Melatonin enhances mitochondrial biogenesis and protects against rotenone-induced mitochondrial deficiency in early porcine embryos

Melatonin, a major hormone of the pineal gland, exerts many beneficial effects on mitochondria. Several studies have shown that melatonin can protect against toxin-induced oocyte quality impairment during maturation. However, there is little information regarding the beneficial effects of melatonin on toxin-exposed early embryos, and the mechanisms underlying such effects have not been determined. Rotenone, a chemical widely used in agriculture, induces mitochondrial toxicity, therefore, damaging the reproductive system, impairing oocyte maturation, ovulation, and fertilization. We investigated whether melatonin attenuated rotenone exposure-induced impairment of embryo development by its mitochondrial protection effect. Activated oocytes were randomly assigned to four groups: the control, melatonin treatment, rotenone-exposed, and “rotenone + melatonin” groups. Treatment with melatonin abrogated rotenone-induced impairment of embryo development, mitochondrial dysfunction, and ATP deficiency, and significantly decreased oxidative stress and apoptosis. Melatonin also increased SIRT1 and PGC-1α expression, which promoted mitochondrial biogenesis. SIRT1 knockdown or pharmacological inhibition abolished melatonin's ability to revert rotenone-induced impairment. Thus, melatonin rescued rotenone-induced impairment of embryo development by reducing ROS production and promoting mitochondrial biogenesis. This study shows that melatonin rescues toxin-induced impairment of early porcine embryo development by promoting mitochondrial biogenesis.     

Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model

In the present study, we evaluated the effect of melatonin, a well-known free radical scavenger and neuroprotector, against rotenone-induced oxidative stress in a hemiparkinsonian rat model. The effect of melatonin on glutathione (GSH) depletion caused by unilateral, intranigral infusion of rotenone was investigated employing a spectrofluorimetric procedure. We also studied the effect of melatonin on rotenone-induced changes in the antioxidant enzymes superoxide dismutase (SOD) and catalase in the cytosolic fractions of substantia nigra (SN), employing spectrophotometric procedures. Rotenone-induced hydroxyl radicals (*OH) in the isolated mitochondria, as measured employing a sensitive HPLC-electrochemical method, were significantly scavenged by melatonin. Melatonin treatment restored the rotenone-induced decrease in GSH level and changes in antioxidant enzyme (SOD and catalase) activities in the SN. Our results strongly indicate melatonin's beneficial use in Parkinson's disease therapy as an antioxidant.     

Melatonin protects against apoptotic and autophagic cell death in C2C12 murine myoblast cells

In this study, we investigated whether or not melatonin inhibits apoptotic and autophagic cell death in C2C12 murine myoblast cells. Treatment of cells with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, was shown to induce cell death, and treatment with melatonin (100 μm) significantly attenuated the occurrence of NO-induced cell death. Decreased p-Akt expression in response to NO was also arrested by melatonin. Under these conditions, p-Bad (Ser 136) expression increased with melatonin treatment prior to NO treatment. Treatment with Akt inhibitors (LY 294002, wortmannin) plus melatonin reduced p-Akt expression. Compared with NO treatment, Bcl-2 expression increased with melatonin treatment, while Bax expression was inhibited by melatonin treatment. Expression of catalase and Mn-superoxide dismutase (SOD) was elevated with melatonin treatment, whereas Cu/Zn-SOD expression decreased with melatonin, lower than NO treatment, respectively. Next, we investigated the question of whether or not melatonin may restrain autophagic cell death in C2C12 cells. Nutrient starvation induced a rise in expression of the microtubule-associated protein 1 light chain 3 (LC3)-II; however, melatonin treatment suppressed LC3-II expression by nutrient deprivation. Expression of Bcl-2, Bax, catalase, and Cu/Zn-SODs coincided with results of apoptotic cell death. Together, these results suggest that melatonin protects against apoptotic and autophagic cell death through the common pathway resulted in the increment of Bcl-2 expression and the reduction of Bax expression in C2C12 murine myoblast cells.     

