Cisplatin, cis-diamminedichloroplatinum II, is broadly and effectively used antineoplastic agent in chemotherapy of most solid tumors. The therapeutic effectiveness, of Cisplatin, has been compromised by its dose limiting toxicities, mainly nephrotoxicity, which leads to the discontinuation of therapy.69 Despite its severe toxicities, it has been proven to be effective in variety of tumors and has not lost its use in clinical therapeutics. Cisplatin-induced nephrotoxicity is majorly associated with its metabolites to cause intracellular oxidative stress and subsequent vigorous inflammatory pathways in proximal tubular cells.70 Free radicals are believed to induce the intracellular signaling, of NF-κB and TNF-α, through P38 MAPK pathway and formation of DNA adducts which ultimately leads to pro-inflammatory cytokines release and apoptosis.71,72 In this regard, Sener et al. performed an animal study to evaluate whether melatonin can attenuate the cisplatin-induced nephrotoxicity.73 It was observed that cisplatin significantly depletes the renal GSH content while enhanced the malondialdehyde (MDA – lipid peroxidation), creatinine level, blood urea nitrogen (BUN) suggesting renal injury. The histological examination of kidney revealed the glomeruli shrinkage, vacuolization in proximal and distal tubular cells, disrupted microvili and leukocytes infiltration in parenchyma. Melatonin co-administration presented comparatively moderate cortical damage and leucocytes infiltration. However, with melatonin pre- and post-treatment in cisplatin administration, histological appearance was overall normal with fewer vacuolization and minor degeneration at the proximal and tubular cells. The biochemical profile of this group revealed the significant improvement in GSH levels and marked reduction in the MDA, creatinine and BUN as compare to cisplatin-only treated group. In this way Sener et al. documented the melatonin potential, which was more prominent when it was given before and after cisplatin, to ameliorate cisplatin induced nephrotoxicity. It is noteworthy that severity of cisplatin-induced nephrotoxicity is influenced by the physiological concentration of circulatory melatonin that in lower levels (e.g. pineal insufficiency or aging) may result into the more pronounced cisplatin-induced acute tubular necrosis (ATN). However, pre-treatment with exogenous melatonin has been found to significantly alleviate the cisplatin-induced nephrotoxicity even at suboptimal physiological concentration of circulatory melatonin.74 Hara et al. further investigated the comparative nephroprotective potential of melatonin and its metabolite, 6-hydroxymelatonin (6-OHM), that suggested the superior capacity of melatonin to recover the GSH/GSSH ratio and induction of GPx in cisplatin-induced nephrotoxicity.75 Electron spin resonance study revealed that OH. Free radical to be the main offender in cisplatin-induced oxidative insult and melatonin significantly suppressed the formation of OH adducts as compare to 6-OHM, mannitol and glutathione.76 Furthermore, in vivo study elucidated the more detailed underlying nephroprotective mechanism of melatonin against cisplatin. Melatonin was found to enhance the nuclear concentrations of activated nuclear factor-E2-related factor (Nrf2) which amplified the expression of antioxidant enzymes, i.e. heme oxygenase (HO-1) through nuclear activation of antioxidant response element (ARE) (Fig. 2). It was suggested that melatonin ameliorates the cisplatin-induced nephrotoxicity by inhibiting the nuclear-factor κB (NF-κB) and activator proteins (AP-1) along with augmentation of Nrf2/HO-1 signaling in the kidneys of cisplatin treated rats.77 Therefore, melatonin tends to improve the nephroprotective pathways which serves to counterbalance the cisplatin dose-related nephrotoxicity and extends the therapeutic index of cisplatin.

Fig. 2.

Transcriptional control of Melatonin (M) to alleviate cisplatin-induced nephrotoxicity. Melatonin inhibits the cisplatin-induced production of NF-κB and AP-1 while induces the expression of Nrf-2 to mediate the ARF derived activation of HO-1 in alleviation of cisplatin-induced nephrotoxicity.

