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The protective effect of melatonin on renal ischemia-reperfusion in rat
Abstract
Oxygen free radicals are considered to be important components involved in the pathophysiological tissue alterations observed during ischemia-reperfusion (I/R). In this study, we investigated the putative protective effects of melatonin treatment on renal I/R injury. Wistar albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 1, 3, 6, 24, 48 hr or 1 wk of reperfusion. Melatonin (10 mg/kg, s.c.) or vehicle was administered twice, 15 min prior to ischemia and immediately before the reperfusion period. At the end of the reperfusion periods, rats were decapitated. Kidney samples were taken for histological examination or the determination of renal malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and protein oxidation (PO). Serum creatinine and blood urea nitrogen (BUN) concentrations were measured for the evaluation of renal function. The results revealed that I/R induced nephrotoxicity, as evidenced by increases in BUN and creatinine levels at each time point, was reversed by melatonin treatment. The decrease in GSH and increases in MDA, MPO and PO induced by I/R indicated that renal injury involves free radical formation. As melatonin administration reversed these oxidant responses, improved renal function and microscopic damage, it seems likely that melatonin protects kidney tissue against oxidative damage.
... Our observation of increased kidney MDA after IRI is in agreement with the previous study of Sener et al. (28), in which elevated levels of lipid peroxidation products were increased from 40 to 100% above basal values. ...
... Melatonin has been shown to act as a cytoprotective agent in IR-induced lesions, reversing the damage caused by IR nephrotoxicity (17). Also, Sener et al. (28) reported that melatonin has protective 4 Table 4. Histopathological assessment of control group (C), sham operation group (S), and renal ischemia-reperfusion groups with no pretreatment (IRI), ischemic preconditioning (IRI+Ipc), melatonin-pretreatment (IRI+M), or both preconditioning and melatonin pretreatment (IRI+Ipc+M) Number of rats in each group was eight (n=8). The Chi-square test (x^2) is used to compare between groups regarding the histopathological score effects on IR-induced renal injury and the histopathological changes are reversed by melatonin treatment. ...
... The Chi-square test (x^2) is used to compare between groups regarding the histopathological score effects on IR-induced renal injury and the histopathological changes are reversed by melatonin treatment. They (28) proposed that melatonin appears to play a cytoprotective role in the kidney insulted by IR. Supporting this proposal, it was realized that melatonin has protective effects on glomerular and tubular function. ...
Objectives:
Studying the effect of melatonin pretreatment and ischemic preconditioning on renal ischemia-reperfusion injury (IRI).
Materials and methods:
Forty-eight Wistar rats were randomized into six groups: control, sham operation, IRI (IRI in left kidney + right nephrectomy), IRI+ischemic preconditioning, IRI+Melatonin, and IRI+ischemic preconditioning+Melatonin groups. Melatonin (10 mg/kg) was intraperitoneally injected for 4 weeks before renal IRI. Ischemic preconditioning was performed by three cycles of 2 min-ischemia followed by 5 min-reperfusion period. A right nephrectomy was initially done and the left renal artery was clamped for 45 min. After 24 hr of ischemia-reperfusion, rats were decapitated. Kidney tissue samples were taken for histopathological assessment and the determination of kidney proinflammatory and anti-inflammatory cytokines, apoptotic protein caspase-3, oxidative stress markers, and activities of antioxidant enzymes. Serum creatinine and blood urea nitrogen (BUN) concentrations were measured for evaluation of renal function.
Results:
Renal IRI animals showed increased levels of creatinine, BUN, tumor necrosis factor-α (TNF-α), caspase-3, total nitrite/nitrate, and malondialdehyde (MDA), and decreased levels of interleukin-13 (IL-13), and activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD). Melatonin pretreatment or ischemic preconditioning resulted in decreased creatinine, BUN, TNF-α, caspase-3, nitrite/nitrate, and MDA, and increased IL-13, GPx, and SOD, with improved histopathological changes. Combined melatonin and ischemic preconditioning showed more effective improvement in renal IRI changes rather than melatonin or ischemic preconditioning alone.
Conclusion:
Combined melatonin and ischemic preconditioning have better beneficial effects on renal IRI than applying each one alone.
... An elevation in aspartate transaminase (AST), alanine aminotransferase (ALT) and low-density lipoproteins (LDL) caused by hepatic injury was found to be decreased with melatonin treatment (Sigala et al., 2006). Melatonin prevents the accumulation of neutrophils in damaged renal tissue (Sener et al., 2002b) and decreases lipid peroxidation and protein oxidation in the kidneys after drug-induced nephrotoxicity (Hara et al., 2001;Sener et al., 2002a). Furthermore, melatonin protects the kidneys against fibrosis due to its antiinflammatory properties (Ersoz et al., 2009;Hu et al., 2015). ...
... Various studies in humans and rodents have been shown that melatonin decreases free fatty acids (FFA), dyslipidaemia, triglycerides and very low-density lipoprotein (VLDL) (Agil et al., 2011;Mohammadi-Sartang et al., 2017;Sun et al., 2016). In the present study, the melatonin treatment included a significant decrease in serum lipid levels compared to the control, which correlates with studies conducted by Mylonas and Kouretas (1999) and Sener et al. (2002aSener et al. ( , 2002b. This decrease is most likely due to the action of melatonin to decrease body weight, reduce inflammation and increase lipoprotein lipase (LPL) activity (Mohammadi-Sartang et al., 2017; Sun et al., 2016). ...
... Thus, the smaller PCT parameters is indicative of the early stages of nephrotoxicity in the cART group, whereas no degradation of the PCT parameters were seen in the groups exposed to melatonin. As melatonin reduces nephrotoxicity caused by lipid peroxidation and protein oxidation (Hara et al., 2001;Sener et al., 2002b), it is expected that melatonin may have caused a cytoprotective action in the PCTs as seen in the melatonin group and combined treatment group of the present study. ...
Combination antiretroviral therapy (cART) has shown to cause inflammation, cellular injury and oxidative stress, whereas melatonin has been successful in reducing these effects. The aim of the study was to determine potential morphometric changes caused by cART in combination with melatonin supplementation in human immunodeficiency virus (HIV)-free rats. Tissue samples (N = 40) of the pancreas, liver and kidney from a control (C/ART-/M-), cART group (C/ART + ), melatonin (C/M + ) and experimental group (ART+/M + ) were collected and stained with haematoxylin and eosin (H&E) and evaluated for histopathology. The pancreata were labelled with anti-insulin and anti-glucagon to determine α- and β-cell regions. Kidneys were stained with periodic acid Schiff (PAS) to measure the area, perimeter, diameter and radius of renal corpuscles, glomeruli and proximal convoluted tubules (PCTs). Blood tests were conducted to determine hepatotoxicity. No significant changes in histopathology were seen. Melatonin stimulated pancreatic islet abundance, as the number of islets per mm2was significantly higher in the C/M+ than in the C/ART-/M- and ART+/M+. Parameters of the renal corpuscle, glomeruli, renal space and PCTs were significantly lower in the C/ART+ compared to the other groups, thus cART may have caused tubular dysfunction or cellular damage. A significant increase in serum haemoglobin was observed in the C/ART+ compared to the C/ART-, which showed cART increases serum haemoglobin in the absence of immune deficiency. Serum lipids were significantly decreased in the C/M+ compared to the C/ART-, possibly due to the effect of melatonin on the decrease of lipolysis, decreasing effect on cholesterol absorption and stimulation of lipoprotein lipase (LPL) activity. In conclusion, we have demonstrated that melatonin stimulated α-cell production, increased the number of pancreatic islets and caused a decrease in total lipids, whereas cART increased serum haemoglobin and decreased various parameters of the nephron in an HIV-free rat model, suggestive of tubular dysfunction.
... Because some study believed that mitochondrial reactive oxygen species (ROS) production during IRI plays an important role in kidney damage (48). On the other hand reperfusioninduced local inflammatory response in kidney tissue has been well documented previously in a number of studies (49). It has been shown that TNF-α and other cytokines play an important role in early I/R injury (49). ...
... On the other hand reperfusioninduced local inflammatory response in kidney tissue has been well documented previously in a number of studies (49). It has been shown that TNF-α and other cytokines play an important role in early I/R injury (49). Our previous study showed that GABA is able to reduce TNF-α and other cytokine in diabetic mice (20). ...
... Such finding was not observed by high dose of GABA possibly related to reverse action of antioxidant when use with high doses. Previous study (49) has been suggested to be closely related to lipid peroxidation, as a free radical generating system, and I/R induced tissue damage, and MDA is a good indicator of the rate of lipid peroxidation. ...
