dimethyl arginine (ADMA) as a risk marker for stroke and TIA in a Swedish population. Atherosclerosis 2006; 185: 271-277.
16. Harkin AJ, Bruce KH, Craft B, Paul IA. Nitric oxide synthase inhibitors have antidepressant-like properties in mice: 1. Acute treatments are active in the forced swim test. Eur J Pharmacol 1999; 372: 207-213.
17. Yildiz F, Erden BF, Ulak G, Utkan T, Gacar N. Antidepressantlike effect of 7-nitroindazole in the forced swimming test in rats. Psychopharmacology 2000; 149: 41-44.
18. Ferreira VMM, Valenzuela CF, Morato GS. Role of nitric oxide dependent pathways in ethanol induced anxiolytic effects in rats. Alcohol Clin Exp Res 1999; 23: 1898-1904.
19. Yildiz F, Ulak G, Erden BF, Gacar N. Anxiolytic-like effect of 7-nitroindazole in the rat plus-maze test. Pharmacol Biochem Behav 2000; 65: 199-202.
20. First MB, Spitzer RL, Gibbon M. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) Clinical Version. Washington, DC, USA: American Psychiatric Press; 1997.
21. Özkürkçügil A, Aydemir Ö, Yıldız M, Esen Danacı A, Köroğlu E. DSM-IV eksen I bozuklukları için yapılandırılmış klinik görüşmenin Türkçeye uyarlanması ve güvenilirlik çalışması. İlaç ve Tedavi Dergisi 1999; 12: 233-236 (in Turkish).
22. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS. The Yale Brown Obsessive Compulsive Scale I, II. Development, use, reliability and validity. Arch Gen Psychiatry 1989; 46: 1006- 1016.
23. Tek C, Uluğ B, Gürsoy Rezaki B. Yale Brown ObsessiveCompulsive Scale and US National Institute of Mental Health Global Obsessive-Compulsive Scale in Turkish; reliability and validity. Acta Psychiatr Scand 1995; 91: 411-413.
24. Karamustafalıoğlu O, Üçışık AM, Ulusoy M. The validity and reliability study of Yale-Brown Obsessive-Compulsive Scale. In: 29th National Congress of Psychiatry Summary Book; Bursa, Turkey; 1993.
25. Cortas NK, Wakid NW. Determination of inorganic nitrate in serum and urine by kinetic cadmium reduction method. Clin Chem 1990; 36: 1440-1443.
26. Vishwanathan K, Tackett RL, Stewart JT, Bartlett MG. Determination of arginine and methylated arginines in human plasma by liquid chromatography tandem mass spectrometry. J Chromatogr B 2000; 748: 157-166.
27. Ueda S, Yamagishi S, Kaida Y, Okuda S. Asymmetric dimethylarginine may be a missing link between cardiovascular disease and chronic kidney disease. Nephrology 2007; 12: 582- 590.
28. Lynch DR, Dawson TM. Secondary mechanism in neuronal trauma. Curr Opin Neurol 1994; 7: 510-516.
29. Dawson VL. Nitric oxide: role neurotoxicity. Clin Exp Pharmacol Physiol 1995; 22: 305-308.
30. Selley ML. Increased (E)-4-hydroxy-2-nonenal and asymmetric dimethylarginine concentrations and decreased nitric oxide concentrations in the plasma of patients with major depression. J Affect Disord 2004; 80: 249-256.
31. Selley ML. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimers disease. Neurobiol Aging 2003; 24: 903-907.
32. Zincir SB, Zincir S. Role of asymmetric dimethylarginine in psychiatric disorders. Current Approaches in Psychiatry 2014; 6: 355-362 (in Turkish with abstract in English).
33. Paiva H, Lehtimaki T, Laakso J, Ruokonen I, Rantalaiho V, Wirta O, Pasternack A, Laaksonen R. Plasma concentrations of asymmetric-dimethyl-arginine in type 2 diabetes associate with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy. Metabolism 2003; 52: 303- 307.
34. Kittel-Schneider S, Reuß M, Meyer A, Weber H, Gessner A, Leistner C, Kopf J, Schmidt B, Hempel S, Volkert J et al. Multilevel biomarker analysis of nitric oxide synthase isoforms in bipolar disorder and adult ADHD. J Psychopharmacol 2015; 29: 31-38.
35. Mommersteeg PM, Schoemaker RG, Eisel UL, Garrelds IM, Schalkwijk CG, Kop WJ. Nitric oxide dysregulation in patients with heart failure: the association of depressive symptoms with L-arginine, asymmetric dimethylarginine, symmetric dimethylarginine, and ısoprostane. Psychosom Med 2015; 77: 292-302.
36. Oliveira J, Debnath M, Etain B, Bennabi M, Hamdani N, Lajnef M, Bengoufa D, Fortier C, Boukouaci W, Bellivier F et al. Violent suicidal behaviour in bipolar disorder is associated with nitric oxide synthase 3 gene polymorphism. Acta Psychiat Scand 2015; 132: 218-225.
37. Faraci FM, Brian JE Jr, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol 1995; 269: 1522-1527.
38. Szabo C, Salzman AL, Ischiropoulos H. Peroxynitrite-mediated oxidation of dihydrorhodamine 123 occurs in early stages of endotoxic and hemorrhagic shock and ischemia-reperfusion injury. FEBS Lett 1995; 372: 229-232.
39. Kirkeboen KA, Strand QA. The role of nitric oxide in sepsis-an overview. Acta Anaesthesiol Scand 1993; 43: 275-288.
40. Karatinos J, Rosse RB, Deutsch SI. The nitric oxide pathway: potential implications for treatment of neuropsychiatric disorders. Clin Neuropharmacol 1995; 18: 482-499.