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Ifosfamide is an structural analogue of cyclophosphamide that is widely used antineoplastic agent in various malignancies such as breast cancer, non-small cell lung cancer, soft tissue sarcomas but its effectiveness has been compromised by its nephrotoxicity.78–81 It is a prodrug that is metabolized into active but toxic metabolite chloracetaldehyde (CAA) in order to produce its pharmacological antitumor effect.82 Ifosfamide conversion into nephrotoxic chloracetaldehyde (CAA), mainly in renal proximal tubules, results into renal dysfunction that is associated with oxidative stress and impaired tubular transporters functions which is most commonly presented as Fanconi's syndrome.83–85 Sener et al. investigated putative role of melatonin in alleviation of ifosfamide induced nephrotoxicity in an animal study that involved the biochemical and histological considerations.86 Ifosfamide 50mg/kg for 5 days induced the GSH depletion and severe lipid peroxidation, myeloperoxidase activity, fibrosis which implied the marked oxidative stress and neutrophil infiltration. Moreover, ifosfamide was also found to severely impaired the tubular reabsorption by diminishing the activity of Na+-K+ ATPase which results into defective and enhanced urinary excretion of glucose, calcium, phosphate and plasma proteins, i.e. Fanconi's syndrome. Increase in oxidative stress and inflammatory process resulted in renal morphological degeneration such as vascular congestion, glomerular degeneration and tubular interstitial oedema which were alleviated with melatonin (10mg/kg) co-administration. Melatonin co-administration reversed the GSH depletion and significantly reduced MDA, myeloperoxidation, abnormal collagen accumulation thereby attenuating oxidative stress, inflammation and tissue fibrosis. Apart of this, melatonin concomitant administration was also shown to restore the Na+-K+ ATPase activity which improved the tubular re-absorption process and subsequently attenuated the Fanconi's syndrome. These finding suggested that melatonin can be effectively use as nephroprotective adjunct to ameliorate the oxidative stress, inflammatory process and renal metabolic impairments in ifosfamide nephrotoxicity.

Anthracycline are broadly used antineoplastic agents that are effectively used to treat variety of solid and hematological malignancies. The therapeutic vitality of these antineoplastic agents, such as daunorubicin and doxorubicin, has been compromised by increased resistance and dose-dependent toxicities including severe nephrotoxicity.87 The mechanism of anthracycline associated nephrotoxicity is not clearly understood but it has been proposed that anthracycline metabolism may induce the mitochondrial toxicities such as membrane disruption, impairment of calcium homeostasis, induction of free radical, lipid peroxidation and release of cytochrome C that may contribute toward apoptosis or necrosis of glomerular and tubular cells.88–90 Montilla et al. first time reported the melatonin potential to ameliorate the doxorubicin (adriamycin) induced nephrotoxicity in terms of oxidative stress and hyperlipidemia.91 In this study melatonin co-administration was found to attenuate the adriamycin-induced oxidative stress by reducing the lipid peroxides and recovering the depleted GSH and CAT activity. Moreover, melatonin co-administration also efficiently recovered the depleted high density lipoprotein-cholesterol (HDL-C) and condensed the higher levels of total cholesterol (TC) and triglycerides (TG) except phospholipids (PL) which were induced in adriamycin nephropathy (Fig. 3). In addition to this, simultaneous melatonin administration also restored the normal serum creatinine, urea, total proteins and urinary protein in adriamycin treatment thereby limits the adriamycin induced nephrotic syndrome. Together these findings demonstrated that melatonin may impart protection against oxidative stress, nephrotic syndrome and hyperlipidemic nephropathies of adriamycin. In addition to doxorubicin, Dziegiel et al. also studied the daunorubicin and the putative nephroprotective role of melatonin in their toxicities.92 Biochemical investigations revealed that melatonin prevented the amplification of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA) which were increased due to lipid peroxidation by sub-chronic administration of daunoruicin and doxorubicin. This protection was further supplemented with histological data which revealed the melatonin co-administration alleviate the protein deposits in lumen of tubules and glomerular vacuolization in nephrotoxicity of daunoruicin and doxorubicin. Hrenak et al. further substantiated the nephroprotection of melatonin, against doxorubicin, and revealed that melatonin offer the nephroprotection comparable to other reno-protective drugs such as captoprils, olmesartan and compound 21.93 Taking all these findings into considerations, authors suggested that melatonin addition into the daunorubicin and doxorubicin treatment may provide excellent protection to avoid their renal toxicities.