... Epithelial cells, particularly those of the S3 segment of the proximal tubule in the outer renal medulla, are particularly exposed to both ischemia and reperfusion phases of I/R injury, which can lead to acute tubular necrosis [69,70]; on the contrary, glomerular vessels degeneration was described only in the reperfusion phase [69]. Histopathological evaluation revealed the presence of extensive vascular dilatation, slight interstitial edema, tubular dilatation, tubular cell swelling, brush border, and nuclear loss [71]. ...
... Epithelial cells, particularly those of the S3 segment of the proximal tubule in the outer renal medulla, are particularly exposed to both ischemia and reperfusion phases of I/R injury, which can lead to acute tubular necrosis [69,70]; on the contrary, glomerular vessels degeneration was described only in the reperfusion phase [69]. Histopathological evaluation revealed the presence of extensive vascular dilatation, slight interstitial edema, tubular dilatation, tubular cell swelling, brush border, and nuclear loss [71]. ...
... As to the drugs acting on the ROS production and/or scavenging in the kidney, the pretreatment with the pineal hormone melatonin had a protective effect against oxidative damage caused by free radicals in a number of models both in vivo and in vitro of I/R injury: in particular, when administered prior to ischemia and immediately before the reperfusion, melatonin reduced the renal structural changes and limited the neutrophils infiltration [69]. ...
Ischemia and reperfusion (I/R) causes a reduction in arterial blood supply to tissues, followed by the restoration of perfusion and consequent reoxygenation. The reestablishment of blood flow triggers further damage to the ischemic tissue through reactive oxygen species (ROS) accumulation, interference with cellular ion homeostasis, and inflammatory responses to cell death. In normal conditions, ROS mediate important beneficial responses. When their production is prolonged or elevated, harmful events are observed with peculiar cellular changes. In particular, during I/R, ROS stimulate tissue inflammation and induce NLRP3 inflammasome activation. The mechanisms underlying the activation of NLRP3 are several and not completely elucidated. It was recently shown that NLRP3 might sense directly the presence of ROS produced by normal or malfunctioning mitochondria or indirectly by other activators of NLRP3. Aim of the present review is to describe the current knowledge on the role of NLRP3 in some organs (brain, heart, kidney, and testis) after I/R injury, with particular regard to the role played by ROS in its activation. Furthermore, as no specific therapy for the prevention or treatment of the high mortality and morbidity associated with I/R is available, the state of the art of the development of novel therapeutic approaches is illustrated.
... [7,9] Ayrıca, melatoninin farklı iskemi/reperfüzyon modellerinde SOR'un etkisizleştirici etkisi gösterilmiştir. [7,[9][10][11] CAPE, bal arısının oluşturduğu propolis maddesinden elde edilen ve SOR'un etkisizleştirici özelliğe sahip diğer önemli bir antioksidan moleküldür. [8,12] Çalışmamızda melatonin ve kafeik asit fenetil ester (CAPE) antioksidan moleküllerinin iskemik ortamda kırık iyileşmesi üzerine etkisinin incelenmesi amaçlandı. ...
... [19] Reperfüzyon, iskemik dokularda nötrofillerin birikimine ve endotel hücrelerinde ksantin oksidaz aktivitesinin art-Tablo 2. Gruplara göre radyoloji skoru ve 6. hafta histolojik skor değerlendirmesi. [11,[18][19][20] Kırık iyileşmesini hızlandırmak için birçok yazar farklı kimyasal ajanları kullanarak in vitro ve in vivo ortamlarda çalışmalar yapmıştır. Histing ve ark. ...
... Çeşitli deneysel çalışmalarla melatoninin iskemi üzerine olumlu etkileri gösterilmiştir. [6,10,11] CAPE, bal arılarının ürettiği propolisin etken moleküllerinden biridir. CAPE güçlü bir immunomodülatör, antikarsinojenik, antiinflamatuar ve antioksidandır. ...
Objective:
The aim of this study was to investigate the effects of antioxidant molecules melatonin and caffeic acid phenethyl ester (CAPE) on fracture healing under ischemic conditions.
Methods:
A right tibia fracture was created and fixed with an intramedullary pin in forty four male Wistar-albino rats. The rats were then randomly allocated to fracture, fracture-ischemia, fracture- ischemia-melatonin, and fracture-ischemia-CAPE groups. Ischemia was created by clamping femoral arteries four and a half hours. Animals were killed and radiographic, histological and biomechanical evaluation was performed sixth week after surgery.
Results:
The radiological and histological scores of the fracture-ischemia-CAPE group were significantly better than the fracture- ischemia group at 6th week follow-up. Complete radiographical and histological healing of all fractures was detected in all groups. There was a significant difference between the maximum fracture force between the groups (fracture-ischemia<fracture-ischemia-melatonin<fracture<fracture-ischemia-CAPE) (p<0.005). Although difference was not statistically significant between fracture and fracture-ischemia-CAPE groups, all other groups revealed statistically significant difference with respect to toughness (N/mm). Fracture-ischemia group revealed the lowest toughness.
Conclusion:
Ischemia adversely affects the fracture healing of rat tibias. Melatonin and CAPE eradicate adverse effects of ischemia. Possible adverse effects of ischemia on fracture healing can be eradicated with melatonin and CAPE in patients with tibia fractures associated with vascular injury or compartment syndrome.
... On the other hand, melatonin ameliorated histopathological disorders induced by IR injury compared to controls. The increases of urea and creatinine levels had been demonstrated in IR models which were caused by infrarenal aortic occlusion and the renal artery occlusion [29,[39][40][41]. Sezgin et al. showed that melatonin improved the increased urea and creatinine levels due to the renal clamping model [42]. ...
... The increased tissue levels of free oxygen radicals in acute and chronic inflammation were shown in many clinical and experimental studies [7,39,40,51,52]. One of the main causes of acute renal failure related to IR injury is the damage by free oxygen radicals [18,41]. Kurcer et al. [39] demonstrated that melatonin also reversed the tissue levels of TAS and TOS to control IR in kidneys in accordance to biochemical and histopathological improvement. ...
... Furthermore, there are many studies which had shown the antioxidant effect of melatonin [21,24,31,[53][54][55]. Sener et al. [41] also found that the level of malonyl dialdehyde (MDA) which is the end product of lipid peroxidation increased and the level of glutathione (GSH) which is an antioxidant decreased in renal tissue of IR-exposed rats, because of the consumption of this antioxidant molecule during inflammation. At the same time, they showed that melatonin application decreased the levels of MDA, while they did not detect any effect on the levels of GSH. ...
INTRODUCTIONAortic cross-clamping is frequently exerted during surgery of the abdominal aorta (AA). Ischemia–reperfusion (IR) damage, which is observed in the surgery of AA, is a complex situation and is considered not only in lower extremities but also in remote tissues and organs like the lungs, kidneys, heart, and liver [1–6]. IR damage leads to important morbidity and mortality because of its systemic complications [7, 8]. Acute renal dysfunction, which is one of the most important complications following elective surgery of AA, is still a frequently seen condition (15–22 %), but acute kidney injury (AKI) is relatively rare (1.8–4 %) [9, 10]. Infrarenal clamping of the aorta has been shown to decrease renal blood flow especially in patients who postoperatively developed renal failure [11–13]. This clamping procedure can cause vasoconstriction in renal arteries by forming turbulent flow in the aorta at the level of renal arteries [13].The mechanisms underlying IR-induced organ damag
... Increased serum and tissue levels of MDA have been reported in various studies following RIRI-induced oxidative stress. Different results of the studies are due to differences in ischemia model, ischemia duration, reperfusion duration, and even gender differences (Rhoden et al. 2002;Sener et al. 2002Sener et al. , 2006. Studies suggest that MDA levels may increase at the beginning of the reperfusion phase but then decrease. ...
... Studies suggest that MDA levels may increase at the beginning of the reperfusion phase but then decrease. One possible explanation may be the process of lipid peroxidation is involved in renal injury during the anoxia stage and before reperfusion (Sener et al. 2002;Tucci Junior et al. 2008). In addition, increasing activity of enzymes such as superoxide dismutase (Singh et al. 1993;Erdogan et al. 2006) or other antioxidant enzymes such as glutathione peroxidase, which was observed in the study conducted by Ne cas et al. (2005) reduces free radicals and lipid peroxidation and ultimately reduces MDA levels. ...
