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International Journal of Pharmacology

Year: 2012 | Volume: 8 | Issue: 6 | Page No.: 496-509
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Research Article

The Mechanisms of Positive Effects of Melatonin in Dyslipidemia: A Systematic Review of Animal and Human Studies

Shilan Mozaffari, Shirin Hasani-Ranjbar and Mohammad Abdollahi

ABSTRACT

Dyslipidemia and following atherosclerosis as a chronic affection remain one major cause of death all over the world. Given multiple reports on positive effects of melatonin on dyslipidemia, there is a need for reviewing all these studies in order to reach a convincing conclusion. Towards this goal, we have reviewed all previous investigations on use of melatonin in dyslipidemia found from PubMed, Cochrane, Google Scholar, Scopus and web of Science up to January 2012. Of the publications identified in the initial database, 11 clinical trials and 43 nonclinical trials (18 in vitro and 25 animal studies) were included and reviewed. Most of the results reveal the potency of melatonin as an antioxidant in preventing lipid peroxidation through different mechanisms and therefore, improving the lipid profile. Melatonin has anti-inflammatory and antioxidative effects, neutralizes free radicals, increases antioxidative enzymes and glutathione levels, prevents electron leakage from the mitochondrial respiratory chain, acts synergistically with vitamin C, E and glutathione, reduces levels of pro-inflammatory cytokines and therefore prevents Low-density Lipoprotein (LDL) oxidation and decreases lipid peroxidation. The results indicate a need for further studies on safety/efficacy measures if melatonin was used in long-term.
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Received: April 05, 2012;   Accepted: June 11, 2012;   Published: September 06, 2012

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INTRODUCTION

The increasing prevalence of diabetes, obesity and dyslipidemia in the world is associated with serious health problems such as cardiovascular disease and cancer, which are considered major causes of the death in the world (Hasani-Ranjbar et al., 2011). Dyslipidemia presents itself as increased plasma low-density Lipoprotein (LD) resulting in inflammation in the vascular system and vessel of the heart. Liver and intestine have the main role in production and metabolism of lipoproteins. Free fatty acids are converted to acyl-coenzyme A (acyl-CoA) by the acyl-CoA synthetase (ACS) in the liver. Esterification of acyl-CoA produces Triglycerides (TG) and phospholipids. The lipoproteins that transport lipids (TG and cholesterol) in blood are classified by their density. Chylomicrons transport TG from the intestine to the liver. LDL carries cholesterol from liver to the body cells and High-density Lipoprotein (HDL) carries it back to the liver. LDL has the potential to be oxidized by free radicals and damage cells. Its cholesterol content is released into the vessel wall and oxidized. Then, it starts an inflammatory process. Immune system responds to the damage by sending macrophages to absorb oxidized LDL but when it is not enough, it results in deposition of a greater amount of cholesterol.

The lipid-laden macrophages make the fatty streak as the first step in the development of atherosclerosis (Nishida et al., 2003; Tailleux et al., 2002).

In this process, if there is no longer enough HDL to carry back the extra cholesterol to the liver, inflammation gets worse. Furthermore, increase of LDL oxidability alters its metabolism resulting in more atherogenesis rate (Tailleux et al., 2002). The most current prescribed drugs in atherosclerosis treatment are different statins. Besides, their proved efficacy in clinical trials, they have shown side effects both in short term and long term use. Statins are believed to have the antioxidant effect and thus, they can both prevent and reduce inflammation and risk factors in atherosclerosis. Although statins are generally well tolerated, some patients experience adverse effects, including elevated hepatic enzyme levels, gastrointestinal symptoms and statin-associated myalgias (Hadjibabaie et al., 2006, 2007; Hasani-Ranjbar et al., 2010). Other available drugs are niacin, fibrates and ezetimibe, which are used alone or in combination with statins. However, in some patients, there is a need for combine and use the complex regimen to reach the normal lipid profile and get the main target that is lowering the risk of cardiovascular diseases.

There is increasing evidence that in certain pathologic states, the increased production and ineffective scavenging of Reactive Oxygen Species (ROS) play a critical role. High reactivity of ROS determines chemical changes in virtually all cellular components, leading to lipid peroxidation (Hasani-Ranjbar et al., 2009; Rahimi et al., 2005).

