Role of Asymmetric Dimethylarginine in Psychiatric Disorders

Öz

Asymmetric dimethylarginine has been a post-translational modified form of the aminoasid arginine. Being a competitive inhibitor of nitric oxide synthase enzyme, makes asymmetric dimethylarginine important. Findings of previous studies and observations show that the accumulation of asymmetric dimethylarginine may have an important role for the regulation of signal transduction in nitric oxide system, and this accumulation may be a new mechanism for the regulation of nitric oxide production in the brain. Studies have suggested that increased asymmetric dimethylarginine levels could lead to a decrease in the level of nitric oxide production by inhibiting nitric oxide synthase enzyme. Therefore asymmetric dimethylarginine may be important in the pathophysiology of various psychiatric disorders. In this review, findings of research studies on asymmetric dimethylarginine and nitric oxide conducted with psychiatric patients so far and possible role of these molecules in the etiopathogenesis of various psychiatric disorders were discussed.

Anahtar Kelimeler

• Asymmetric dimethylarginine, Nitric Oxide, Psychiatric disorders

Psikiyatrik Bozukluklarda Asimetrik Dimetilarjininin Rolü

Öz

Asimetrik dimetilarjinin, arjinin aminoasitinin translasyon sonrasında modifiye olmuş bir formudur. Asimetrik dimetilarjinini önemli kılan nitrik oksit sentaz enzimini yarışmalı olarak inhibe etmesidir. Günümüze kadar yapılan araştırma ve gözlemler asimetrik dimetilarjinin birikiminin nitrik oksit sisteminde sinyal iletiminin düzenlenmesinde önemli bir role sahip olabildiğini ve bu birikimin beyinde nitrik oksit üretiminin düzenlenmesinde yeni bir mekanizma olduğunu göstermektedir. Çalışmalar çeşitli psikiyatrik bozukluklarda asimetrik dimetilarjinin düzeylerinin yükseldiğini, bu yüksekliğin nitrik oksit sentaz enziminde inhibisyon yaparak nitrik oksit üretimini azalttığını ve bu hastalıkların fizyopatolojisinde yeri olduğunu ileri sürmektedir. Bu derlemede günümüze kadar psikiyatri hastalarında yapılmış asimetrik dimetilarjinin ve nitrik oksit ile ilgili çalışma sonuçları tartışılarak bu moleküllerin çeşitli psikiyatrik bozuklukların etiyopatogenezindeki yeri ele alınmıştır.

Anahtar Kelimeler

• Asimetrik dimetilarjinin (ADMA), Nitrik Oksit (NO), Psikiyatrik bozukluklar

Kaynakça

1. Boger RH, Vallance P, Cooke JP. Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase. Atheroscler Suppl 2003; 4:1-3.
2. Ogawa T, Kimoto M, Sasaoka K. Purification and properties of a new enzyme, NG,NG-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 1989; 264:10205-10209.
3. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; 339:572-575.
4. Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004; 24:1023-1030.
5. Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler Suppl 2003; 4:33-40.
6. Holven KB, Haugstad TS, Holm T, Aukrust P, Ose L, Nenseter MS. Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Br J Nutr 2003; 89:359-363.
7. Murray-Rust J, Leiper J, McAlister M, Phelan J, Tilley S, Santa Maria J et al. Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nat Struct Biol 2001; 8:679-683.
8. Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci U S A 2002; 99:13527-13532.

9. Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 2003; 108:3042-3047.
10. Erbil M, Kurt YG, Yaman H, Akgül EÖ, Çaycı T. Asimetrik dimetilarginin metabolizması ve klinik önemi. Türk Biyokimya Dergisi 2012; 37:99-105.
11. Nijveldt RJ, Teerlink T, van Leeuwen PA. The asymmetrical dimethylarginine (ADMA)-multiple organ failure hypothesis. Clin Nutr 2003; 22:99-104.
12. Das I, Khan NS, Puri BK, 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.
13. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329:2002-2012.
14. Anggard E. Nitric oxide: mediator, murderer, and medicine. Lancet 1994; 343:1199-1206.
15. Dawson VL, Dawson TM. Physiological and toxicological actions of nitric oxide in the central nervous system. Adv Pharmacol 1995; 34:323-342.
16. Dawson TM, Snyder SH. Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J Neurosci 1994; 14:5147-5159.
17. Xie Q, Nathan C. The high-output nitric oxide pathway: role and regulation. J Leukoc Biol 1994; 56:576-582.
18. Lancaster JR, Jr. Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci U S A 1994; 91:8137-8141.
19. Kiss JP, Vizi ES. Nitric oxide: a novel link between synaptic and nonsynaptic transmission. Trends Neurosci 2001; 24:2112
20. Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 1993; 52:127-136.
21. Garthwaite J, Boulton CL. Nitric oxide signaling in the central nervous system. Annu Rev Physiol 1995; 57:683-706. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43:109-142.
22. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J 1992; 6:3051-3064.
23. Boger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR, Tangphao O et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; 98:1842-1847.
24. Akyol O, Zoroglu SS, Armutcu F, Sahin S, Gurel A. Nitric oxide as a physiopathological factor in neuropsychiatric disorders. In Vivo 2004; 18:377-390.
25. Lu TM, Ding YA, Lin SJ, Lee WS, Tai HC. Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 2003; 24:1912-1919.
26. Valkonen VP, Paiva H, Salonen JT, Lakka TA, Lehtimaki T, Laakso J et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 2001; 358:2127-2128.
27. Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 1999; 99:1141-1146.
28. 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.
29. Lentz SR, Rodionov RN, Dayal S. Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA. Atheroscler Suppl 2003; 4:61-65.
30. Yılmaz MI, Sağlam M, Cağlar K, Çakir E, Sönmez A, Özgürtaş T et al. The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine. Am J Kidney Dis 2006; 47:42-50.
31. Xiong Y, Fu YF, Fu SH, Zhou HH. Elevated levels of the serum endogenous inhibitor of nitric oxide synthase and metabolic control in rats with streptozotocin-induced diabetes. J Cardiovasc Pharmacol 2003; 42:191-196.
32. Paiva H, Lehtimaki T, Laakso J, Ruokonen I, Rantalaiho V, Wirta O et al. Plasma concentrations of asymmetric-dimethylarginine in type 2 diabetes associate with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy. Metabolism 2003; 52:303-307.
33. Das UN, Repossi G, Dain A, Eynard AR. L-arginine, NO and asymmetrical dimethylarginine in hypertension and type 2 diabetes. Front Biosci 2011; 16:13-20.
34. Kielstein JT, Zoccali C. Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis. 2005; 46:186-202.
35. Aneman A, Backman V, Snygg J, von Bothmer C, Fandriks L, Pettersson A. Accumulation of an endogenous inhibitor of nitric oxide synthase during graded hemorrhagic shock. Circ Shock 1994; 44:111-114.
36. Siroen MP, Warle MC, Teerlink T, Nijveldt RJ, Kuipers EJ, Metselaar HJ et al. The transplanted liver graft is capable of clearing asymmetric dimethylarginine. Liver Transpl 2004; 10:1524-1530.
37. Lluch P, Torondel B, Medina P, Segarra G, Del Olmo JA, Serra MA et al. Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis. J Hepatol 2004; 41:55-59.
38. Celik C, Cayci T, Ozdemir B, Akgul EO, Zincir S, Balikci A, et al. Plasma asymmetric dimethylarginine (ADMA) concentrations in patients with first and multiple episode schizophrenia. Psychiatry Res 2011; 190:177-180.
39. Suzuki E, Nakaki T, Nakamura M, Miyaoka H. Plasma nitrate levels in deficit versus non-deficit forms of schizophrenia. J Psychiatry Neurosci 2003; 28:288-292.
40. 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.
41. Aykut D, Tiryaki A, Özkorumak E, Karahan C. Nitric oxide and asymmetrical dimethylarginine levels in acute mania. Klinik Psikofarmakoloji Bülteni 2012; 22:10-16.
42. Zincir S. İlk atak şizofreni hastalarında tedaviye yanıt ile plazma asimetrik dimetilarginin düzeyleri arasındaki ilişki (Uzmanlık tezi). Ankara, Gülhane Askeri Tıp Akademisi, 2012.
43. Wilcken DE, Sim AS, Wang J, Wang XL. Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of L-arginine on its metabolism. Mol Genet Metab 2007; 91:309-317.
44. Ohkuma S, Katsura M. Nitric oxide and peroxynitrite as factors to stimulate neurotransmitter release in the CNS. Prog Neurobiol 2001; 64:97-108.
45. Faraci FM, Brian JE, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol 1995; 269:1522-1527. Selma Bozkurt Zincir, Uzm.Dr., Erenköy Ruh ve Sinir Hastalıkları Eğitim ve Araştırma Hastanesi, İstanbul; Serkan Zincir, Uzm.Dr., Gölcük Asker Hastanesi, Gölcük Yazışma Adresi/Correspondence: Selma Bozkurt Zincir, Erenköy Ruh ve Sinir Hastalıkları Eğitim ve Araştırma Hastanesi, İstanbul, Turkey. E-mail: [e-mail] Yazarlar bu makale ile ilgili herhangi bir çıkar çatışması bildirmemiştir. The authors reported no conflict of interest related to this article. Çevrimiçi adresi / Available online at: www.cappsy.org/archives/vol6/no4/ Çevrimiçi yayım / Published online 29 Nisan/April 29, 2014; doi: 10.5455/cap.20140429100756