Fig. 3.

Melatonin (M) attenuates the Anthracycline-induced renal dysfunction. Melatonin blocks the Anthracycline-induced lipid peroxidation, nephrotic syndrome and impairments in lipid profile to attenuate the development of renal dysfunction.

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Methotrexate is, a dihydrofolate reductase inhibitor, extensively studied and clinically useful cytotoxic drug in multiple cancers (such as breast cancer, acute leukemia, head and neck carcinoma) and autoimmune diseases. Most of the cancers required higher doses of methotrexate which may induce the renal dysfunction and subsequently decreases its renal clearance. Reduced renal clearance of methotrexate has been associated to increase its half-life and making leucovorin ineffective which may induce the further toxicities such as myelosuppression, mucositis and more pronounced nephrotoxicity.94 Higher plasma concentration of methotrexate significantly decreases the NADPH production and subsequent depletion of GSH that ultimately results into impaired antioxidant defense system and cellular oxidative stress.95 Jahovic et al. suggested the melatonin (10mg/kg) potential to ameliorate the methotrexate associated GSH depletion, lipid peroxidation and myeloperoxidation.96 However, a more extensive study was conducted by Abraham et al. to investigate the melatonin ability to regulate the antioxidant defense system and evaluate its nephroprotective role in higher doses of methotrexate.97 In addition to previously studied biochemical parameter, they found that methotrexate severely reduced the cellular content of antioxidant enzymes such as SOD, CAT, GPx, GRd and GST. Apart of these biochemical impairments, methotrexate also caused the severe cortical glomerulo-tubular nephritis and medullary tubular edema and distention. Interestingly, when melatonin was co-administered, it significantly recovered the enzymes of cellular antioxidant defense system and alleviated the histopathological complications of methotrexate nephrotoxicity. It was found that melatonin does not only recover the antioxidant enzymes but also stimulate them to eradicate the cellular oxidative stress in methotrexate nephrotoxicity. Therefore, authors concluded that co-administration of melatonin in high dose methotrexate treatment might attenuate the nephrotoxicity and enhance the safety of methotrexate.

Mechlorethamine is a chemical warfare and strong DNA alkylating antineoplastic agent that has limited effectiveness due to its toxicity in healthy tissue owing to its vesicant property.98,99 Kunak et al. performed a study which not only highlighted the nephrotoxic behavior of mechlorethamine, but also investigated the protective role of melatonin and S-methylisothiouria (potent iNOS inhibitor) by taking biochemical and histological data into consideration.100 Transdermal administration of mechlorethamine 3.5mg/kg demonstrated the severe induction in TNF-α, IL-1β and NO and morphological damages such as glomerulo-peritubular congestion and mild mesangiolysis. In the present study, melatonin co-administration after 30min of mechlorethamine showed significant reductions in TNF-α to a level even lower than S-methylisothiourea. Moreover, simultaneous administration of melatonin also decreased the IL-1β levels comparable to the S-methylisothiourea co-administration in mechlorethamine nephrotoxicity. Although melatonin also significantly limits the NO levels but this rescue was comparatively lower than S-methylisothiourea. In addition to these biochemical parameters, melatonin and S-mehtylisothiourea were also found to mitigate the morphological abnormalities which suggested that melatonin does not only attenuate the oxidative stress but also alleviate the inflammatory injuries in mechlorethamine nephrotoxicity.