Antioxidants could be the first line of treatment against atherosclerosis (Sener et al., 2009). Based on mechanisms behind pathogenesis and progress of atherosclerosis and the statin’s antioxidant power, there is a hope for any other antioxidant as an alternative or combinative therapy. The pineal endogenous hormone, melatonin (5-methoxy-n-acetyl-tryptamine), may be a valuable help in protecting LDL from oxidation. Melatonin may prevent degenerative diseases by protecting macromolecules (DNA, lipids and proteins) from free-radical damage (Mozaffari and Abdollahi, 2011). Therefore, melatonin has been tested for its potential to regulate lipid profile and prevent LDL oxidation. It is known that melatonin protects macromolecules from oxidation damage not just by its free-radical scavenging but also by its direct effect on antioxidant enzymes (Tan et al., 2002). The belief is that endogenous melatonin decreases and oxidative stress increase by aging (Momtaz and Abdollahi, 2012). Therefore, considering the increase in prevalence of cardiovascular and degenerative problems by age, it may be logic to use exogenous melatonin as a therapeutic agent.

Besides antioxidant power, melatonin’s lipophilic and hydrophilic property allows it to enter all types of cells and detoxify free radicals (Baydas et al., 2002).

DATA SOURCES AND STUDY SELECTION

All investigations using melatonin in dyslipidemia were reviewed by use of relevant bibliographic databases such as PubMed, Cochrane, Google Scholar, Scopus and Web of Science up to January 2012. Of the publications identified in the initial database, 11 clinical trials and 43 non-clinical trials (18 in vitro and 25 animal studies) were included and reviewed.

REVIEW OF FINDINGS

In vitro studies: The results of in vitro studies showed the protective properties of melatonin against lipid peroxidation in LDL by different mechanisms (Marchetti et al., 2011; Bonnefont-Rousselot et al., 2003; Sewerynek et al., 1995; Daniels et al., 1995; Wang et al., 2001). The demonstrated results and suggested mechanisms are summarized in Table 1. One of the markers of lipid peroxidation is formation of conjugated dienes (Abdollahi et al., 2004). Melatonin can decrease the formation of conjugated dienes (Marchetti et al., 2011; Bonnefont-Rousselot et al., 2003). It delays the onset of the propagation phase for conjugated dienes and lipid peroxides. It protects polyunsaturated fatty acids of LDL lipids against peroxidation. It prolongs the lag time, delays the peak time and decreases the rate of diene formation (Bonnefont-Rousselot et al., 2002, 2003; Walters-Laporte et al., 1998; Seegar et al., 1997; Pieri et al., 1996). In addition, it delays the consumption of LDL endogenous β-carotene and reduces its rate of disappearance but it has no protective effect on α-tocopherol due to its lower scavenging capacity (Marchetti et al., 2011; Bonnefont-Rousselot et al., 2003, 2002). Melatonin acts like a chain breaking antioxidant (Abuja et al., 1997). It scavenges hydroxyl peroxide and other toxic free radicals derived from oxidized LDL (Ox-LDL) (Marchetti et al., 2011; Bonnefont-Rousselot et al., 2003, 2002). By its antioxidant effect, it reduces lipid peroxides, protein carbonyl and phosphatidylserine levels and increases glutathione level (Sener et al., 2009).

A component of oxidized lipoprotein is Lysophosphatidylcholine (LPC) that reduces endothelial nitric oxide (NO) and causes the vasospastic effects. Melatonin significantly inhibits the activity of LPC demonstrated by suppressing its vasospastic effect. This effect is via scavenging hydroxyl radicals arising from LPC (Okatani et al., 2000a, b). Melatonin activates monocytes through protein kinase C and induces their cytotoxic properties, along with the IL-1 secretion (Morrey et al., 1994). In addition, melatonin reduces the numbers of LDL receptors and inhibits the synthesis of cholesterol in the cells (mononuclear leukocytes). Some studies indicated the association of melatonin receptors with circulating TG and HDL levels (Bhattacharyya et al., 2006; Muller-Wieland et al., 1994). Melatonin can inhibit the increased expression and activity of Myosin Light Chain Kinase (MLCK) via extracellular signal regulated kinase (ERK/MAPK) signal transduction. Ox-LDL increases expression and activity of MLCK by phosphorylation of ERK (Zhu et al., 2008). Melatonin increases the immunoreactivity of LDL (Kelly and Loo, 1997). In vitro studies have extensively reported the need for higher doses of melatonin to inhibit LDL oxidation, than its physiological concentrations (Tailleux et al., 2002). Some of these studies showed the concentration dependent manner in melatonin inhibitory effect on lipid peroxidation (Sewerynek et al., 1995; Daniels et al., 1995; Kozel’tsev et al., 2007).