41. Ceylan NÖ, Çimenci İG, Kılınçaslan A, Bülbül F, Savaş HA. Alterations in plasma nitric oxide level and arginase activity during the treatment of bipolar depressive episode. Journal of Mood Disorders 2011; 1: 1-6.
42. Savas HA, Herken H, Yurekli M, Uz E, Tutkun H, Zoroglu SS, Ozen ME, Cengiz B, Akyol O. Possible role of nitric oxide and adrenomedullin in bipolar affective disorder. Neuropsychobiology 2002; 45: 57-61
43. Celik C, Cayci T, Ozdemir B, Akgul EO, Zincir S, Balikci A, Uzun O, Yaman H. Plasma asymmetric dimethylarginine (ADMA) concentrations in patients with first and multiple episode schizophrenia. Psychiat Res 2011; 190: 177-180.
44. Papageorgiou C, Grapsa E, Christodoulou NG, Zerefos N, Stamatelopoulos S, Christodoulou GN. Association of serum nitric oxide levels with depressive symptoms: a study with endstage renal failure patients. Psychother Psychosom 2001; 70: 216-220.
45. Suzuki E, Yagi G, Nakaki T, Kanba S, Asai M. Elevated plasma nitrate levels in depressive states. J Affect Disord 2001; 63: 221- 224.
46. Srivastava N, Barthwal MK, Dalal PK, Agarwal AK, Nag D, Seth PK, Srimal RC, Dikshit M. A study on nitric oxide, beta-adrenergic receptors and antioxidant status in the polymorphonuclear leukocytes from the patients of depression. J Affect Disord 2002; 72: 45-52.
47. Raw A, Gallaher M, Powers RW. Arginine and asymmetric dimethylarginine in pregnant women with major depression. Psychosom Med 2014; 76: 430-436.
48. Wu J, Wang Y, Rowan MJ, Anwyl R. Evidence for involvement of the neuronal isoform of nitric oxide synthase during induction of long-term potentiation and long-term depression in the rat dentate gyrus in vitro. Neuroscience 1997; 78: 393- 398.
49. Blond O, Daniel H, Otani S, Jaillard D, Crepel F. Presynaptic and postsynaptic effects of nitric oxide donors at synapses between parallel fibres and Purkinje cells: involvement in cerebellar long-term depression. Neuroscience 1997; 77: 945- 954.
50. Wegener G, Volke V, Harvey BH, Rosenberg R. Local, but not systemic, administration of serotonergic antidepressants decreases hippocampal nitricoxide synthase activity. Brain Res 2003; 959: 128-134.
51. Algül S, Erman F, Kara B, Kara M, Erman O. The effect of shortterm antidepressant treatment on serum levels of nesfatin-1, nitric oxide and ghrelin in patients with major depressive disorder. Medical Journal of Fırat University 2013; 27: 69-73 (in Turkish with abstract in English).
52. Arlt S, Schulze F, Eichenlaub M, Maas R, Lehmbeck JT, Schwedhelm E, Jahn H, Böger RH. Asymmetrical dimethyl arginine is increased in plasma and decreased in cerebrospinal fluid of patients with Alzheimer disease. Dement Geriatr Cogn Disord 2008; 26: 58-64.
53. Sarkar SR, Kaitwacharaichai C, Levin WN. Basic science and dialysis: Nitric oxide and hemodialysis. Semin Dialysis 2004; 17: 3224-3228.
54. Thuarisingham RC, Yaqoob MM. Oxidative consumption of nitric oxide: A potential mediator uremic vascular disease. Kid Int 2003; 63: 29-32.
55. Akyol S, Alıcı Ö, Altuntaş A, Pehlivan S, Kurşunlu SF, Alaçam H. Asymmetric dimethyl arginine (ADMA) induces acute tubular necrosis in rats. Yeni Tıp Dergisi 2015; 32: 13-16 (in Turkish with abstract in English).
56. Alacam H, Avci B, Salis O, Dilek A, Kozan A, Mertoglu C, Şahin M, Okuyucu A. Does ADMA affect the oxidant/antioxidant balance in rats?. Turk J Med Sci 2013; 43: 405-410.
57. Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Boger SM. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethioninedependent methyltransferases. Circ Res 2000; 87: 99-105.
58. Oğuz A, Uzunlulu M. Short term fluvastatin treatment lowers serum asymmetric dimethylarginine levels in patients with metabolic syndrome. Int Heart J 2008; 49: 303-311.
59. Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction its role in hypercholesterolemia. Circulation 1998; 98: 1842-1847.
60. Lundman P, Eriksson MJ, Stuhlinger M, Cooke JP, Hamsten A, Tornvall P. Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am Coll Cardiol 2001; 38: 111-116.
61. Stuhlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP, Reaven GM, Tsao PS. Relationship between insulin resistance and an endogenous nitricoxide synthase inhibitor. JAMA-J Am Med Assoc 2002; 287: 1420-1426.
62. Erbil M, Kurt YG, Yaman H, Akgül EÖ, Çaycı T. Metabolism of asymmetric dimethylarginine and its clinical significance. Turk J Biochem 2012; 37: 99-105 (in Turkish with abstract in English).
63. Lee SY, Lee SJ, Han C, Patkar AA, Masand PS, Pae CU. Oxidative/nitrosative stress and antidepressants: targets for novel antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 2013; 46: 224-235.
64. Zlatković J, Todorović N, Tomanović N, Boković M, Djordjević S, Lazarević-Pati T, Bernardi RE, Djurdjević A, Filipović D. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study. Eur J Pharm Sci 2014; 59: 20-30.