Renal ischemia-reperfusion injury (RIRI) as a pathological process induces remote organ injury such as lung complications and it is regulated in a hormone-dependent manner. This study investigates the effect of estrogen on RIR-induced pulmonary injury in ovariectomized (OV) rats. A total of 60 female Wistar rats were divided into six groups: (i) intact sham, (ii) OV sham, (iii) OV sham + estradiol valerate (E), (iv) intact ischemia, (v) OV ischemia, and (vi) OV ischemia + E. Bilateral ischemia was performed for 45 min in all groups except sham. Before the ischemia, OV groups received an intramuscular (i.m.) injection of E. After reperfusion, blood samples were collected for serum analysis and kidney and lung tissue were separated for pathological experiment and malondialdehyde (MDA) and nitrite measurement. The left lung was weighed to measure pulmonary edema. Estrogen deficiency caused a greater increase in blood urea nitrogen and creatinine levels during IRI. Ischemia reduced nitrite of serum and lung tissue. The increased level of MDA during ischemia, returned to normal levels via estrogen injection. The severity of renal and lung damage in ischemic groups increased significantly, and estrogen improved this injury. Estrogen as an antioxidant agent can reduce oxidative stress and may improve renal function and ameliorating lung damage caused by RIR.
... Melatonin was also found to regulate the enhancement of autophagy through the TLR4/MyD88/MEK/ERK/mTORC1 signaling pathway in ischemia-reperfusion injury when given prophylactically 45 . Another mechanism by which melatonin decreased the oxidative stress in renal ischemia-reperfusion injury was by the reduction in renal malondialdehyde (MDA), myeloperoxidase (MPO), and protein oxidation 64 . A few studies also observed an increase in glutathione production and a decrease in lipid peroxidation when melatonin was administered in renal ischemia-reperfusion injury 64,65 . ...
Acute kidney injury secondary to ischemia-reperfusion injury can occur after an infarction, sepsis or a renal transplantation. If not treated promptly, it can be fatal due to widespread oxidative tissue injury and inflammation. Melatonin, previously known for its circadian regulatory properties, has been of recent interest in preventing and treating renal ischemic reperfusion injury because of its antioxidant and anti-inflammatory properties. In this review we summarize the pharmacokinetic properties of melatonin, the pathophysiology of renal ischemic reperfusion injury and how we can use melatonin to prevent renal ischemic reperfusion injury. Furthermore, we discuss the recent clinical trials evaluating the impact of melatonin on the renal ischemic reperfusion injury. This review summarizes the current evidence on the beneficial effects of melatonin and prospects using melatonin to improve patient care and prevent fatalities from acute kidney injury. The initial data on the effects of melatonin in preventing and treating renal ischemic reperfusion injury looks promising. However, more randomized control trials on humans need to be conducted to evaluate the complete impact of melatonin on the renal ischemic reperfusion injury, the correct formulations, dosage and the possible adverse effects. Only then can melatonin be used as an agent to prevent renal ischemic reperfusion injury.
... Effect during Anti−Apoptosis in Kidney EP [65], Renal NOx [63], TAC [57] Increase Creatinine [56], Urea [66], MDA [60] Decrease * EP = epinephrine, MDA = manoldialdahyde, NOx = total nitrite/nitrate, TAC = total antioxidant capacity. ...
The present study aims to discover novel derivatives as antiapoptotic agents and their protective effects against renal ischemia/reperfusion. Therefore, a series of new thiadiazole analogues 2a–g was designed and synthesized through cyclization of the corresponding opened hydrazinecarbothioamides 1a–g, followed by confirmation of the structure via spectroscopic tools (NMR, IR and mass spectra) and elemental analyses. The antiapoptotic activity showed alongside decreasing of tissue damage induced by I/R in the kidneys of rats using N-acetylcysteine (NAC) as an antiapoptotic reference. Most of the cyclized thiadiazoles are better antiapoptotic agents than their corresponding opened precursors. Particularly, compounds 2c and 2g were the most active antiapoptotic compounds with significant biomarkers. A preliminary mechanistic study was performed through caspase-3 inhibition. Compound 2c was selected along with its corresponding opened precursor 1c. An assay of cytochrome C revealed that there is an attenuation of cytochrome C level of about 5.5-fold, which was better than 1c with a level of 4.1-fold. In caspases-3, 8 and 9 assays, compound 2c showed more potency and selectivity toward caspase-3 and 9 compared with 1c. The renal histopathological investigation indicated normal renal tissue for most of the compounds, especially 2c and 2g, relative to the control. Finally, a molecular docking study was conducted at the caspase-3 active site to suggest possible binding modes.
... Besides, melatonin can boost the immune system and plays a prominent role in regulating fluid nitrogen and acid-base balance. 11,13,24,[34][35][36][37][38][39] In the present study, we found that the sedative effect of melatonin was statistically significant, and a significant difference was observed between the melatonin and placebo groups. This was in line with the findings of previous studies that melatonin can reduce pain and anxiety levels and increase sedation. ...
Background:
Ischemic reperfusion injury (IRI) causes cellular damage and dysfunction. The present study aimed to evaluate the effect of melatonin on pneumatic tourniquet-induced IRI in orthopedic surgery of the lower extremities.
Methods:
A randomized clinical trial was conducted at Chamran Hospital, Shiraz University of Medical Sciences (Shiraz, Iran), from September to November 2019. The target population was patients scheduled for elective orthopedic surgery of the lower extremities. A total of 67 patients were randomly divided into two groups, placebo (n=34) and melatonin (n=33). The groups received 10 mg melatonin or placebo the night before surgery and two hours before surgery. Primary outcome variables were the serum levels of superoxide dismutase (SOD) and malondialdehyde (MDA). Hemodynamic parameters, sedation score, and drug side effects were also evaluated. Data were analyzed using SPSS version 21.0 software. P<0.05 was considered statistically significant.
Results:
In the analysis phase, due to loss to follow-up (n=26), 41 patients divided into two groups of melatonin (n=20) and placebo (n=21) were evaluated. There was no significant difference in demographic data, duration of surgery (P=0.929), and tourniquet time (P=0.496) between the groups. The serum levels of SOD and MDA were not significantly different between the groups (P=0.866 and P=0.422, respectively), nor were the incidence of postoperative nausea (P=0.588) and patients' satisfaction (P=0.088). However, the postoperative sedation score and vomiting between the groups were significantly different (P<0.001).
Conclusion:
Administration of 10 mg melatonin provided effective sedation, but had no significant effect on the serum levels of SOD and MDA, nor on pneumatic tourniquet-induced IRI in orthopedic surgery of the lower limbs.
Trial registration number:
IRCT20141009019470N87.
... In the present study, increased MDA concentrations were observed after IRI in untreated control groups of both WKY and L-NAME rats. This finding is consistent with previous published studies on the same IRI animal model [78][79][80][81][82][83]. Interestingly, increased levels of MDA were observed following NaHS treatment. ...
Our main objective was to investigate the effect of chronic administration of hydrogen sulphide donor (sodium hydrosulphide) on the expression of intercellular adhesion molecule-1 (ICAM-1) and concentration of nuclear factor-kappa B (NF-kB) in a renal ischemia-reperfusion injury (IRI) model of WKY and L-nitro-arginine-methyl-ester (L-NAME)-induced hypertensive rats. Sodium hydrosulphide (NaHS) was administered intraperitoneally (i.p.) for 35 days while cystathionine gamma lyase (CSE) inhibitor dL-propargylglycine (PAG) was administered at a single dose of 50 mg/kg. Animals were anesthetised using sodium pentobarbitone (60 mg/kg) and then prepared to induce renal ischemia by clamping the left renal artery for 30 min followed by 3 h of reperfusion. Pre-treatment with NaHS improved the renal functional parameters in both WKY and L-NAME-induced hypertensive rats along with reduction of blood pressure in hypertensive groups. Oxidative stress markers like malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glutathione (GSH) were also improved by NaHS treatment following renal IRI. Levels of ICAM-1 and NF-kB concentration were reduced by chronic treatment with NaHS and increased by PAG administration after renal IRI in plasma and kidney. Treatment with NaHS improved tubular morphology and glomerulus hypertrophy. Pre-treatment with NaHS reduced the degree of renal IRI by potentiating its antioxidant and anti-inflammatory mechanism, as evidenced by decreased NF-kB concentration and downregulation of ICAM-1 expression.
... Regarding its physiological role, MLT is a key regulator of the circadian rhythm (Reiter et al., 2010). For example, MLT plays a protective role in the body, including protecting the kidneys, through its powerful anti-inflammatory and antioxidative stress capabilities (Reiter et al., 1994(Reiter et al., , 2010Sener et al., 2002;Luchetti et al., 2010;Galano et al., 2011;Mauriz et al., 2013). In addition, numerous studies have confirmed that MLT affects the occurrence and development of cells and the biological functions of MSCs and oocytes in various ways (Luchetti et al., 2009(Luchetti et al., , 2014Shi et al., 2009;Rocha et al., 2013;Tian et al., 2014;Maria et al., 2018;Liu et al., 2019). ...