衰老心肌中Omi/HtrA2表达增加可促进心肌细胞自噬

目的探讨衰老心肌中增加的Omi／HtrA2在心肌细胞自噬中的作用。方法用D-半乳糖干预胎鼠心肌细胞系H9c2建立衰老细胞模型,B-半乳糖苷酶染色观察细胞的衰老情况,cck8试剂盒检测细胞存活率,并以分析细胞乳酸脱氢酶（Lactic Dehydrogenase,LDH）水平反映其活性;给予Omi／HtrA2特异性抑制剂ucf_101降低Omi／HtrA2活性,构建稳转Omi／HtrA2的H9c2细胞株过表达Omi／HtrA2;采用westernblot法测定心肌细胞中Omi／HtrA2、beclinl及LC3．II蛋白的表达。结果（1）与H9c2心肌细胞相比,D．半乳糖诱导的H9c2心肌细胞内B-半乳糖苷酶染色阳性率显著升高[（87．7±3．6％）VS（18．3±2_8％）,P〈0．01];cck8结果显示,两组之间无显著性差异（P〉0．05）,但D-半乳糖诱导的H9c2心肌细胞中LDH活性明显升高（7．07±0．65w5．93±0．34,P〈0．01o（2）与H9c2细胞相比,D-半乳糖诱导的H9c24心肌细胞中Omi／HtrA2蛋白表达升高（P〈0．05）,而beclinl表达下降（P〈0．01）;给予ucf-101后,衰老细胞中Omi／HtrA2蛋白表达明显下降（P〈0．05）,而beclinl表达则进一步降低（P〈0．01）。（3）与H9c2细胞相比,过表达Omi／HtrA2的H9c2心肌细胞Omi／HtrA2蛋白表达增高,LC3-Ⅱ蛋白表达也增高（P〈0．05）;给予过表达Omi／HtrA2的H9c2心肌细胞ucf-101后,LC3-Ⅱ表达下降（P〈0．05o结论衰老心肌细胞中Omi／HtrA2的表达增加可促进心肌细胞自噬。     

Melatonin-induced autophagy protects against human prion protein-mediated neurotoxicity

Melatonin has neuroprotective effects in the models of neurodegenerative disease including Alzheimer's and Parkinson's disease. Several studies have shown that melatonin prevents neurodegeneration by regulation of mitochondrial function. However, the protective action of melatonin has not been reported in prion disease. We investigated the influence of melatonin on prion-mediated neurotoxicity. Melatonin rescued neuronal cells from PrP(106-126)-induced neurotoxicity by prevention of mitochondrial dysfunction. Moreover, the protective effect of melatonin against mitochondrial dysfunction was related with autophagy activation. Melatonin-treated cells were dose-dependently increased in LC3-II, an autophagy marker. Melatonin-induced autophagy prevented a PrP(106-126)-induced reduction in mitochondrial potential and translocation of Bax to the mitochondria and cytochrome c release. On the other hand, downregulation of autophagy protein 5 with Atg5 siRNA or the autophagy blocker 3-methyladenine prevented the melatonin-mediated neuroprotective effects. This is the first report demonstrating that treatment with melatonin appears to protect against prion-mediated neurotoxicity and that the neuroprotection is induced by melatonin-mediated autophagy signals. The results of this study suggest that regulation of melatonin is a therapeutic strategy for prion peptide-induced apoptosis.     

Melatonin‐enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage

Melatonin is a strong antioxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes reduced mortality and brain water content. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on neural apoptosis and the potential mechanism of these effects in EBI following SAH using the filament perforation model of SAH in male Sprague Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. The results show that melatonin treatment markedly reduced caspase‐3 activity and the number of TUNEL‐positive cells, while the treatment increased the LC3‐II/LC3‐I, an autophagy marker, which indicated that melatonin‐enhanced autophagy ameliorated apoptotic cell death in rats subjected to SAH. To further identify the mechanism of autophagy protection, we demonstrated that melatonin administration reduced Bax translocation to the mitochondria and the release of cytochrome c into the cytosol. Taken together, this report demonstrates that melatonin improved the neurological outcome in rats by protecting against neural apoptosis after the induction of filament perforation SAH; moreover, the mechanism of these antiapoptosis effects was related to the enhancement of autophagy, which ameliorated cell apoptosis via a mitochondrial pathway.     