Aminoglycosides are widely used antibiotics against most gram negative bacterial infections due their low bacterial resistance and potent bactericidal properties. Therapeutic benefits associated with the use of aminoglycoside have been restricted due to their high propensity to cause serious nephrotoxicity.101 Gentamicin, a strong cationic moiety, is mostly considered as prototype drug in studies of aminoglycosides associated nephrotoxicity as it is most nephrotoxic among this group.102 Gentamicin is believed to cause nephrotoxicity by its accumulation mainly in renal proximal tubular cells which results into lysosomal phospholipidosis mediated mitochondrial oxidative/nitrosative stress and subsequent inflammatory cascade and apoptosis.103 Shiffow and co-workers found that gentamicin cause severe degenerative granulation of renal cortex with marked lipid peroxidation. Biochemical analysis of rats, treated with gentamicin alone, revealed the significant elevation of malondialdehyde (MDA), reduction in creatinine clearance, increased blood urea and enhanced N-acetyl-β-D-glucosaminidase (β-NAG) renal excretion. However, these biochemical changes were reversed or significantly prevented when gentamicin was co-administered with melatonin. Simultaneous administration of melatonin and gentamicin revealed the marked reduction in the cortical granular degeneration and necrosis.104 Moreover, melatonin was also found to restore the enzymatic activity of antioxidant enzymes, i.e. SOD, CAT and GPx which were compromised in gentamicin induced oxidative stress.105 Ozbek et al. also found the melatonin role to moderate serum γ-glutamyltranspeptidase levels in gentamicin induce nephropathy that may suggest the possible mechanism to restore the GSH levels. Taking these findings into consideration, Sener et al. investigated the modulation of biochemical parameters to further elucidate the nephroprotective mechanism of melatonin against gentamicin. In addition to protection against lipid peroxidation, their investigation revealed that melatonin pretreatment demolishes the up regulated activity of myeloperoxidase (MPO) which is correlated to neutrophil infiltration in gentamicin nephropathy. In addition, Protein carbonyl concentration (indicator of protein oxidation – PO), was also decreased with melatonin pretreatment which suggests the melatonin potential to protect proteins from gentamicin induced oxidative damage.106 These finding substantiated the hypothesis of these researchers and suggested that melatonin may provide nephroprotection against gentamicin. Nephropathic pattern of amikacin is related to that of gentamicin but, comparatively, with lower nephrotoxicity.107 Parlakipnar et al. performed an animal study to investigate the melatonin physiological and pharmacological concentration relationship in attenuation of amikacin induced nephrotoxicity.108 It was found that amikacin treated rats with lower physiological concentration of melatonin, when given exogenous melatonin, showed significant improvements in GSH levels and reductions in lipid peroxidation. On the other hand, these improvements were not seen, when exogenous melatonin was given, in the amikacin treated rats with normal melatonin physiological concentration. This interplay of pharmacological and physiological concentration of melatonin has indicated the researchers to further investigate the role of exogenous melatonin to attenuate the amikacin induced nephrotoxicity in normal physiological concentration of melatonin.

Colistin, aka polymixin E, is a peptide antibiotic that is used as last resort in infections of multidrug resistant gram negative microbes such as Pseudomonas aurigenosa, Klebsiella pneumonia and Acinetobacter baumannii. It has been suggested, with emergence of resistance against colistin suboptimal plasma concentration following current recommended regimen, to increase the recommended dose which is, however, limited due to its severe nephrotoxicity.109,110 Mechanism of colistin nephrotoxicity involves the increase cellular membrane permeability in tubular epithelium, increase in nitric oxide synthase (NOS) and increase caspase activity which results into cellular swelling, lysis, oxidative stress and subsequent apoptosis or necrosis of renal tubules.111 Yousef et al. evaluated the protective role of melatonin against colistin-induced nephrotoxicity through biochemical, histopathological and pharmacokinetic studies in an animal model.112 In preliminary studies, they determined the nephrotoxic potential of four different regimens of colistin to benchmark the regimen for reproducible nephrotoxicity. Accordingly, the increasing twice daily dose with cumulative 36mg/kg dose of colistin for 7 days caused the significant increase in serum creatinine and 2.4-fold elevation in N-acetyl-β-D-glucosamindase (NAG) renal excretion which were further substantiated with cortico-tubular necrosis in histopathological studies. In pharmacokinetic studies, significant urinary excretion of colistin was observed when it was administered alone. More interestingly, plasma concentration vs. time studies revealed the 2.5-fold increase in colistin plasma concentrations with 10mg/kg melatonin co-administration which suggested the increase in half life and decreased clearance of colistin. In addition to this, biochemical and histopathological parameters were also significantly improved with melatonin co-administration. Therefore, these finding proposed that melatonin co-administration may reduce the nephrotoxicity of colistin through pharmacokinetic modification. However, the mechanism by which melatonin alter the pharmacokinetics of colistin is still poorly known and needs further investigations into this domain. Moreover, the melatonin mediated scavenging of free radicals, in colistin induced oxidative stress, also require further studies in order to further explore its protective behavior in colistin nephrotoxicity.