Abundant evidence proves the therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) in the treatment of diabetes mellitus. However, the problems have not been solved that viability of ADMSCs were inconsistent and the cells quickly undergo senescence after in vitro cell culture. In addition, the therapeutic effect of ADMSCs is still not satisfactory. In this study, melatonin (MLT) was added to canine ADMSC culture medium, and the treated cells were used to treat type 2 diabetes mellitus (T2DM). Our research reveals that adding MLT to ADMSC culture medium can promote the viability of ADMSCs. This effect depends on the binding of MLT and MLT receptors, which activates the transforming growth factor β (TGF-β) pathway and then changes the cell cycle of ADMSCs and improves the viability of ADMSCs. Since ADMSCs were found to be used to treat T2DM by anti-inflammatory and anti-endoplasmic reticulum (ER) stress capabilities, our data demonstrate that MLT augment several effects of ADMSCs in remission hyperglycemia, insulin resistance, and liver glycogen metabolism in T2DM patients. This suggest that ADMSCs and MLT-ADMSCs is safe and vabulable for pet clinic.
... In case of LDH, ELE significantly decreasd the elevated enzymatic activity, shown in the I/R group, reaching 229% of the normal group value. Effect of ELE on kidney antioxidant systems, GSH level; GST and SOD activities, in rats subjected to renal I/R; as indicated in table (5), the kidney antioxidant, GSH level; GST and SOD activities, were significantly decreased reaching 33%; 59% and 75%, respectively, of the normal control values by I/R. ELE increased significantly GSH level; GST and SOD activities reaching 56% 66% and 80%, respectively, of the normal control values. ...
Objective: In acute ischemic renal failure, loss of renal blood supply results in tissue hypoxia and leads to a complex cascade of events resulting in renal injury. As free radical scavengers are protective in renal ischemia / reperfusion (I/R) injury, the purpose of this study was to confirm the protective effect of Eriobotrya japonica aqueous leaves extract (ELE) against oxidative stress during ischemia /reperfusion injury of the kidney in Wistar rats. Materials and Methods: Nephrotoxicity is induced by occluding the left renal pedicle for 45 min to induce ischemia, followed by 90 min reperfusion. Renal superoxide dismutase (SOD); lactate dehydrogenase (LDH); glutathione-S-transferase (GST) activities; glutathione (GSH) and lipid peroxidation product, measured as malondialdehyde (MDA), determinants of possible renal tissue damage, were evaluated. Serum creatinine; urea and albumin levels were measured as indicators of nephrotoxicity. Serum potassium; calcium; chloride and sodium levels were also measured. In addition, histopathological examination of kidney sections of the different groups was carried out. Results: Results showed that ischemia / reperfusion produced significant deleterious changes in the histopathological examination, along with significant increase in serum creatinine, urea, sodium and renal MDA contents and LDH activity. Ischemia / reperfusion produced also significant decrease in serum potassium; calcium; renal GSH levels; GST and SOD activities. Eriobotrya japonica aqueous leaves extract administration could improve the histopathological examination, together with the protection of kidney tissue against most of the damaging effects caused by ischemia / reperfusion insults. Eriobotrya japonica aqueous leaves extract significantly increase serum albumin; renal GST; SOD activities and GSH content. In addition, significant decrease in serum creatinine; urea; renal MDA levels and LDH activity was observed in such treated group. Eriobotrya japonica aqueous leaves extract could not improve serum potassium; calcium; chloride or sodium levels. Conclusion: Eriobotrya japonica aqueous leaves extract showed nephroprotective efficiency, against ischemia/reperfusion-induced renal damage in Wistar rats.
... In line with this point, in the current study, we identi ed that IRI increased the production of kidney MDA of male rats in 3 h after reperfusion bot not in females. Kiris et al was observed enhanced MDA 30 and 60 min following reperfusion [27] also another study showed the peak of MDA enhancement take place 6 h reperfusion time [28]. These data was similar of our study suggesting that MDA increase the rst hours of reperfusion and then reduced. ...
Background
Renal ischemia/reperfusion injury (IRI) may influence distance organ such as lung. The severity of IRI induced - lung injury can be affected by gender. The aim of this study was to determine the role of gender in IRI induced- lung injury in different of renal reperfusion time.
Methods
80 male and female Wistar rats were assigned into 8 groups; 4 groups in each gender including sham, renal ischemia (ISC) for 45 min by clamping renal vessels followed by 3 hr, 24 hr or 48 hr reperfusion.blood samples were obtained for measuring the serum level of blood urea nitrogen (BUN), creatinine (Cr), nitrite, and malondialdehyde (MDA). The kidneys and lung tissues were removed and used for MDA and nitrite measurements and the histological changes evaluation.the percentage of lung water content was calculated.
Results
In both genders, the rise in Cr and BUN reached the peak at 24 h reperfusion. In 3 h reperfusion female rats, lead to significant increase in serum level of nitrite compared with males. In male rats subjected to 3 h reperfusion, the renal MDA level increased but not seen in females. The enhanced lung tissues damages were depended to reperfusion time in both genders. The water content of lung was reduced in 3 h of reperfusion groups.
Conclusions
IRI caused kidney and lung dysfunction depends on reperfusion time. Considering gender difference, female gender may be more sensitive to alteration of nitrite level compared with males. It seems that the effect of IRI is more rapid in males than females.
... By possessing antioxidant and anti-inflammatory properties, 66,67 melatonin was found to be a potent free radical scavenger and present protective effects in multiple dysfunctional organs, including the kidneys. 68,69 Immune function during the course of prostate cancer therapy has also been demonstrated. 70 Based on the fact that inflammation, oxidative stress, thermal injury and hypoxia are four main factors that cause the dysfunction of injected MSCs under disease conditions, preconditioning with melatonin may become a wonderful strategy. ...
Based on multiple studies in animal models, mesenchymal stem cell (MSC)‐based therapy appears to be an innovative intervention approach with tremendous potential for the management of kidney disease. However, the clinical therapeutic effects of MSCs in either acute kidney injury (AKI) or chronic kidney disease (CKD) are still under debate. Hurdles originate from the harsh microenvironment in vivo that decreases the cell survival rate, paracrine activity and migratory capacity of MSCs after transplantation, which are believed to be the main reasons for their limited effects in clinical applications. Melatonin is traditionally regarded as a circadian rhythm‐regulated neurohormone but in recent years has been found to exhibit antioxidant and anti‐inflammatory properties. Because inflammation, oxidative stress, thermal injury, and hypoxia are abnormally activated in kidney disease, application of melatonin preconditioning to optimize the MSC response to the hostile in vivo microenvironment before transplantation is of great importance. In this review, we discuss current knowledge concerning the beneficial effects of melatonin preconditioning in MSC‐based therapy for kidney disease. By summarizing the available information and discussing the underlying mechanisms, we aim to improve the therapeutic effects of MSC‐based therapy for kidney disease and accelerate translation to clinical application.
... Melatonin, the major secretion product of the pineal gland, is a direct scavenger of free radicals and an indirect antioxidant. When describing the role of melatonin as a scavenger, it should be noted that it can neutralize OH, superoxide anion radical, singlet oxygen, peroxyl radical, and OONO ± [16]. The finding of Dun-Xian Tan's study showed that melatonin has potent hydroxyl radicals scavenging ability compared to other well-known free radical scavenger such as glutathione and mannitol, however, the doses of melatonin used was much larger than its physiologic range. ...
Background:
One of the important factors in the occurrence of acute kidney injury (AKI) among renal transplant patients (RTPs) is ischemia reperfusion injury (IRI). The current study aimed at determining the anti-inflammatory and anti-oxidative effects of melatonin on the complications of IRI and the level of Klotho expression in these patients.
Methods:
A total of 40 renal transplant candidates were randomly assigned into placebo or melatonin group receiving the same dose of 3 mg/day. In order to measure serum melatonin levels, inflammatory and oxidative stress factors, renal function biomarkers, and Klotho gene/protein expression, venous blood samples were taken from patients over two different time points, i e, 24 h before the transplantation and at discharge from hospital.
Results:
Melatonin was associated with improvement in renal transplantation, since the serum level of neutrophil gelatinase-associated lipocalin, as a renal functional marker, significantly decreased (P < .001). The effect of melatonin as a suppressor of inflammation and oxidative stress was also evident in the melatonin group due to a significant reduction in the serum levels of MDA, CP, 8-OHdG, and TNF-α markers (P < .001).
Conclusions:
Reduction in serum levels of renal function and oxidative stress/inflammatory markers in the melatonin group indicates that melatonin can inhibit IRI outcomes in RTPs through its anti-oxidant and anti-inflammatory properties. However, these properties do not appear as a result of influence on the level of Klotho gene/protein expression.
