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Kushnir O.Yu., Yaremii I.N.
THE EFFECT OF MELATONIN ON ANTIOXIDANT SYSTEM DURING DIABETES MELLITUS
Bukovinian State Medical University, Department of Bioorganic and Biological Chemistry and Clinical Biochemistry, Chernivtsi, Ukraine
Summary. This study investigated the possible protective effects of melatonin as an antioxidant against diabetic disorders.
Key words: melatonin, diabetes mellitus, antioxidant protection.
Кушнир О.Ю., Яремий И.Н.
ВЛИЯНИЕ МЕЛАТОНИНА НА АНТИОКСИДАНТНУЮ СИСТЕМУ В УСЛОВИЯХ САХАРНОГО ДИАБЕТА
Буковинский государственный медицинский университет, кафедра биоорганиче-
ской и биологической химии и клинической биохимии,
г. Черновцы, Украина
Резюме. В статье показан возможный защитный эффект мелатонина как антиоксидантного средства против диабетических нарушений.
Ключевые слова: мелатонин, диабет, антиоксидантная система.
Melatonin is a lipophilic neurohormone produced by the Pineal gland during the night [19]. It may act as a paracrine, in-tracrine and autocrine agent expressing an overall homeostatic function and plei-otropic effect. It is responsible for carrying out the following functions by controlling other hormones: 1) regulation of circadian sleep-wake cycle; 2) controls sex drive and reproduction by inhibiting release of GnTH (Gonadotrophic Hormone); 3) controls body weight and energy balance; 4) controls appetite; 5) controls metabolic function; 6) controls balance; 7) controls muscular coordination; 8) controls immune system when it is affected by bacterial and viral diseases, affected by chemical pollutants and in the presence of excessive radical activity; 9) antioxidant effects; 10)may reduce damage
caused by types of Parkinson’s disease; 11) prevent cardiac arrhythmia; 12) increase longevity; 13) prevents damage to DNA by some carcinogens.
Human melatonin production decreases as a person ages[6]. It is believed that as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times [2].Melatonin production is controlled by the Pineal gland, which itself is controlled by the suprachiasmatic nuclei (SCN)[3]. The timing mechanism in the SCN is light dependent i.e. controlled by the amount of sunlight which enters the retina and reaches the SCN via the retinohypotha-lamic pathway[20].
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Издание зарегистрировано в Федеральной службе по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор). Свидетельство о регистрации СМИ ПИ № ФС77-49390 Журнал представлен в НАУЧНОЙ ЭЛЕКТРОННОЙ БИБЛИОТЕКЕ - головном исполнителе проекта по созданию Российского индекса научного цитирования (РИНЦ).
Melatonin production is inhibited when there is an increase in the light received by the retina while production is stimulated when there is a decrease in the light received by the retina (darkness stimulates production) [21]. Hence, during evenings, as the light received by the retina reduces melatonin production sets in, this evening onset is called the dim-light melatonin onset (DLMO).Exposure to light inhibits the enzyme N-acetyltransferase, the enzyme which converts Serotonin to Melatonin, hence reducing melatonin produc-tion.Being exposed to bright lights in the evening or too little light during the day can disrupt the body’ s normal melatonin cycles. For example, jet lag, shift work, and poor vision can disrupt melatonin cycles.Most functions of melatonin are produced through activation of melatonin receptors, while other functions are carried out due to its pervasive and powerful antioxidant, with a particular role in protection of nuclear and mitochondrial DNA [4].