Table 1: In vitro studies considering the effects of melatonin in hyperlipidemia
Image for - The Mechanisms of Positive Effects of Melatonin in Dyslipidemia: A Systematic Review of Animal and Human Studies
Image for - The Mechanisms of Positive Effects of Melatonin in Dyslipidemia: A Systematic Review of Animal and Human Studies
2,2’-azo-bis- (2-amidinopropane) dihydrochloride, AAPH: Adenosine diphosphate, ADP: Apo lipoprotein B (apo-B), CCl4: Carbon tetrachloride, CD: Conjugated diene, ERK: Extracellular signal-regulated kinase, G6Pase: Glucose-6 phosphatase, GSH: Reduced glutathione, HDL: high-density-lipoprotein, h: Hour (h), ●OH: hydroxyl radical, LDH: Lactate dehydrogenase (LDH); low-density lipoproteins, LPC: Lysophosphatidylcholine, LPS: Lipopolysaccharide, MDA: Malondialdehyde, MARK: Mitogen-activated protein kinase, MLCK: Myosin light chain kinase, NA: Not available, NO: Nitric oxide, Ox-LDL: Oxidized low-density lipoprotein, PC: protein carbonyl, PLPC: 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine, RO(2)*: Peroxyl radicals. O(2)* Superoxide anion, TBARS: Thiobarbituric acid reactive substances, TG: Triglyceride, ↑: increased, ↓: decreased

ANIMAL STUDIES

By a review of Table 2, we can see specific effects of melatonin in different models of rats and mice. There are large numbers of studies showing that melatonin; with its antioxidant potential protects atherogenesis and fatty liver disease in obese animal models. There are other models such as myocardial infarction, drug-induced cardiotoxicity, oxidative injuries and finally diabetes. The most obvious and bold beneficial results were the potential to decrease and restore the elevated total cholesterol, TG, LPO, LDL, tumor necrosis factor (TNF-α) and lipid peroxide. Melatonin also reduced body weight in obese rat models besides its regulatory effects on lipid profile. It, furthermore, decreased heart muscle cholesterol and augmented cholesterol clearance. Moreover, it stimulated glutathione to help protecting LDL from oxidation. Melatonin influences cholesterol metabolism by modulating the macrophage activity and regulating the secretion of cytokines, such as IL-2 (Hoyos et al., 2000).

CLINICAL TRIALS

The studies included 11 clinical trials examined any relation between melatonin and lipid profile. In seven of them; melatonin was used as an intervention, including four placebo-controlled trials. The doses of melatonin were started at 0.3-10 mg in three to twelve weeks of treatment. Melatonin was administered orally in all seven trials (Table 3).

The reported results showed that melatonin decreased the level of LDL and lipid peroxides in metabolic syndrome patients (Kozirog et al., 2011) and reduced LDL susceptibility to oxidation (Wakatsuki et al., 2000). Besides its lowering effect on LDL, it also increased the HDL level and reduced plasma cholesterol (Tamura et al., 2008). Co-treatment of melatonin and zinc reduced oxidative damage induced by hyperglycemia in type 2 diabetic patients, which were on medical therapy with metformin. Melatonin improved lipid profile in comparison to placebo with a dose of 10 mg (Kadhim et al., 2006) whereas; it had no significant effect on lipid metabolism in diabetic patients with a dose of 2 mg (Garfinkel et al., 2011).

In a study performed to evaluate its role on serum levels of lipids, there was no significant effect on hypercholesterolemia with 3 mg melatonin (Rindone and Achacoso, 1997). Additionally, any significant influence on cholesterol and TG were observed in non-alcoholic fatty liver disease when compared to placebo (Gonciarz et al., 2010) but in comparison between healthy subjects and acute Myocardial Infarction (MI) patients, melatonin concentration was lower in acute MI patients associated with high level of oxidized LDL (Dominguez-Rodriguez et al., 2005). Another trial suggested a relationship between melatonin secretion and acute coronary diseases. They measured urinary melatonin metabolite (6-sulfatoxymelatonin), Cu/Zn Superoxide Dismutase (SOD) activity along with LDL and Malondialdehyde (MDA) in 21 patients with unstable angina. The results showed a lower level of both melatonin metabolite and Cu/Zn SOD in unstable angina in comparison to healthy volunteers. This supports the hypothesis that melatonin level is a clinical marker in coronary atherosclerosis (Vijayasarathy et al., 2010).