... They are often used as a protective factor and antioxidant in many experiments and studies (Reiter et al., 2000;Cipolla-Neto and Amaral, 2018). Several recent studies propose that Mel prevents kidney injury (Sener et al., 2002), pancreatitis injury (Jung et al., 2010), and liver injury (Jung et al., 2009;Kang and Lee, 2012) by decreasing oxidative stress. In terms of neuroprotection, Mel has been reported to play an active role in several neurological disease, such as epilepsy (Brigo et al., 2016), Parkinson's disease (Mendivil-Perez et al., 2017), cerebral ischemia (Yang et al., 2015), intracerebral Hemorrhage (Wang Z. et al., 2018), and SAH (Dong et al., 2016;Zhao et al., 2017). ...
Secondary injuries mediated by oxidative stress lead to deterioration of neurological functions after intracerebral hemorrhage (ICH). Cortical astrocytes are among the most important cells in the central nervous system (CNS), and play key roles in maintaining redox homeostasis by providing oxidative stress defense. Hemin is a product of hemoglobin degradation, which has strong toxicity and can induce reactive oxygen species (ROS). Melatonin (Mel) and its metabolites are well tolerated without toxicity, prevent tissue damage as well as effectively assist in scavenging free radicals. We evaluated the hemin neurotoxicity to astrocytes and the resistance of Mel-treated astrocytes to hemin neurotoxicity. And we found Mel induced PKCα phosphorylation (p-PKC), nuclear translocation of Nrf2 in astrocytes, and upregulation of HO-1, which contributed to the reduction of ROS accumulation and cell apoptosis. Nrf2 and HO1 protein expression upregulated by Mel were decreased after administration of PKC inhibitor, Ro 31-8220 (Ro 31). Luzindole (Luz), a melatonin receptor inhibitor, suppressed p-PKCα, HO-1, and Nrf2 expression upregulated by Mel and increased cell apoptosis rate. The upregulation of HO-1 induced by Mel was depressed by knocking down Nrf2 expression by siRNA, which also decreased the resistance of astrocytes to toxicity of hemin. Mel activates astrocytes through PKCα/Nrf2/HO-1 signaling pathway to acquire resistance to toxicity of hemin and resist from oxidative stress and apoptosis. The positive effect of Mel on PKCα/Nrf2/HO-1 signaling pathway may become a new target for neuroprotection after intracerebral hemorrhage.
... It is important because of encountered frequently and high risk of mortality [1]. Renal I/R injury is occured during kidney transplantation, partial nephrectomy, renal artery angioplasty, cardiopulmonary bypass surgery, sepsis and some urological operations owing to interruption of renal blood flow temporarily and then return, results in acute renal failure [2]. ...
... [12][13][14] Since melatonin levels decline by aging, reduced plasma levels of melatonin was postulated to contribute in the development of post-menopausal osteoporosis. 15 In addition to its beneficial effects shown in several inflammation models [16][17][18] that operate through its antioxidant and free radical scavenging properties, melatonin inhibits bone resorption by suppressing osteoclast formation and osteoclastic activity via its free radical scavenging actions and by down-regulation of the receptor activator of nuclear factor-ĸB (RANK). [19][20][21][22][23][24] Because of these studies that have demonstrated the supportive effect of melatonin on bone remodelling and to several other studies that have verified its gastroprotective action, 25,26 the aim of the present study was to elucidate whether combined treatment with melatonin plus alendronate would have more advantageous effects than either treatment alone. ...
Abstract
The anti‐catabolic bisphosphonate alendronate is considered as the first‐line medical treatment in post‐menopausal osteoporosis; but several side effects, including gastric mucosal injury, are associated with its use. The aim was to elucidate whether combined treatment with melatonin plus alendronate would be more advantageous in the maintenance of bone and the prevention of gastric side effects. Under anaesthesia, female Sprague‐Dawley rats underwent bilateral ovariectomy (OVX), while control group had sham surgery. Four weeks after the surgery, OVX rats were treated with saline, melatonin (25 μg/mL/d), alendronate (70 μg/kg/wk), melatonin + alendronate, melatonin + melatonin receptor antagonist (luzindole, 10 μg/kg/d) or alendronate + melatonin + luzindole for 8 weeks. Rats were euthanized at the end of 12th week. Runx2 expression, apoptotic cells, and trabecular thickness were evaluated in tibiae, while gastric tissues were analysed for oxidative injury parameters. In all OVX groups, Runx2 expression was depressed. Saline‐treated OVX group presented an extreme decrease in calcified area in opposition to melatonin‐ or alendronate‐treated groups, while the bones in alendronate + melatonin‐treated group were similar to those of the sham‐operated group. Concomitant with the improvements examined histologically in bone tissues, quantitative TUNEL (+) cells were similarly lower in alendronate‐ or melatonin‐treated groups. Oxidative gastric damage was increased in saline‐ or alendronate‐treated groups, which were depressed in the presence of melatonin. Although melatonin and alendronate exerted similar supportive effects on the maintenance of bone mass, melatonin may have a more advantageous impact by protecting against OVX‐induced gastric injury, which was aggravated by alendronate use.
Highlights
Our results demonstrate that alendronate and melatonin had similar supportive effects on the maintenance of bone mass, while melatonin prevented the gastric side effects of alendronate, making this combination an advisable therapeutic approach in the treatment of menopausal osteoporosis.
... In studies of IR, antioxidant enzyme activity has been seen to fall following reperfusion, which has been associated with the increased use of these enzymes because of increasing oxidative stress. [21,22] In the present study, a reduction was determined in the activity of SOD antioxidant enzymes in the control group and an increase was determined in SOD enzyme activities in the treatment group. This finding supports IR studies in literature in general. ...
Background:
Montelukast is a selective leukotriene D-4 receptor antagonist, which specifically and reversibly inhibits cysteinyl leukotriene-1 receptor. The aim of this study was to investigate the protective effect of Montelukast on skeletal muscle reperfusion injury created as acute ischemia-reperfusion (IR) injury in Wistar-albino rats.
Methods:
The study comprised 16 male Wistar-albino rats. The rats were randomly separated into two groups as control (IR) and treatment (IR+Montelukast). Ischemia was obtained using a femoral artery clamp. After reperfusion following a 2-hour ischemia, muscle samples were taken for biochemical and histopathological analyses.
Results:
Malondialdehyde levels were determined to be at statistically higher levels in the control compared with that in the Montelukast group (p=0.002, p<0.01). The superoxide dismutase levels were determined to be at statistically higher level in the Montelukast group compared with that in the control group (p=0.001, p<0.01). In the histopathological examination of the ischemic muscles, edema, polymorinfiltration and erythrocyte extravasation levels were found to be statistically significant higher in the control group than in the Montelukast group. Edema, polymorphonuclear infiltration, and erythrocyte extravasation levels were observed to be significantly reduced in the treatment group compared with that in the control.
Conclusion:
In this model of skeletal muscle acute IR injury, the protective effect of Montelukast against skeletal muscle reperfusion injury was emphasized. We concluded that Montelukast could accelerate functional recovery in the extremity by limiting the local and systemic complications caused by reperfusion in cases such as extremity trauma with vascular injuries and extremity surgery with prolonged tourniquet application. However, further experimental and clinical studies are required to confirm this effect.
... Several studies have evaluated the effects of MEL alone or in combination with other substances on I/R injury [18][19][20] . Indeed, one previous study evaluated whether pretreatment with MEL reduced I/R injury 21 . In that study, which used an experimental IR model in rats, pre-treatment with 10 mg/kg MEL 10 minutes before ischemia attenuated histopathological changes and reduced biochemical indices. ...
Purpose:
To evaluate whether their combination was more effective than either alone in decreasing renal damage due to ischemia/reperfusion (I/R) injury in rats.
Methods:
Thirty-two Wistar rats were assigned to four groups. Following right nephrectomy, their left kidneys were subjected to warm ischemia (IR), cold ischemia (TH+IR), intraperitoneal injection of 10 mg/kg melatonin (MEL+IR), or injection of 10 mg/kg melatonin followed by cold ischemia (MEL+TH+IR). Eight randomly assigned right kidneys constituted the control group. After 240 min of reperfusion, left nephrectomy was performed for histopathological evaluation, lipid peroxidation, and measurement of antioxidant enzyme activity. Serum was collected to measure urea and creatinine concentrations.
Results:
Histopathological damage induced by ischemia and reperfusion was more attenuated in the MEL+TH+IR group than in the MEL+IR and TH+IR groups (p<0.037). Superoxide dismutase activity was significantly higher (p<0.029) and creatinine (p<0.001) and urea (p<0.001) concentrations were significantly lower in the MEL+TH+IR group than in the MEL+IR and TH+IR groups.
Conclusion:
The combination of melatonin (MEL) and topical hypothermia (TH) better protects against renal I/R injury than does MEL or TH alone.
