J.ophthalmol.(Ukraine).2017;6:72-77.

https://doi.org/10.31288/oftalmolzh201767277

Metabolic correction of experimental diabetic retinopathy 

I.V. Savitskyi1, Prof., Dr. Sc. (Med)1, V.V. Semenko2 , V.M. Serdiuk2,3

1Odessa National Medical University

2Dnipropetrovsk Regional Ophthalmological Clinical Hospital DOKOL

3Dnipropetrovsk Medical Academy, Ministry of Health of Ukraine

Odessa, Dnipropetrovsk, Ukraine

E-mail: farmakod@ukr.net             

Introduction. Diabetic retinopathy (DR) is diagnosed in 50% of the total number of patients suffering from type 1 diabetes mellitus with diabetes duration of over 10 years and in 75-90% of patients with diabetes duration over 15 years.

Purpose. To ground the possibility of using arginine for correction of vascular changes in the eye at early stage of DR.

Materials and Methods. The study involved outbred white Wistar rats divided into three groups: Group 1, unexposed animals served as controls (Control group); Group 2,  animals with a diabetes mellitus model (DM group); Group 3, diabetic animals which received 7% arginine solution (DM+arginine group).

Results. Glucose test revealed no significant difference between Group 1 and Group 3 (р=0.14) while the difference was highly significant between Groups 2 and 3 (р=0.0019). Histological study of the eyeball tissues showed that fibers were not combined into the homogeneous mass, separate fibers could be defined. In the photoreceptor layer, structural elements were pale stained but had high density of distribution. The outer granular layer of the retina was characterized by nuclei with rather dense distribution to each other. The nuclei were relatively large, round, and brightly stained. The inner granular layer corresponded to the description of the outer granular layer. In the ganglion cell layer, neuron nuclei were round, well-stained and distributed rather evenly.

Conclusions. Arginine enabled to preserve the structure and functions of vessels and to reduce the disease severity.

Keywords: diabetes mellitus, diabetic retinopathy, arginine, histological examination, eyeball, NOS.