Melatonin protects liver against ischemia and reperfusion injury through inhibition of toll-like receptor signaling pathway

Abstract: This study investigated the immunomodulating effect of melatonin on toll‐like receptor (TLR)‐stimulated signal transduction. Rats were subjected to 60 min of ischemia followed by 1 or 5 hr of reperfusion. Melatonin (10 mg/kg) or the vehicle was administered intraperitoneally 15 min prior to ischemia and immediately before reperfusion. Melatonin treatment significantly reduced the level of serum alanine aminotransferase activity. Increased levels of TLR3 and TLR4 protein expression induced by ischemia/reperfusion (I/R) were attenuated by melatonin. Serum level of high‐mobility group box 1 (HMGB1), a potent alarmin of the TLR system, increased significantly in the I/R group, and melatonin inhibited this release. Melatonin suppressed the increase in myeloid differentiation factor 88 (MyD88) protein expression, extracellular signal‐regulated kinase (ERK) and c‐Jun N‐terminal kinase (JNK) phosphorylation and nuclear translocation of nuclear factor κB (NF‐κB) and phosphorylated c‐Jun, a component of activator protein 1. The increased level of toll‐receptor‐associated activator of interferon (TRIF) expression, phosphorylation of interferon (IFN) regulatory factor 3 (IRF3) and serum IFN‐β was attenuated by melatonin. Melatonin attenuated the levels of tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐6 and inducible nitric oxide synthase (iNOS) protein and mRNA expression, while the level of heme oxygenase‐1 (HO‐1) was augmented. Our results suggest that melatonin ameliorates I/R‐induced liver damage by modulation of TLR‐mediated inflammatory responses.     

Melatonin protects against ischemia/reperfusion injury in skeletal muscle

Abstract:  Melatonin has been shown to diminish ischemia-reperfusion (I/R) injury in many tissues. The main aim of this study was to evaluate the protective antioxidant effect of melatonin in skeletal muscle during I/R injury. Wistar albino rats were randomly divided into three groups. Hindlimb ischemia was achieved by clamping the common femoral artery in two groups but not in control group. Limbs were rendered ischemic for 1.5 hr; at the end of the reperfusion period of 1.5 hr muscle tissue samples were taken for the histological evaluation and biochemical analysis. Melatonin (10 mg/kg) was injected i.p. in the I/R + Mel group at the onset of ischemia whereas the vehicle solution was injected in the I/R group. In I/R + Mel group histological damage was significantly less than in the I/R group ( P  < 0.001). In the I/R + Mel group, the mean malonedialdehyde level was lower than in the I/R group ( P  < 0.01) and was quite near to the levels in the control group ( P  > 0.05). Glutathione levels were found to be reduced in the I/R group compared with the control ( P  < 0.01) and I/R + Mel group ( P  < 0.01). Melatonin has a protective effect against I/R injury in skeletal muscle and may reduce the incidence of compartment syndrome, especially after acute or chronic peripheral arterial occlusions.     

Melatonin treatment induces interplay of apoptosis,autophagy, and senescence in human colorectal cancer cells

In Asia, the incidence of colorectal cancer has been increasing gradually due to a more Westernized lifestyle. The aim of study is to determine the interaction between melatonin‐induced cell death and cellular senescence. We treated HCT116 human colorectal adenocarcinoma cells with 10 μm melatonin and determined the levels of cell death‐related proteins and evaluated cell cycle kinetics. The plasma membrane melatonin receptor, MT1, was significantly decreased by melatonin in a time‐dependent manner, whereas the nuclear receptor, RORα, was increased only after 12 hr treatment. HCT116 cells, which upregulated both pro‐apoptotic Bax and anti‐apoptotic Bcl‐xL in the early response to melatonin treatment, activated autophagic as well as apoptotic machinery within 18 hr. Melatonin decreased the S‐phase population of the cells to 57% of the control at 48 hr, which was concomitant with a reduction in BrdU‐positive cells in the melatonin‐treated cell population. We found not only marked attenuation of E‐ and A‐type cyclins, but also increased expression of p16 and p‐p21. Compared to the cardiotoxicity of Trichostatin A in vitro, single or cumulative melatonin treatment induced insignificant detrimental effects on neonatal cardiomyocytes. We found that 10 μm melatonin activated cell death programs early and induced G1‐phase arrest at the advanced phase. Therefore, we suggest that melatonin is a potential chemotherapeutic agent for treatment of colon cancer, the effects of which are mediated by regulation of both cell death and senescence in cancerous cells with minimized cardiotoxicity.     