... In studies of IR, antioxidant enzyme activity has been seen to fall following reperfusion, which has been associated with the increased use of these enzymes because of increasing oxidative stress. [21,22] In the present study, a reduction was determined in the activity of SOD antioxidant enzymes in the control group and an increase was determined in SOD enzyme activities in the treatment group. This finding supports IR studies in literature in general. ...
BACKGROUND: Montelukast is a selective leukotriene D-4 receptor antagonist, which specifically and reversibly inhibits cysteinyl leukotriene-1 receptor. The aim of this study was to investigate the protective effect of Montelukast on skeletal muscle reperfusion injury created as acute ischemia-reperfusion (IR) injury in Wistar-albino rats. METHODS: The study comprised 16 male Wistar-albino rats. The rats were randomly separated into two groups as control (IR) and treatment (IR+Montelukast). Ischemia was obtained using a femoral artery clamp. After reperfusion following a 2-hour ischemia, muscle samples were taken for biochemical and histopathological analyses. RESULTS: Malondialdehyde levels were determined to be at statistically higher levels in the control compared with that in the Montelukast group (p=0.002, p<0.01). The superoxide dismutase levels were determined to be at statistically higher level in the Montelukast group compared with that in the control group (p=0.001, p<0.01). In the histopathological examination of the ischemic muscles, edema, polymorinfiltration and erythrocyte extravasation levels were found to be statistically significant higher in the control group than in the Montelukast group. Edema, polymorphonuclear infiltration, and erythrocyte extravasation levels were observed to be significantly reduced in the treatment group compared with that in the control. CONCLUSION: In this model of skeletal muscle acute IR injury, the protective effect of Montelukast against skeletal muscle reperfusion injury was emphasized. We concluded that Montelukast could accelerate functional recovery in the extremity by limiting the local and systemic complications caused by reperfusion in cases such as extremity trauma with vascular injuries and extremity surgery with prolonged tourniquet application. However, further experimental and clinical studies are required to confirm this effect.
... Şekil 1. TAS düzeyleri (Sonuçlar X ± SD olarak verilmiştir. p<0.05 a,a1: p<0.001, c: p<0.05 İskemi/reperfüzyon üzerinde yapılan bir deneysel çalışmada, reperfüzyon sonrasında antioksidan enzim aktivitesinin azaldığı tesbit edilmiş, yükselen oksidatif stres sebebiyle bazı enzimlerin kullanımının artmasına bağlanmıştır (19,20). Literatürde yapılan bir başka araştırmada, ondört gün boyunca quercetinin verilen ratlarda SOD, CAT, GPx antioksidant gibi enzim aktivitelerinde önemli derecede yükseliş belirlenmiştir (21). ...
INTRODUCTION: It was aimed to determine the protective effectiveness of quercetin in preventing lower extremity ischemia-reperfusion (I/R) injury. METHODS: 30 Sprague-Dawley male rats weighing 250-350 g were divided into three groups. Anaesthesia was applied to the first group of rats without ischemia-reperfusion process. To the second group two hours of ischemia and two hours of reperfusion, with the help of left lower extremities tourniquet, were applied. To the third group, 50mg/kg (ip) quercetin application was performed 45 minutes before the ischemia was initiated, two hours of ischemia and two hours of reperfusion application were carried out. At the end of the process, by taking the tissue samples, total antioxidant status (TAS) and total oxidant status (TOS) levels were evaluated. RESULTS: When TAS was evaluated, it was determined that the decrease (p˂0.001) occurring in I/R group in comparison with the control group was significant, the decrease (p˂0.05) in I/R+Q group in comparison with control group, and again the increase (p˂0.001) in I/R+Q group in comparison with I/R group was also significant. When the TOS amounts were evaluated, it was determined that the increase (p˂0.001) occurring in I/R group in comparison with control group, the increase in I/R+Q group in comparison with control group (p˂0.05), the decrease in I/R+Q group in comparison with I/R group was statistically significant. DISCUSSION AND CONCLUSION: It has been determined that quercetin has protective effect and decrease the injury occurred in experimental Lower Extremity Ischemia- Reperfusion Injury in Rats.
... В экспериментальной работе G. Sener и соавт. (2002) показана способность МТ снижать окислительное повреждение почек, вызванное ишемией [29]. В то же время существует недостаток данных о сравнении и взаимодействии МТ с уровнем NGAL. ...
The survey considers the role of melatonine in human body and possibility to use exogenic melatonine to correct the effect of abiotic factor with ischemic heart disease. It also includes the experimental and clinical studies to use melatonine in therapy for treatment and prevention.
... On the other hand, the attenuating effect of EPO on the morphological changes in the renal tissue caused by IR injury has previously been reported (19,20). Sener et al. (21) reported that melatonin has protective effects on IR-induced renal injury, while the histopathological changes are reversed by MEL treatment. Additionally, they proposed that melatonin appears to play a cytoprotective role in the kidney injured by ischemia-reperfusion. ...
Background:
Renal ischemia-reperfusion (IR) contributes to the development of acute renal failure (ARF). Oxygen free radicals are considered to be the principal components involved in the pathophysiological tissue alterations observed during renal IR.
Objectives:
In this study, we compared the effects of melatonin (MEL) and erythropoietin (EPO), both known antioxidant and anti-inflammatory agents, on IR-induced renal injury in rats.
Materials and methods:
Wistar albino rats were unilaterally nephrectomized and then subjected to 45 minutes of renal pedicle occlusion followed by 24 hours of reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to the onset of ischemia. After 24 hours of reperfusion and following decapitation, blood samples were collected for the determination of the hemoglobin (Hb) and hematocrit (Hct) levels. Additionally, renal samples were taken for histological evaluation.
Results:
Ischemia-reperfusion significantly decreased the observed Hb and Hct values. The histopathological findings in the IR group confirmed that there was an increase in the hyaline cast and thickening of the Bowman capsule basement membrane. Treatment with EPO or MEL significantly increased the Hb and Hct values. In the MEL + IR group, the histopathological changes were lower than those found in the EPO + IR group.
Conclusions:
Treatment with EPO and MEL had a beneficial effect on renal IR injury. The results may also indicate that MEL protects against morphological damage better than EPO in renal IR injury.
... Damage due to radiation is a process which has direct relation to inflammation [13]. It has been referenced that melatonin decreases damage occurring due to inflammation in radiation and several inflammation models other than radiation (burn damage, sepsis, ischemia/reperfusion, etc.) [19,28,[30][31][32][33]. Since it can directly scavenge toxic free radicals which may cause inflammatory response and associated tissue destruction, melatonin decreases macromolecular damage in all organs [32,33]. ...
The aim of the present study was to evaluate the radioprotective effects of melatonin on the biomechanical properties of bone in comparison to amifostine (WR-2721). Forty Sprague Dawley rats were divided equally into 5 groups namely; control (C), irradiation (R; single dose of 50 Gy), irradiation + WR-2721 (R + WR-2721; irradiation + 200 mg/kg WR-2721) radiation + melatonin 25 mg/kg (R + M25; irradiation + 25 mg/kg melatonin), and radiation + melatonin 50 mg/kg (R + M50; irradiation + 50 mg/kg melatonin). In order to measure extrinsic (organ-level mechanical properties of bone; the ultimate strength, deformation, stiffness, energy absorption capacity) and intrinsic (tissue-level mechanical properties of bone; ultimate stress, ultimate strain, elastic modulus, toughness) features of the bone, a three-point bending (TPB) test was performed for biomechanical evaluation. In addition, a bone mineral density (BMD) test was carried out. The BMD and extrinsic properties of the diaphyseal femur were found to be significantly higher in the R + M25 group than in group R (p < 0.05). A significant increase was observed in R + M50 (p < 0.05) in comparison to group R in the cross-sectional area of the femoral shaft and elastic modulus parameter. The protective effect of melatonin was similar to that of WR-2721. Thus, biomechanical quality of irradiated bone can be ameliorated by free radical scavenger melatonin.
... Melatonin, which is an extremely strong antioxidant and a molecule with free radical scavenging characteristics, has receptors in a variety of tissues, including those of the kidney 26,35 . A number of previous studies of renal ischemia-reperfusion have reported the protective effects of melatonin on tissues 19,20,36 . The present study explored the combined effects of zinc and melatonin in preventing ischemia-reperfusion injury. ...