Vancomycin is a glycopeptide antibiotic reserved for serious resistant gram positive infection such as methicillin-resistant staphylococcus aureus, enterococcus faecium and methicillin-resistant coagulase negative staphylococci. Vancomycin use has been reported to cause severe but reversible dose and duration limiting nephrotoxicity which compromise its therapeutic potential.113 Nephrotoxicity mechanism of vancomycin is suggested to be associated with its increase uptake in renal proximal tubular cells which induces the oxidative phosphorylation and generation of free radicals. Free radicals mediate the mitochondrial membrane depolarization and release of cytochrome C which in turn activate and induce the apoptosis process.114,115 A single study has reported the protective role of melatonin against vancomycin-induced nephrotoxicity in comparison with other important antioxidants.116 Intraperitoneal administration of vancomycin 10mg/kg, for 7 days, severely enhanced the serum creatinine, urea and malondialdehyde (MDA) levels which indicated the impaired renal function and cellular injury. In addition to this, vancomycin was also found to reduce cellular superoxide dismutase and glutathione peroxidase levels that implied the weaken antioxidant system. Co-administration of melatonin 10mg/kg resulted in restoration of creatinine excretion, MDA levels, SOD and GPx activity comparable to control group. Melatonin was found to be most effective in restoring the creatinine and glutathione (GSH) levels as compare to ginkgo biloba, α-lipoic acid and amrinone. However, melatonin mediated restoration of MDA, urea, superoxide dismutase (SOD) was comparable to ginkgo biloba and amrinone but more than α-lipoic acid. Therefore, this study provided some key findings to evaluate the nephroprotective effect of melatonin as compare to other important antioxidants and suggested that melatonin co-administration can be effective adjunct to compensate the vancomycin nephrotoxicity and improve the effectiveness of vancomycin.

Ciprofloxacin is broad spectrum fluoroquinolone antibiotic, effective against gram negative and gram positive micro-organisms. Acute renal failure is, a dose limiting adverse effect, considered one of most common toxicity that complicates the treatment with ciprofloxacin. Mechanism of ciprofloxacin toxicity is not clearly understood but is manifested as crystal nephropathy, interstitial nephritis and renal failure.117–120. Shaki et al. conducted a study to elucidate the mechanism of ciprofloxacin nephrotoxicity and its attenuation by melatonin co-administration.121 They found that ciprofloxacin 100mg/kg/day, for 8 days, significantly increase the serum creatinine and BUN levels which were effectively restored with melatonin 10mg/kg co-administration. Amplification of lipid peroxidation, protein carbonyl concentration, reactive oxygen species and depletion of GSH were also observed with ciprofloxacin administration and these were also alleviated with melatonin co-administration. Besides melatonin co-administration, vitamin E co-administration was also investigated to compare the effectiveness of melatonin. Although Vitamin E, comparable to melatonin, lowered the lipid peroxidation, reactive oxygen species and protein carbonyl concentrations but it was ineffective to restore the creatinine, BUN and GSH. Moreover, tissue necrosis factor alpha (TNF-α) and nitric oxide were also significantly increase in ciprofloxacin administration which were effectively prevented with melatonin co-administration. These findings were further endorsed with significant reduction in severity of tubular dilation, epithelial degeneration, hyaline granules and necrosis by melatonin co-administration. Therefore, together all these findings proposed that ciprofloxacin may induced nephrotoxicity through increased generation of free radicals, nitric oxide, TNF-α and stimulate the inflammatory process which can be effectively attenuate by melatonin co-administration owing to melatonin's antioxidant effect.