References

  1. Zelinska NB, Khoroshaia OO, Starynets NA. [Frequency of diabetic retinopathy among children and adolescents with diabetes mellitus according to screening data in the regions of Ukraine]. Klinichna endokrynolohiia ta endokrynna khirurhiia. 2005; 4 (13):27-31. In Ukrainian.
  2. Kosobjan EP, Jarek-Martynova YIa, Parfjonov AS, Shestakova MV. [Vasomotor function of the endothelium and elasticity of the arterial wall among patients with type 1 diabetes mellitus at different stages of diabetic retinopathy]. Problemy Endokrynolohyy. 2012;4:22-26. In Russian
  3. Balabolkin MI. [The role of glycation of proteins, oxidative stress in the pathogenesis of vascular complications in diabetes mellitus]. Saharnyj diabet. 2002;4:8-16. In Russian.
  4. Verma S, Buchanan MR, Anderson TJ.  Endothelial Function Testing as a Biomarker of  Vascular Disease . Circulation.  2003;108:2054-2059.
  5. Bonetti PO, Lerman LO, Lerman A.  Endothelial Dysfunction: A Marker of Atherosclerotic Risk . Arterioscler Thromb Vascular Bio. 2003;23:168-175.
  6. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. Journal of the A merican College of Cardiology. 2003;42:1149–1160.
  7. Chatterjee A, Catravas JD. Endothelial nitric oxide (NO) and its pathophysiologic regulation . Vascul. Pharmacol.  2008;49(4-6):134-140.
  8. Gudyrev OS, Radzhkumar DSR, Fajtelson AV et al. [Osteoprotective action of L-arginine in experimental osteoporosis]. Nauchnyie vedomosti BelGU. Serija Medicina. Farmatsiia. 2012;22(141);20/3:94-97.  In Russian.
  9. Reutov VP, Sorokina EG, Ohotin VE, Kosicyn NS. [Cyclic transformations of nitric oxide in the body of mammals]. Moscow: Nauka;1997. 156p. In Russian.
  10. Malaja LT, Korzh AH, Balkovaja LB. [Endothelial dysfunction in the pathology of the cardiovascular system]. Kharkiv: Forsing; 2000. 245p. In Russian.
  11. Bryan  NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Frontiers in Bioscience. 2009;14:1–18.
  12. Babushkina AV. [L-arginine in terms of evidence-based medicine]. Ukrainskyi medychnyi chasopys. 2009;74 (XI/XII):43–48. In Russian.
  13. Boger  RH. The pharmacodynamics of L-arginine. J. Nutr.  2007:137:1650-1655.
  14. Lisicyna NV. [Medications that affect the synthesis of nitric oxide and their place in the pathogenetic therapy of preeclampsia]. Nauchnye vedomosti BelGU. Serija  Medicina. Farmacija. 2010;10(81) :46-54. In Russian.
  15. Lishnevskaja VJu. [Endothelial dysfunction: what does practical doctor need to kmow?]. Zdorovia Ukrainy. 2010;7:2. In Russian.
  16. Lloyd Z, Gossrau R, Scheibler T. [Histochemistry of enzymes (laboratory methods). Translated from English]. Moscow: Mir;1982. 272p. In Russian.
  17. Semenko VV, Serdiuk VM, Savytskyi IV. [Development of experimental aloxane model of diabetes mellitus]. Mezhdunarodnyi endokrinologicheskii zhurnal.  2017;13(4):34-39. In Ukrainian.
  18. Danilova ІG, Gette ІF, Bulavinceva TS. [Method of Alloxan Diabetes Modeling. Patent of the Russian Federation] No. 2534411, dated 27.11.2014. [Internet]. 2014 Dec 27 [cited 2017 Aug 1]: Available from http://www.findpatent.ru/patent/253/2534411.html. In Russian.
  19. Baranov VH, Sokoloverova IM, Hasparian EH et al. [Experimental diabetes mellitus. Role in clinical diabetes]. Lviv: Nauka;1983. 240 p. In Ukrainian.
  20. Elsner M, Tiedge M, Guldbakke B et al. Importance of the GLUT2 glucose transporter for pancreatic beta cell toxicity of alloxan.  Diabetologia. 2002; 45 (11):1542-1549.
  21. Evan AP, Mong SA, Connors BA et al. The effect of alloxan, and alloxan-induced diabetes on the kidney. Anat. Rec. 1984;208(1):33-47.
  22. Palchikova NO, Kuznecova NV, Kuzminova OІ, Seljaticka VG. [Hormonal-biochemical features of alloxan and streptotrozotocin models of experimental diabetes]. Bjuleten  SO RAMN. 2013;33(6):18-24. In Russian.
  23. Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia. 2008;51:216 – 226.
  24. Marini JC. Arginine and ornithine are the main precursors for citrulline synthesis in mice. J. Nutr. 2012;142(3):572–580.
  25. Haida HZ,  Stasiuk NIe, Honchar MV. [Methods of L-arginine analisis]. Вiotechnologia acta. 2014; 7(1):31-39.  In Ukrainian.
  26. Yokoro M, Suzuki M, Murota K, Otsuka C, Yamashita H, Takahashi Y, Tsuji H,
  27. Kimoto M. Asymmetric dimethylarginine, an endogenous NOS inhibitor, metabolized in rat erythrocytes. Biosci. Biotechnol. Biochem. 2012;76(7):1334–1342.
  28. Oka RK, Szuba A, Giacomini JC, Cooke  JP. A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease. Vasc. Med. 2005;10(4):265-274.
  29. Markov HM. [Oxidative stress and endothelial dysfunction]. Patologicheskaia fiziologiia i eksperimentalnaia  terapiia. 2005;4:5-9. In Russian.
  30. Loscalzo J. L-arginine and Atherothrombosis.  J. Nutr.  2004;134:2798-2800.
  31. Bоger RH, Bode-Bоger SM, Mugge A, Kienke S, Brandes R. Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production . Atherosclerosis.  1995;117:273-284.
  32. Huk I, Nanobashvili J, Neumayer C, Punz A, Muеller M et al. L-arginine treatment alters the kinetics of nitric oxide and superoxide release and reduces ischemia/reperfusion injury in skeletal muscle . Circulation. 1997;96:667-675.
  33. Zweier JL, Samouilov A, Kuppusamy P. Non-enzymatic nitric oxide synthesis in biological systems . Biochim. Biophys. Acta.  1999;1411:250-262.
  34. Surdacki A, Nowicki M, Sandmann J, Tsikas D, Boger RH et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetrical dimethylarginine in men with essential hypertension . J. Cardiovasc. Pharmacol. 1999;33: 652-658.
  35. Lerman A, Burnett JC, Jr, Higano ST, McKinley LJ, Holmes DR. Jr. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation. 1998;97(21):2123-2128.
  36. Treshhinskaja MA. [Anti-aging effect of L-arginine]. Meditsina neotlozhnyh sostoianii. 2012: 3 (42):50-54.  In Russian.
  37. Greager MA. L-arginin in endothelial and vascular health. J. Nutr.-Supp. 1997;10:2880-2887. 
  38. Morikawa E, Moskowitz MA, Huang Z et al. L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat. Stroke. 1994;25:429-435.
  39. Umans JG, Levi R. Nitric oxide in the regulation of blood flow and arterial pressure. Ann. Rev. Physiol. 1995;57:771-790.
  40. Lishnevskaja VJu, Parasjuk EI. [Age features of correction of endothelial dysfunction among patients with essential hypertension]. Simeina medytsyna. 2011;2:50-52. In Russian.
  41. Marchesi S, Lupattelli G, Siepi D et al. Oral L-arginine administration attenuates postprandial endothelial dysfunction in young healthy males. J. Clin. Pharm. Ther. 2001;26:343-349.
  42. Lin CC, Tsai WC, Chen JY, Li YH, Lin LJ, Chen JH. Supplements of L-arginine attenuate the effects of highfat meal on endothelial function and oxidative stress. Int. J. Cardiol. 2008; 127(3):337-341.
  43. Lyons CR. The role of nitric oxide in inflammation. Adv. Immunol. 1995;60:323-371.
  44. Brune B, Messmer UK, Sandau K. The role of nitric oxide in cell injury. Toxicol. Lett. 1995;82–83:233-237.
  45. Lee C, Li D, Channon K, Paterson DJ. L-arginine supplementation reduces cardiac noradrenergic neurotransmission in spontaneously hypertensive rats. J. Mol. Cell Cardiol. 2009July;47(1):149-155.
  46. Grishina GV, Gerbut KA. [The effect of L-arginine on the circulatory system in the infusion therapy of experimental hemorrhagic shock]. Aktualnyie voprosy transfuziologii i klinicheskoi meditsiny. 2015;1:53-55. In Russian.
  47. Kalinin RE, Suchkov IA, Pshennikov AS, Nikiforov AA. [Medication correction of endothelial function among patients with obliterating atherosclerosis of arteries of lower limbs]. Kazanskii meditsinskii zhurnal. 2013;94(2):181-185. In Russian.