Renal ischemia-reperfusion directly affects glomerular and tubular epithelium. Oxygen free radicals have a significant part in the pathophysiology of renal ischemia-reperfusion injury. The present study aimed to identify the effects of 3-week zinc, melatonin, and zinc + melatonin supplementation on malondialdehyde (MDA) levels in tissue and plasma and glutathione levels (GSH) in erythrocytes and tissue of rats with experimentally induced renal ischemia-reperfusion injury. The study included Wistar albino rats with a mean weight of 250 g. Study groups were formed as follows: control, sham-control, ischemia + reperfusion, zinc + ischemia-reperfusion, melatonin + ischemia-reperfusion, and zinc + melatonin + ischemia-reperfusion. Animals were supplemented with zinc and melatonin 3 mg/kg/day i.p. for 3 weeks before the induction of ischemia-reperfusion. Renal ischemia-reperfusion was induced in the left kidney under general anesthesia and consisted of ischemia for 45 minutes and reperfusion for 1 hour. After the procedure, animals were sacrificed and blood and kidney samples were collected to analyze MDA and GSH levels. GSH values in kidney tissues and erythrocytes were found to be elevated in the groups supplemented with zinc and melatonin (p<0.005). When MDA values in renal tissue and plasma were examined, it was seen that ischemia significantly elevated this parameter, while zinc and melatonin supplementation significantly inhibited MDA values (p<0.002). The results of the study indicated that oxidative injury of the blood and renal tissues of rats increased in association with ischemia-reperfusion, but zinc and melatonin supplementation before ischemia-reperfusion markedly reduced this oxidative damage.
... Poor kidney function in the first week of graft life is detrimental to the longevity of the allograft (17). Because of this reason, agents proposed to be useful in the clinical setting of renal IRI, continues to investigate (16). ...
Although it is not performed as common as in humans, kidney transplantation is an effective treatment option for end-stage renal failure in dogs and cats. Ischemia/reperfusion injury is an inevitable result of kidney transplantation and it may cause delayed graft function that leads to a reduction in the longevity of allograft. In this study we aimed to evaluate the effects of Morinda citrifolia derived fruit juice on post-autotransplant ischemia/reperfusion injury. Twenty four adult, male Spraque-Dawley rats weighing 300-350 g were used. The rats were randomly divided into three groups of eight each. Rats in the Control Group were orally administered with saline solution (0.5 ml/day), for 7 days. Rats in M1 Group were orally administered with morinda citrifolia fruit juice (Alnoni, Hanojou-Europe Ltd, Dinxperlo, Holland), 0.5 ml/day, for 7 days whereas rats in M2 Group were orally administered with the same morinda citrifolia fruit juice (1 ml/day), for 7 days. In the 8th day, rats were anesthetized and orthotopic unilateral renal autotransplantation was performed. Rats were euthanized after 24 hour reperfusion and ischemic kidneys were sent for histopathological examination. Formalin-fixed paraffin-embedded tissue sections were evaluated and scored according to the parameters of tubular brush border loss, mononuclear cell infiltration, degeneration, hyalin formation in tubul lumens, thrombosis and tubular necrosis. Mononuclear cell infiltration in M2 group was found to be significantly different (P<0.05) than those of Control and M1 groups. Thrombosis was not observed in any of the histopathological sections. As a result, a significant improving effect on the ischemia/reperfusion injury of Morinda citrifolia fruit juice was not determined in rats after renal autotransplantation. © 2016, Chartered Inst. of Building Services Engineers. All rights reserved.
... The antioxidative supplementation had beneficial effects on the IRKI induced by the oxidative stress [145][146][147]. In the studies of Sener and Sahna it was shown that melatonin has antioxidative effect and that it reduced the renal damage during the IRKI [148,149]. The blocade of catecholamine release and inhibition of sympathetic nerve may be the other mechanisms which are influenced by melatonin, resulting in the renal protection against IRKI [150]. ...
Ischemic reperfusion kidney injury (IRKI) is a complex pathophysiological event, which is the most common cause of the acute kidney injury. The key characteristic of IRKI is a reduction in glomerular filtration rate, which implies an underlying impairment in hemodynamic regulation. In recent decades, convincing evidence illuminated the molecular and pathological events in the acute kidney injury, revealing the role of ischemia/reperfusion, oxidative stress, apoptosis, inflammation, fibrosis and changes in gene expression which activate different signaling pathways. The cascade of inflammation events is a key mediator of IRKI, which includes the inflammation process, complement activation and mobilization of innate immunity. Oxidative stress represents the increased presence of various free radicals that cannot be buffered by the antioxidant capacity which comprises of enzymatic and non-enzymatic components. Renal tissue injury during ischemia/reperfusion comes as a result of membrane lipids peroxidation, oxidative damage of proteins and DNA and results in apoptosis and necrosis. It is evident from many studies that augmentation of the antioxidant defense mechanisms has a protective role on kidney tissue. In recent years, the importance of heat-shock proteins and MicroRNAs in the pathogenesis of IRKI has been revealed and there are promising indications that in future they could serve as diagnostic biomarkers or therapeutic targets. Striking changes in global gene expression were shown, providing a great potential for fundamental understanding and clinical management of IRKI. The clinical outcome among patients with kidney transplantation will have the furthermost advance from the better understanding of the underlying molecular pathology of IRKI.
... Melatonin (MLT) has been reported to ameliorate renal ischemic re-perfusion injury through its radical-scavenging activity (9,10). However, only few studies have been conducted to investigate its roles in hypertension-induced renal injury (11). ...
The aim of the present study was to investigate the protective effects of melatonin (MLT) on hypertension-induced renal injury and identify its mechanism of action. Twenty-four healthy male Wistar rats were divided into a sham control group (n=8), which was subjected to sham operation and received vehicle treatment (physiological saline intraperitoneally at 0.1 ml/100 g), a vehicle group (n=8), which was subjected to occlusion of the left renal artery and vehicle treatment, and the MLT group (n=8), which was subjected to occlusion of the left renal artery and treated with MLT (10 mg/kg/day). Pathological features of the renal tissues were determined using hematoxylin and eosin staining and Masson staining. Urine protein, serum creatinine (Scr), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical analysis was performed to determine the expression of heme oxygenase‑1 (HO‑1), intercellular adhesion molecule‑1 (ICAM‑1), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Furthermore, reverse transcription polymerase chain reaction was conducted to determine the mRNA expression of HO‑1, ICAM‑1, eNOS and iNOS. A marked decrease in blood pressure was noticed in the MLT group at week 4 compared with that of the vehicle group (P<0.01). Furthermore, MLT treatment attenuated the infiltration of inflammatory cells and oedema/atrophy of renal tubules. MLT attenuated hypertension-induced increases in urine protein excretion, serum creatinine and MDA as well as decreases in SOD activity in renal tissues. Furthermore, MLT attenuated hypertension-induced increases in iNOS and ICAM‑1 as well as decreases in eNOS and HO‑1 expression at the mRNA and protein level. In conclusion, the results of the present study indicated that MLT had protective roles in hypertension‑induced renal injury. Its mechanism of action is, at least in part, associated with the inhibition of oxidative stress.
... Poor kidney function in the first week of graft life is detrimental to the longevity of the allograft (17). Because of this reason, agents proposed to be useful in the clinical setting of renal IRI, continues to investigate (16). ...
... There are numerous studies documenting the protective effects of melatonin against the ischemia-reperfusion-induced damage to various organs of the body, including brain [109][110], gastric mucosa [111,112], liver [113], kidney [114], and heart [115][116][117]. Though reports from human studies are limited, numerous animal model studies provide evidence of protective effect of melatonin against cardiovascular diseases [115][116][117]. ...
The antioxidant melatonin and the non-proteinogenic excitotoxic amino acid homocysteine (Hcy) are very distinct but related reciprocally to each other in their mode of action. The elevated Hcy level has been implicated in several disease pathologies ranging from cardio- and cerebro-vascular diseases to neurodegeneration owing largely to its free radical generating potency. Interestingly, melatonin administration potentially normalizes the elevated Hcy level, thereby protecting the cells from the undesired Hcy-induced excitotoxicity and cell death. However, the exact mechanism and cross talk between them remains obscure. Through a literature survey we have found an indistinct but a vital link between melatonin and Hcy i.e. the existence of reciprocal regulation between them, and this aspect has been thoroughly described herein. In this review, we focus on all the possibilities of co-regulation of melatonin and Hcy at the level of their production and metabolism both in basal and in pathological conditions, and appraised the potential of melatonin in ameliorating homocysteinemia-induced cellular stresses. Also, we have summarized the differential mode of action of melatonin and Hcy on health and disease states.
Copyright © 2015. Published by Elsevier Inc.
... Supplementations with antioxidants agents have protective effects in IRI induced oxidative stress (50)(51)(52). Oxygen free radicalmediated renal damage during the reperfusion period following ischemia was prevented by free radical scavengers and antioxidants activity of melatonin (53,54). In addition, inhibition of sympathetic nerve and decrease of catecholamine release (55) may be other mechanisms that melatonin protects renal against IRI. ...