Tenofovir, a nucleoside reverse transcriptase inhibitor (NRTI), is effectively used in HIV and Hepatitis B viral infections. The therapeutic efficacy of tenofovir has been limited by its dose and time related nephrotoxicity which is manifested by Fanconi's syndrome, nephrogenic diabetes inspidus and acute tubular necrosis.122 Nephrotoxicity of tenofovir implies the reduced efflux transport activity of multidrug resistant proteins (i.e. MRP2, MRP-4) and enhanced activity of organic anion transporter (hOAT-1) in proximal tubules which results into the accumulation of tenofovir in tubular cells. Sub-cellularly, tenofovir inhibits the mitochondrial DNA polymerase-γ mediated replication of mitochondrial DNA (mtDNA). Subsequently it reduces the mitochondrial enzymatic content for oxidative phosphorylation and electron transport chain which ultimately leads to the impaired mitochondrial function and oxidative cellular injuries.123 Ramamoorthy et al. found that 600mg/kg oral tenofovir was able to induce the Fanconi syndrome, acute tubular nephrotoxicity and renal dysfunction and these abnormalities were effectively countered by melatonin pretreatment.124 Biochemical data revealed that tenofovir induce the urinary potassium, phosphate, bicarbonates, urea and serum uric acid which were restored, except phosphate, with melatonin (20mg/kg) pretreatment. Melatonin also completely restored the tenofovir associated twofold increased protein carbonylation and nine fold increased myeloperoxidase activity that explained the melatonin's ability to attenuate the tenofovir induced oxidative stress and inflammation. Following tenofovir administration GSH levels and activity of major antioxidant enzymes, such as SOD, GPx, GRd and GST, were reduced to about half of their physiological activity. Melatonin pre-treatment significantly improved the activity of GST and GRd whereas it was found ineffective against tenofovir induced reductions in the SOD, GPx activity and GSH levels. Apart of its effect on oxidative stress, melatonin also strongly inhibits the 50% rise of nitrosative stress in tenofovir nephrotoxicity. Histopathological data also revealed the melatonin ability to alleviate the severity of cytosolic vacuolization, mitochondrial swelling, cristae fragmentation, epithelial disruptions and interstitial oedema in tenofovir induced nephrotoxicity. Therefore, together, these investigations suggested the melatonin potential to ameliorate the oxidative, nitrosative and inflammatory damages of tenofovir nephrotoxicity.

Cyclosporin, a calcineurin inhibitor, is effectively used immunosuppressant in prevention of allograft rejection of most solid organs and autoimmune aggravations. Cyclosporin has proven its therapeutic efficacy in prevention of transplantation rejection for short period which is limited by its severe dose-dependent deleterious nephrotoxicity in long term use.125–127 Mechanism underlying the cyclosporine induced nephrotoxicity involves the reversible hemodynamic impairments and irreversible tubule-interstitial chronic inflammation and fibrosis. Renal hemodynamic damages are associated with the marked vasoconstrictions mediated by provoked renin–angiotension–aldosterone system (RAS), cyclooxygenase pathway and reduced nitric oxide (NO) which further induced the ischemic oxidative damage, macrophage infiltration and acute inflammatory cascades. However, long-term use of cyclosporine may impart the chronic inflammation which may further induce irreversible tubulo-interstitial fibrosis and scarring in cortico-medullary area by profibrogenic mediators such as TGF-β.128 Kumar et al. first time investigated the nephroprotective capacity of melatonin in cyclosporine induced nephrotoxicity.129 In this animal study, melatonin was found to attenuate the cyclosporine-induced lipid peroxidation and cortico-medullary microcalcification. In addition to this, cyclosporine was also found to impair the renal function implied by elevated blood urea and reduction in creatinine and lithium clearance which were improved by the melatonin co-administration. Subsequently, another study also reported the melatonin ability to reduce the lipid peroxidation and improve the renal function during cyclosporine administration without compromising the effectiveness of cyclosporine.130 Stacchiotti conducted the electron microscopic analysis to reveal the effectiveness of melatonin to attenuate the cyclosporine-induced nephropathies at ultrastructural level.131 This morphometric study provided that melatonin alleviates the apoptotic nuclei, distended mitochondria, microvilli disruption, fused podocytes and glomerular basement membrane destructions in cyclosporine nephrotoxicity. Moreover, quantitative data suggested that melatonin may attenuate the cyclosporine induced tubule-interstitial fibrosis and atrophy. Longoni et al. further supported previous studies in an isolated and perfused rat kidney model to investigate the melatonin effect without any metabolic regulation.132 Lipid peroxidation was found to be the primary outcome of cyclosporine-induced nephrotoxicity which was manifested by elevated malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA). Moreover, morphological abnormalities, such as glomerular collapse and tubular damage, and NO metabolites were also fostered as part of nephrotoxicity progression. Pre-treatment with melatonin was found to significantly reduce the lipid peroxidation and morphological damages which they endorsed to the antioxidant property of melatonin. Besides, melatonin did not reveal any important reduction in reactive metabolites of NO. Therefore, authors concluded that melatonin might attenuate the oxidative damaged in cyclosporine nephrotoxicity. However, studies are needed to further investigate the possible mechanism of melatonin to attenuate the cyclosporine induced nephrotoxicity.