Melatonin suppresses cyclosporine A‐induced autophagy in rat pituitary GH3 cells

Abstract: Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the induction of chronic nephrotoxicity including endoplasmic reticulum (ER) stress in tubular cells. Recently, it was reported that autophagy is induced by ER stress and serves to alleviate the associated deleterious effects. In the current study, CsA treatment (0–100 μm ) decreased cell survival of rat pituitary GH3 cells in a dose‐dependent manner. At concentrations ranging from 1.0 to 10 μm , CsA induced a dose‐dependent increase in the expression of microtubule‐associated protein 1 light chain 3 (LC3)‐I and LC3‐II. Cells treated with 2.5 μm CsA exhibited cytoplasmic vacuolation, indicating that CsA induces autophagy in rat pituitary GH3 cells. In the presence of 1.0–10 μm CsA, the expression of catalase decreased while that of the ER stress markers, ER luminal binding protein (BiP) and inositol‐requiring enzyme 1 alpha (IRE1α), increased as compared those levels in untreated cells. These results suggested that CsA‐induced autophagy is dependent on ER stress. To determine whether melatonin would protect cells against CsA‐induced autophagy, we treated rat pituitary GH3 cells with melatonin in the presence of CsA. Melatonin treatment (100 and 200 μm ) suppressed autophagy induced by 2.5 and 5 μm CsA. Furthermore, co‐treatment with 100 μm melatonin inhibited LC3‐II expression, and increased catalase and phosphorylated p‐ERK levels in the presence of 2.5 and 5 μm CsA. BiP and IRE1α expression in melatonin‐co‐treated cells was superior to that in cells treated with 2.5 and 5 μm CsA alone. Thus, melatonin suppresses CsA‐mediated autophagy in rat pituitary GH3 cells.     

Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis

Endoplasmic reticulum (ER) is a dynamic organelle that participates in a number of cellular functions by controlling lipid metabolism, calcium stores, and proteostasis. Under stressful situations, the ER environment is compromised, and protein maturation is impaired; this causes misfolded proteins to accumulate and a characteristic stress response named unfolded protein response (UPR). UPR protects cells from stress and contributes to cellular homeostasis re‐establishment; however, during prolonged ER stress, UPR activation promotes cell death. ER stressors can modulate autophagy which in turn, depending of the situation, induces cell survival or death. Interactions of different autophagy‐ and apoptosis‐related proteins and also common signaling pathways have been found, suggesting an interplay between these cellular processes, although their dynamic features are still unknown. A number of pathologies including metabolic, neurodegenerative and cardiovascular diseases, cancer, inflammation, and viral infections are associated with ER stress, leading to a growing interest in targeting components of the UPR as a therapeutic strategy. Melatonin has a variety of antioxidant, anti‐inflammatory, and antitumor effects. As such, it modulates apoptosis and autophagy in cancer cells, neurodegeneration and the development of liver diseases as well as other pathologies. Here, we review the effects of melatonin on the main ER stress mechanisms, focusing on its ability to regulate the autophagic and apoptotic processes. As the number of studies that have analyzed ER stress modulation by this indole remains limited, further research is necessary for a better understanding of the crosstalk between ER stress, autophagy, and apoptosis and to clearly delineate the mechanisms by which melatonin modulates these responses.     

Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats

Abstract:  Parkinson's disease (PD) is a movement disorder resulting from nigrostriatal dopaminergic neurodegeneration. The impairment of mitochondrial function and dopamine synaptic transmission are involved in the pathogenesis of PD. Two mitochondrial inhibitors, 1-methyl-4-phenylpyridine (MPP⁺) and rotenone, have been used to induce dopaminergic neuronal death both in in vitro and in vivo models of PD. Because the uptake of MPP⁺ is mediated by the dopamine transporter (DAT), we used a cell-permeable rotenone-induced PD model to investigate the role of DAT and dopamine D2 receptor (D2R) on dopaminergic neuronal loss. Rotenone subcutaneously infused for 14 days induced PD symptoms in rats, as indicated by reduced spontaneous locomotor activity (hypokinesis), loss of tyrosine hydroxylase (TH, a marker enzyme for dopamine neurons) immunoreactivity in the substantia nigra and striatum, obvious α-synuclein accumulation, downregulated DAT protein expression, and upregulated D2R expression. Interestingly, rotenone also caused significant noradrenergic neuronal loss in the locus coeruleus. Melatonin, an antioxidant, prevented nigrostriatal neurodegeneration and α-synuclein aggregation without affecting the rotenone-induced weight loss and hypokinesis. However, rotenone-induced hypokinesis was markedly reversed by the DAT antagonist nomifensine and body weight loss was attenuated by the D2R antagonist sulpiride. In addition, both antagonists significantly prevented the reduction of striatal TH or DAT immunoreactivity but not the loss of nigral TH- and DAT-immunopositive neurons. These results suggested that oxidative stress and DAT downregulation are involved in the rotenone-induced pathogenesis of nigrostriatal dopaminergic neurodegeneration, whereas D2R upregulation may simply represent a compensatory response.     