Furthermore, there was a report represented the reduced concentration of nocturnal melatonin in multiple sclerosis patients with hypercholesterolemia that indicates melatonin as a reducing factor on serum cholesterol by affecting its metabolism (Sandyk and Awerbuch, 1994). There is another study, analyzed nine women’s salivary melatonin, plasma TG and non-essential fatty acids showing the correlation between melatonin as a circadian rhythm marker and TG (Morgan et al., 1998).

DISCUSSION

Lipids have the main role in cardiovascular diseases via development of atherosclerosis plus modifying the structure and stability of the cellular membranes. It has been documented that serum LDL and HDL levels have opposing influence on the risk of cardiovascular diseases (Patel et al., 2010). Ox-LDL increases free radical production, lipid peroxidation and platelet activation resulting in an increase in the sensitivity to aggregating (Sener et al., 2009). During LDL oxidation process, lipid peroxides such as MDA are produced following the formation of conjugated dienes. In this process, endogenous antioxidants such as α-tocopherol and β-carotene are used (Vijayasarathy et al., 2010). The complete lipid peroxidation in LDL has been explained by Abuja et al. (1997). This process can be assumed as three phases; first, the lag phase in which conjugated dienes are produced slowly because of LDL resistance to oxidation. In lag phase, lipophilic antioxidants are able to inhibit radical chain propagation. After the lag time, while antioxidants are used, chain propagation speeds the conjugated formation. However, amphiphilic antioxidants can lower the rate of this phase. Finally, the last phase is destroying the conjugated dienes during subsequences reactions (Abuja et al., 1997). There are reviews explaining the melatonin's extensive role in metabolic regulation and cardiovascular system (Korkmaz et al., 2009; Nishida, 2005; Sewerynek, 2002) but we emphasized on the regulatory effect of the hormone on lipid profile both in clinical and non-clinical setting.

Table 2: Animal studies considering the effects of melatonin in hyperlipidemia
Image for - The Mechanisms of Positive Effects of Melatonin in Dyslipidemia: A Systematic Review of Animal and Human Studies
Image for - The Mechanisms of Positive Effects of Melatonin in Dyslipidemia: A Systematic Review of Animal and Human Studies
Image for - The Mechanisms of Positive Effects of Melatonin in Dyslipidemia: A Systematic Review of Animal and Human Studies
CCl4: Carbon tetrachloride, CAT: Catalase, CDs: Conjugated dienes, d: Day, GGT: Gamma-glutamyltransferase, GSH: Reduced glutathione, HDL: High density lipoprotein, h: hour, i.p.: Intra peritoneal LPO: Liver lipid peroxide, LDL: Low density lipoprotein, MDA: Malondialdehyde, mth: Month, NA: Not available, NAFLD: Non-alcoholic fatty liver disease, p.o.: Orally, PL: Phospholipid, Sig: Significant Sc: Subcutaneously, STZ: Streptozocin, TG: Triglyceride, TNF-β: Tumor necrosis factor-β, VLDL: Very low-density lipoprotein, Weeks: Weeks, ↓: Increased, ↑: Decreased

Table 3: Clinical studies considering the effects of melatonin in hyperlipidemia.
Image for - The Mechanisms of Positive Effects of Melatonin in Dyslipidemia: A Systematic Review of Animal and Human Studies
BP: Blood pressure, CAT: Catalase, d: Day, DM: Diabetes mellitus, F: Female, HDL: High-density-lipoprotein, h: Hour, LDL: Low-density lipoproteins, M: Male, Mth: Month, NAFLD: Non-alcoholic fatty liver disease, Ox-LDL: Oxidized low-density lipoprotein, PO: Orally, Sig: Significant, TBARS: Thiobarbituric acid reactive substances, TG: Triglyceride,TNF-β: Tumor necrosis factor-β, Wk: Week Year: Year, ↑: Increased, ↓: Decreased

Melatonin is known to take part in many metabolic processes as a regulator. Thus, any disturbance in its rhythm and secretion leads to several consequences known as metabolic diseases (Korkmaz et al., 2009). Morgan et al. (1998) determined the correlation of the internal clock to metabolic factors based on a hypothesis of the increased risk of cardiovascular disease in the shift workers. They observed delayed TG postprandial clearance after the phase shift showing the role of nocturnal melatonin level in lipid levels (Morgan et al., 1998). In another study, Damian et al. (1988) evaluated the effect of melatonin on HDL-cholesterol and serum cholesterol in the rat. Administration of melatonin-free pineal extract, in doses of 2 mL/day/animal along 3, 6 and 12 days caused a significant decrease in HDL-cholesterol and resulted in a reduction of testosterone due to decline of its major precursor, cholesterol.