Tacrolimus is a calcineurin inhibitor which is broadly used in the heart, liver and kidney allograft transplantation. Tacrolimus associated immunosuppression involves the inhibition of calcium-calmodulin dependent phosphatase activity of calcineurin which ultimately modulate the intracellular calcium concentration, NF-κB translocation, IL-2 production and activation of T lymphocytes. Tacrolimus-induced nephropathy follows the similar molecular mechanism to cyclosporine but with lower nephrotoxic potential and less severe pathological manifestations.133 Ara et al. reported the intraperitoneal 5mg/kg tacrolimus was found to induce the MDA, IL-6, NO and TNF-α concentrations which were correlated to acute and chronic nephrotoxicity of tacrolimus.134 Whereas melatonin (4mg/kg) co-administration was shown to significantly reduce the NO, TNF-α and IL-6 concentrations owing to its nephroprotective potential against tacrolimus induced renal inflammation. But MDA levels, in tacrolimus co-administered with melatonin, were not significantly different from that of tacrolimus alone which implied that further investigations are needed to elucidate the melatonin ability to attenuate the tacrolimus induced lipid peroxidation or oxidative stress and its correlation to endogenous antioxidant defense.

Acetaminophen, N-acetyl-P-aminophenol, is widely and most commonly used antipyretic and analgesic drug. It has been reported to be the most common toxic ingestion and purported to be nephrotoxic in overall 1–2% cases of overdose. Nephrotoxic mechanisms of acetaminophen have been proposed to be associated with its renal CYP450 metabolism, activation through prostaglandin endoperoxidase synthetase and de-acetylation through N-deacetylase into reactive metabolites or free radicals.135 Sener et al. evaluated the protective role of melatonin in acetaminophen nephrotoxicity in an animal study while comparing its protective efficacy against vitamin E and N-acetyl cysteine.136 A single intraperitoneal 900mg/kg injection of acetaminophen was shown to significantly enhance the plasma MDA, tissue myeloperoxidase (MPO) activity and protein oxidation (PO) after 4h of administration while such damage was more evident after 24h. These enhanced biochemical parameters were accompanied with marked reduction in the GSH levels which implied the oxidative stress or renal damage. When 10mg/kg melatonin was given 30min before acetaminophen, it significantly restored the GSH and reduced the oxidative damage by lowering MDA, MPO activity and PO comparable to the N-acetylcysteine pretreatment while it was shown more effective than vitamin E pretreatment. Protective role of melatonin was further investigated with respect to its potential to induce the antioxidant enzyme system. Melatonin co-administration, with acetaminophen, was found to markedly stimulate the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) which were compromised in the acetaminophen administration only. Histopathological data of melatonin co-administration revealed the marked reduction in the acetaminophen induced vacuolization, degeneration, cellular desquamation and necrosis in proximal tubules. These studies suggested the nephroprotective activities of melatonin might be associated with its potent antioxidant properties which implied the melatonin to be a nephroprotective adjunct in the treatment of acetaminophen overdose.