Melatonin protects against oxidized low-density lipoprotein-induced inhibition of nitric oxide production in human umbilical artery

We evaluated the antioxidative effect of melatonin on the oxidized low-density lipoprotein (LDL)-induced impairment of nitric oxide (NO) production in human umbilical artery, which may be the prime cause of endothelial dysfunction in pre-eclampsia. Umbilical artery sections with intact endothelium were obtained from healthy pregnant women who were delivered between 37 and 40 wk of gestation. The production of NO in the umbilical arteries was stimulated by adding L-arginine followed by incubation for 60 min. NO concentrations were estimated by measuring nitrite ions (NO(2) using high-performance liquid chromatography. LDL was oxidized by incubation with 5 microM CuSO(4) at 37 degrees C for 4 hr, followed by dialysis at 4 degrees C for 24 hr. Prior to the addition of L-arginine, the segments were treated with native or oxidized LDL (0, 50, 100, 200, 400 microg/mL), or were pre-treated with either mannitol (50 mM) or melatonin (20, 100, 500 microM) before adding oxidized LDL. Changes in L-arginine-induced NO(2)(-) production were expressed as a percentage of NO(2)(-) production at the end of pre-incubation. Treatment with oxidized LDL significantly reduced L-arginine-induced NO(2)(-) production (P<0.05), while NO(2)(-) production did not change by incubation with native LDL. Pre-treatment with melatonin significantly increased NO(2)(-) production that had been decreased by oxidized LDL (P<0.05). Similarly, pre-treatment with mannitol reversed the oxidized LDL-induced reduction in NO(2)(-) production (P<0.05). These results indicate that melatonin protects against oxidized LDL-induced inhibition of NO production in the endothelium of human umbilical arteries, most likely through its ability to scavenge hydroxyl radicals.     

Melatonin attenuates methamphetamine-induced deactivation of the mammalian target of rapamycin signaling to induce autophagy in SK-N-SH cells

Abstract:  Methamphetamine (METH) is a commonly abused drug that damages nerve terminals by causing reactive oxygen species (ROS) formation, apoptosis, and neuronal damage. Autophagy, a type of programmed cell death independent of apoptosis, is negatively regulated by the mammalian target of the rapamycin (mTOR) signaling pathway. It is not known, however, whether autophagy is involved in METH-induced neurotoxicity. Therefore, we investigated the effect of METH on autophagy and its upstream regulator, the mTOR signaling pathway. Using the SK-N-SH dopaminergic cell line, we found that METH induces the expression of LC3-II, a protein associated with the autophagosome membrane, in a dose-dependent manner. Moreover, METH inhibits the phosphorylation of mTOR and the action of its downstream target, the eukaryotic initiation factor (eIF)4E-binding protein, 4EBP1. Melatonin, a major secretory product of pineal, is a potent naturally produced antioxidant that acts through various mechanisms to ameliorate the toxic effects of ROS. We found that a pretreatment with melatonin enhances mTOR activity and 4EBP1 phosphorylation and protects against the formation of LC3-II in SK-N-SH cells exposed to METH. This work demonstrates a novel role for melatonin as a neuroprotective agent against METH.     

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling

This study investigated the effects of melatonin on diabetic cardiomyopathy (DCM) and determined the underlying mechanisms. Echocardiography indicated that melatonin notably mitigated the adverse left ventricle remodeling and alleviated cardiac dysfunction in DCM. The mechanisms were attributed to increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin inhibited Mst1 phosphorylation and promoted Sirt3 expression in DCM. These results indicated that melatonin may exert its effects through Mst1/Sirt3 signaling. To verify this hypothesis, a DCM model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1^?/?) mice was constructed. As expected, melatonin increased autophagy, reduced apoptosis and improved mitochondrial biogenesis in Mst1 Tg mice subjected to DCM injury, while it had no effects on Mst1^?/? mice. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe the mechanisms involved. Melatonin administration promoted autophagic flux as demonstrated by elevated LC3‐II and lowered p62 expression in the presence of bafilomycin A1. The results suggest that melatonin alleviates cardiac remodeling and dysfunction in DCM by upregulating autophagy, limiting apoptosis, and modulating mitochondrial integrity and biogenesis. The mechanisms are associated with Mst1/Sirt3 signaling.     