Nishida et al. (2003) investigated the effect of pinealectomy on lipid metabolism in type 2 diabetic rats. Pinealectomy caused an increase in free cholesterol and hepatic TG via Acyl-CoA Synthetase (ACS) that its activity was significantly augmented, while Microsomal TG Transfer Protein (MTP) decreased.

Plasma pharmacokinetic of melatonin has been poorly investigated. There are no studies on the plasma melatonin pharmacokinetics in healthy subjects after prolonged administration of melatonin (Gonciarz et al., 2010). Prunet-Marcassus et al. (2003) demonstrated that melatonin efficiency was time dependent (Prunet-Marcassus et al., 2003). The effect of melatonin when administered before the end of the light period was increased due to an increased density of melatonin receptor and longer duration of high melatonin level. Melatonin is an amphipathic antioxidant diffusible into cells freely (Vijayasarathy et al., 2010; Korkmaz et al., 2011). After oral administration, melatonin rapidly passes into the blood stream (Korkmaz et al., 2011). Considering the short half-life of melatonin to get a prolonged effect, some studies used melatonin infusion, implants, or melatonin in water (Prunet-Marcassus et al., 2003). Pharmacologically pure form of melatonin is easily synthesized and affordable with a very long shelf life (Korkmaz et al., 2011). In administration of melatonin, its variable oral absorption, short biological half-life and high amount of its first-pass metabolism should be considered besides attention to its solubility profile in aqueous medium (Vlachou et al., 2006). By hypothesized radical scavenging power of melatonin depending on its location and partitioning into lipid or aqueous medium (Mekhloufi et al., 2007) assessed the location of melatonin in lipid assemblies. For LDL, melatonin was mostly seen in the aqueous phase containing phospholipids, unesterified cholesterol and apo-lipoprotein B100, verifying that melatonin is not incorporated into LDL completely when protects it from oxidation by free radicals (Mekhloufi et al., 2007). It is indicated that lipophilicity of melatonin is not enough to permit accumulation in the lipid phase and its antioxidant activity is lower than that of α-tocopherol. Therefore, the effective concentrations of melatonin in an in vitro aqueous medium to protect LDL against lipid peroxidation should be higher than that of in vivo situation (Abuja et al., 1997).

Melatonin has a benign safety profile even in pregnancy or neonates (Gitto et al., 2009). It has no toxicity and teratogenicity when administered in physiological and pharmacological amounts to humans and animals (Korkmaz et al., 2011). There is a report for decreased serum uric acid, bilirubin and increased serum glucose following melatonin administration (Hoyos et al., 2000). In the year 2000, Seabra et al. (2000) performed a randomized double blind placebo controlled clinical trial to assess melatonin’s probable toxicity. Forty healthy volunteers received either placebo or melatonin in a dose of 10 mg daily orally for four weeks (10 placebo and 30 melatonin). At the end of the study by measuring different factors, they observed no significant difference between melatonin and placebo group and there was no report of any toxicity or side effects (Seabra et al., 2000).

Taking collectively, the present review support the positive effects of melatonin in dyslipidemia that is mediated through its anti-oxidative potentials and protection from detrimental effects of pro-inflammatory cytokines like IL-6, IL-12, TNF-α and IFN-γ that all lead to lower oxidation of LDL (Broncel et al., 2007). In the recent years, several studies have brought strong evidences that antioxidant compounds obtained from herbal products (Sarwar et al., 2011) can protect body from dyslipidemia (Momtaz and Abdollahi, 2010) and ailments related with dyslipidemia like nonalcoholic fatty liver disease (Malekirad et al., 2012), acute hepatic failure (Rahimi et al., 2012), diabetes (Mehri et al., 2011), aging (Hasani-Ranjbar et al., 2012), multi-diseases (Mohammadirad et al., 2011) and even in healthy subjects (Malekirad et al., 2011).

This review reveals that there is a simple and clear mechanism defining melatonin's defensive effect on the oxidation process of LDL but justifying the effective dose, duration of treatment and adverse effects remain to be elucidated in further controlled clinical trials in the hope to use melatonin as a supplementary in dyslipidemia and related disorders.

ACKNOWLEDGMENT

This study is an outcome of an in-house none financially supported study and authors do not have any conflict of interest.

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