It acts as an antioxidant, neutralizing harmful oxidative radicals, and it is capable of activating certain antioxidant en-zymes[2].It is a powerful antioxidant that easily crosses the cell membranes and blood-brain barrier [12, 22].It acts as a direct scavenger of OH, O2, and NO. Unlike other antioxidants, melatonin does not undergo redox cycling(ability of a molecule to undergo reduction and oxidation repeatedly). The redox cycling allows other antioxidants to regain their antioxidant properties. Since melatonin doesn’t undergo redox cycling it cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant. The first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-
formyl-5-methoxykynuramine (AFMK) rather than the common, excreted 6-hy-droxymelatonin sulfate. A single AFMK molecule can neutralize up to 10reactive oxygen / reactive nitrogen species(ROS/RNS) since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This cascade does not occur in conventional antioxidants. It demonstrates to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer. It also has been found to be effective in protecting against brain injury caused by ROS release in experimental hypoxic brain damage [23, 24].
Melatonin, stimulates the natural antioxidant system such as superoxide dis-mutase and glutathione peroxidase. Hence melatonin is used to inhibit oxidative damage in various neurological diseases where free radicals have been suspected as being in part causative of the condition [16, 18]. Thus melatonin is highly efficient as a protector against ROS and RNS [15].The administration of melatonin at pharmacological doses has been shown not only to be an effective scavenger of reactive oxygen and nitrogen species but also to enhance the levels of reduced glutathione(GSH) and the expression and activities of the GSH-related enzymes. It stimulates the rate limiting enzyme - glutamylcysteine synthase - which increases intracellular GSH concentrations. This action of melatonin is mediated by specific receptors [7, 14].
Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The increase in glycoxidation and lipoxidation
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Издание зарегистрировано в Федеральной службе по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор). Свидетельство о регистрации СМИ ПИ № ФС77-49390 Журнал представлен в НАУЧНОЙ ЭЛЕКТРОННОЙ БИБЛИОТЕКЕ - головном исполнителе проекта по созданию Российского индекса научного цитирования (РИНЦ).
products in plasma and tissue proteins suggests that oxidative stress is increased in diabetes [5, 11]. The metabolic abnormalities of diabetes [1, 9] cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: 1) polyol pathway flux; 2) increased formation of AGEs (advanced glycation end products); 3) increased expression of the receptor for AGEs and its activating ligands; 4) activation of protein kinase C isoforms; 5) overactivity of the hex-osamine pathway.It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase [10].These pathways result in an increase in intracellular ROS. This may lead to the following complications: defective angiogenesis in response to ischemia; activate a number of proinflammatory pathways; result in hyperglycemic memory.
According to our investigations [8, 13, 17] the introduction of melatoninintra-peritoneally in a dose of 10 mg/kg at 8 a. m. daily during 7 days to alloxan diabetic rats under conditions ofequinox or constant dark is conducive to a decrease in them of the level of fasting glucose and glycosylated hemoglobin (Hba1c), as well as - a stabilization of the indices of the body’s antioxidant defense (glucose-6-phosphate
dehydrogenase, glutathioneperoxidase,
glutathionereductaseand reduced glutathione in blood and liver) disturbed under the conditions of an absolute deficit of insulin.
Conclusion. Oxidative stress appears to be the most important pathogenic factor in underlying diabetic complications.
Melatonin is an effective scavenger of different ROS, such as hydroxyl and per-oxyl radicals cross all morphophysiological barriers, is distributed throughout all cells
and also has a powerful capacity to scavenge free radicals and prevents tissue damage. In a recent study, melatonin was showed to decrease oxidative stress in diabetic patients.
Hence it can be concluded that Melatonin can be used pharmacologically to treat patients of Diabetes Mellitus, for their complications related to the antioxidant system, since melatonin plays an effective role directly and indirectly(stimulates Glutathione system) in the antioxidant system.
REFERENCES:
1. Biomarkers of oxidative stress and endothelial dysfunction in glucose intolerance and diabetes mellitus / E.C. Pereira, S. Ferderbar, M.C. Bertolami et al. // Clinical Biochemistry. - 2008. - Vol. 41, № 18. - P. 1454 - 1460.
2. Claustrat B. The basic physiology and phath-ophysiology of melatonin / B. Claustrat, J. Braun, G. Chazot // Sleep Medicine Reviews. -2005.-Vol. 9.-P. 11-24.
3. Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response / C. Langenberg, L. Pascoe, A. Mari et al. // Dia-betologia. - 2009. - Vol. 52, № 8. - P. 1537 -1542.
4. Dave G.S. Hyperglycemia induced oxidative stress in type-1 and type-2 diabetic patients with and without nephropathy / G.S. Dave, K. Kalia // Molecular Biology of the Cell. - 2007. - Vol. 53, № 5.-P. 68-78.
5. Effects of melatonin on lipid peroxidation and antioxidant enzymes in streptozotocin-in-duced diabetic rat testis / A. Armagan, E. Uz, H.R. Yilmaz et al. // Asian Journal of Androl-ogy. - 2006. - Vol. 8, № 5. - P. 595 - 600.
6. Gumieniczek A. Nitrosative stress and glutathione redox system in four different tissues of alloxan-induced hyperglycemic animals / A. Gumieniczek, M. Wilk // Toxicology Mechanisms and Methods. - 2009. - Vol. 19, № 4. -P. 302-307.
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Издание зарегистрировано в Федеральной службе по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор). Свидетельство о регистрации СМИ ПИ № ФС77-49390 Журнал представлен в НАУЧНОЙ ЭЛЕКТРОННОЙ БИБЛИОТЕКЕ - головном исполнителе проекта по созданию Российского индекса научного цитирования (РИНЦ).
7. Klepac N. Effects of melatonin on plasma oxidative stress in rats with streptozotocin induced diabetes / N. Klepac, Z. Rudes, R. Klepac // Biomedicine & Pharmacotherapy. - 2006. -Vol. 60.-P. 32-35.
8. Limon-Pacheco J.H. The glutathione system and its regulation by neurohormone melatonin in the central nervous system / J.H. Limon-Pacheco, M.E.Gonsebatt // Cent.Nerv. Syst. Agents Med .Chem. - 2010. - Vol. 4, N 10. - P. 287-297.
9. Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions / R.J. Reiter, D.X. Tan, M.P. Terron et al. // Actabiochimicapolonica. - 2007. -Vol. 54, № 1.-P. 1-9.
10.Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats / E.J. Sudnikovich, Y.Z. Maksimchik, S.V. Za-brodskaya et al. // European Journal of Pharmacology. - 2007.-Vol. 569, № 3.-P. 180- 187.
11.Nishida S.Metabolic effects of melatonin on oxidative stress and diabetes mellitus /Nishida
S. // Endocrine. - 2005. - Vol. 2, № 27. - P. 131136.
12.Peschke E. Melatonin, endocrine pancreas and diabetes / E. Peschke // Journal of Pineal Research. - 2008. - Vol. 44. - P. 26 - 40.
13.Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways / S.R. Pandi-Perumal, I. Trakht, V. Srinivasan et al. // Progress in Neurobiology. -2008. - Vol. 85, № 3. - P. 335 - 353.
14.Sack R.L. Melatonin as anchronobiotic: treatment of circadian desynchrony in night workers and in the blind / R.L. Sack, A.J. Lewy // Journal of Biological Rhythms. - 2007. - №
12.-P. 595- 603.
15.Significance of melatonin in antioxidative defense system: reactions and products / D.X. Tan, L.C. Manchester, R.J. Reiter et al.// Biol Signals Recept. - 2000. - Vol. 3-4, №9. - P. 137- 159.
16.Therapeutic potential of melatonin in cancer treatment / C. Arbian, F. Kwiatkowski, R. Chevrier et al. // PathologieBiologie (Paris). -2005. - Vol. 53, - № 5. - P. 265 - 268.
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Издание зарегистрировано в Федеральной службе по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор). Свидетельство о регистрации СМИ ПИ № ФС77-49390 Журнал представлен в НАУЧНОЙ ЭЛЕКТРОННОЙ БИБЛИОТЕКЕ - головном исполнителе проекта по созданию Российского индекса научного цитирования (РИНЦ).