Melatonin protects against pressure ulcer-induced oxidative injury of the skin and remote organs in rats

Pressure ulcers (PU) cause morphological and functional alterations in the skin and visceral organs; the damage is believed to be due to ischemia/reperfusion (I/R) injury. In this study, we examined the role of oxidative damage in PU and the beneficial effect of treatment with the antioxidant melatonin. PU were induced by applying magnets over steel plates that were implanted under the skin of rats; this compressed the skin and caused ischemia. Within a 12-hr period, rats were subjected to five cycles of I/R (2 and 0.5 hr respectively), followed by an additional 12 hr of ischemia (to simulate the period at sleep at night). This protocol was repeated for 3 days. In treatment groups, twice a day during reperfusion periods, melatonin (5 mg per rat) was either applied locally as an ointment on skin, or administered i.p. (10 mg/kg). At the end of the experimental period, blood and tissue (skin, liver, kidney, lung, stomach, and ileum) samples were taken for determination of biochemical parameters and for histological evaluation. Local treatment with melatonin inhibited the increase in malondialdehyde levels; an index of lipid peroxidation, myeloperoxidase activity; an indicator of tissue neutrophil infiltration, and the decrease in glutathione; a key antioxidant, in the skin induced by PU, but was less efficient in preventing the damage in visceral organs. However, systemic treatment prevented the damage in the visceral organs. Significant increases in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and collagen levels in animals with PU were prevented by melatonin treatment. The light microscopic examination exhibited significant degenerative changes in dermis and epidermis in the PU rats. Tissue injury was decreased especially in the locally treated group. Findings of the present study suggest that local and/or systemic melatonin treatment may prove beneficial in the treatment of PU.     

Melatonin protects against gentamicin-induced nephrotoxicity in rats

Acute renal failure is a major complication of gentamicin (GEN), which is widely used in the treatment of gram-negative infections. A large body of in vitro and in vivo evidence indicates that reactive oxygen metabolites (or free radicals) are important mediators of gentamicin nephrotoxicity. In this study we investigated the role of free radicals in gentamicin-induced nephrotoxicity and whether melatonin, a potent antioxidant could prevent it. For this purpose female Sprague-Dawley rats were given intraperitoneally either gentamicin sulphate (40 mg/kg), melatonin (10 mg/kg), gentamicin plus melatonin or vehicle (control) twice daily for 14 days. The rats were decapitated on the 15th day and kidneys were removed. Blood urea nitrogen (BUN) and creatinine levels were measured in the blood and malondialdehyde (MDA) and glutathione (GSH) levels, protein oxidation (PO) and myeloperoxidase (MPO) activity were determined in the renal tissue. Gentamicin was observed to cause a severe nephrotoxicity which was evidenced by an elevation of BUN and creatinine levels. The significant decrease in GSH and increases in MDA levels, PO and MPO activity indicated that GEN-induced tissue injury was mediated through oxidative reactions. On the other hand simultaneous melatonin administration protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by GEN treatment.     

Melatonin protects against cardiac toxicity of doxorubicin in rat

Doxorubicin (DOX) is commonly used for the treatment of hematological and solid tumors. However, there are serious toxic effects on the cardiovascular system, which limits the application of the drug. Recently, melatonin has been reported to have immunomodulatory effect in addition to lowering cholesterol levels as well as inhibiting malignant tumors. In this study, the effect of melatonin against the toxicity of doxorubicin was investigated in rats. Hemodynamic function, pathological and biochemical changes were determined in different treated hearts. Our findings showed that a significant protection by melatonin (6 mg kg(-1) for 15 days, cumulative dose of 90 mg kg(-1)) against the DOX-induced toxicity was observed. Cardiac function was improved and lipid peroxidation decreased after melatonin treatment. It is concluded that melatonin provides protection against doxorubicin toxicity via an attenuation of lipid peroxidation.