Ischemia/reperfusion injury (IRI) is caused by a sudden temporary impairment of the blood flow to the particular organ. IRI usually is associated with a robust inflammatory and oxidative stress response to hypoxia and reperfusion which disturbs the organ function. Renal IR induced acute kidney injury (AKI) contributes to high morbidity and mortality rate in a wide range of injuries. Although the pathophysiology of IRI is not completely understood, several important mechanisms resulting in kidney failure have been mentioned. In ischemic kidney and subsequent of re-oxygenation, generation of reactive oxygen species (ROS) at reperfusion phase initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and acute kidney failure. Better understanding of the cellular pathophysiological mechanisms underlying kidney injury will hopefully result in the design of more targeted therapies to prevent and treatment the injury. In this review, we summarize some important potential mechanisms and therapeutic approaches in renal IRI.
... Melatonin, or N-acetyl-5-methoxytryptamine, an indole, the chief secretory product of the pineal gland, is a direct free radical scavenger and an indirect antioxidant that acts to stabilize cell membranes, thereby making them less susceptible to oxidative insult and ultimately suppressing inflammatory reaction [13,[17][18][19][20]. Previous experimental studies have identified the protective ability of melatonin against ischemia-reperfusion injury in multiple organs, including kidney, heart, and intestine [21][22][23][24]. However, whether melatonin therapy might be similarly effective against acute sepsis-induced lung injury remains unclear. ...
This study investigated whether combining melatonin and apoptotic adipose-derived mesenchymal stem cells (A-ADMSC) was superior to ADMSC alone in ameliorating sepsis-induced acute lung injury. Adult male Sprague-Dawley rats (n=50) were randomized equally into five groups: sham controls (SC), sepsis induced by cecal-ligation and puncture (CLP), CLP-melatonin, CLP-A-ADMSC, and CLP-melatonin-A-ADMSC. Circulating interleukin (IL)-6 at 6, 18, and 72 hrs, were highest in CLP and lowest in SC groups, higher in CLP-melatonin than CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups, higher in CLP-A-ADMSC than CLP-melatonin-A-ADMSC groups (all p<0.001). Immune reactivity (indicated by circulating cytotoxic-, and regulatory-T cells) and WBC count at 72 h exhibited the same pattern as that of circulating IL-6 (all p<0.001). Changes in histological scoring of lung parenchyma and the number of CD68+ and CD14+ cells showed a similar pattern compared to that of IL-6 level in all groups (all p<0.001). Changes in protein expressions of inflammatory (oxidative stress, RANTES, TNF-α, NF-κB, MMP-9, MIP-1, IL-1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF-β) markers and those of reactive-oxygen-species (NOX-1, NOX-2) displayed an identical pattern compared to that of circulating IL-6 in all groups (all p<0.001). Anti-oxidative capacities (GR+, GPx+, HO-1, NQO-1+) and angiogenesis marker (CXCR4+ cells) were lowest in SC group but highest in CLP-melatonin-A-ADMSC group, lower in CLP than CLP-melatonin and CLP-A-ADMSC groups, and lower in CLP-melatonin than CLP-A-ADMSC groups (all p<0.001). In conclusion, combined melatonin and A-ADMSC were superior to A-ADMSC alone in protecting the lung from sepsis-induced injury.
... Many substances have been used to prevent destructive changes in experimental renal I/R models. Urtica dioica L., melatonin, glutamine, aliskiren, dexamethasone, cannabidiol, sildenafil, sulfosalazine, and beta carotene are the most commonly used for such purpose [1,2,[26][27][28][29][30][31]. ...
Background and purpose
In our study, we investigated the effects of methylene blue (MB) on histopathological changes in renal ischemia/reperfusion (I/R) injury rat model.
Material and methods
Twenty-one Sprague–Dawley male rats were divided equally into three groups. Group 1 (control) was administered intraperitoneal saline solution. In Groups 2 (untreated group) and 3 (MB treatment), the renal arteries were clamped, and ischemia (for 1 hour) and then reperfusion (for 4 hours) were applied. Thirty minutes before ischemia, the untreated group received physiological saline, whereas the treatment group was administered 30 mg/kg MB through an intraperitoneal route. Blood samples were drawn, and renal specimens were harvested 5.5 hours after physiologic saline injection in the control and immediately after the reperfusion period in the other groups. The levels of tissue superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), total oxidant status (TOS), total antioxidant status (TAS), plasma urea, creatinine and ischemia modified albumin (IMA) were measured. Moreover, the histopathological damage score of the renal tissue was determined.
Results
MB significantly alleviated the severity of histopathological damage by increasing the levels of tissue SOD and TAS and decreasing TOS concentrations in the renal I/R model (p < 0.05).
Conclusion
Administration of MB in renal I/R damage may play a protective role.
... Our luminol-and lucigeninenhanced CL data support the notion that renal injury induced by I/R involves toxic oxygen metabolites. As a free radical generating system, lipid peroxidation has been suggested to be closely related with I/R-induced tissue damage, and MDA is a good indicator of the degree of lipid peroxidation [24,25]. In the present study we observed a significant increase in MDA content during I/R-induced renal injury, which is in agreement with the previous studies, where lipid peroxidation products were increased from 40 to 120% above basal values [26,27]. ...
There is increasing evidence to suggest that reactive oxygen metabolites (ROMs) play a role in the pathogenesis of ischemia/reperfusion injury (I/R) in the kidney. This study was designed to determine the possible protective effect of Ginkgo biloba extract (EGb) on renal ischemia/reperfusion (I/R) injury. Wistar albino rats were unilaterally nephrectomized, and 15 days later they were subjected to 45 min of renal pedicle occlusion followed by 6 h of reperfusion. Ginkgo biloba extract (EGb) (50 mg kg −1 day −1) or saline was administered twice, 15 min prior to ischemia and immediately before the reperfusion period. At the end of the treatment period, all rats were decapitated. Kidney samples were taken for histological examination or determination of the renal malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content. Production of reactive oxidants was monitored by chemiluminescence (CL) assay. Creatinine and urea concentrations in blood were measured for the evaluation of renal function. Tumor necrosis factor-(TNF-) and lactate dehydrogenase (LDH) were also assayed in serum samples. Ischemia/reperfusion caused a significant decrease in GSH level, which was accompanied with significant increases in MDA level, MPO activity and collagen content of kidney tissues. Similarly, serum BUN and creatinine levels, as well as LDH and TNF-, were elevated in the I/R group as compared to control group. On the other hand, EGb treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by I/R. The findings imply that ROMs play a causal role in I/R-induced renal injury and EGb exerts renoprotective effects probably by the radical scavenging and antioxidant activities.
... Moreover, attenuating effect of EPO on the morphological changes in renal tissue caused by IR injury has been reported (67). Sener et al (68) reported that melatonin has protective effects on IRinduced renal injury and the histopathological changes are reversed by MEL treatment. Also, they proposed that melatonin appears to play a cytoprotective role in the kidney insulted by ischemia reperfusion. ...
Objective(s): Renal ischemia reperfusion (IR) contributes to the development of acute renal failure (ARF). Oxygen free radicals are considered to be principal components involved in the pathophysiological tissue alterations observed during renal IR. The purpose of this study was to investigate the effect of co-administration of melatonin (MEL) and erythropoietin (EPO), potent antioxidant and anti-inflammatory agents, on IR-induced renal injury in rats.
Materials and Methods: Wistar albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 hr reperfusion. MEL (10 mg/kg, IP) and EPO (5000 U/kg, IP) were administered prior to ischemia. After 24 hr reperfusion, following decapitation, renal samples were taken for the determination of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) levels and histological evaluation. The level of urea was measured in serum samples.
Results: Ischemia reperfusion significantly increased urea, and MDA levels, and decreased CAT and SOD activities. Histopathological findings of the IR group confirmed that there was renal impairment in the tubular epithelium. Treatment with EPO and MEL markedly decreased urea level and increased SOD and GPx activities.
Conclusion: Treatment with EPO and MEL had a beneficial effect on renal IR injury. These results may show that the co-administration of MEL and EPO cannot exert more beneficial effects than either agent alone.
Iron overload as a highly risk factor, can be found in almost all human chronic and common diseases. Iron chelators are often used to treat iron overload; however, patient adherence to these chelators is poor due to obvious side effects and other disadvantages. Numerous studies have shown that melatonin has a high iron chelation ability and direct free radical scavenging activity, and can inhibit the lipid peroxidation process caused by iron overload. Therefore, melatonin may become potential complementary therapy for iron overload-related disorders due to its iron chelating and antioxidant activities. Here, the research progress of iron overload is reviewed and the therapeutic potential of melatonin in the treatment of iron overload is analyzed. In addition, studies related to the protective effects of melatonin on oxidative damage induced by iron overload are discussed. This review provides a foundation for preventing and treating iron homeostasis disorders with melatonin.
The aim of this study was to assess the protective effect and potential mechanism of melatonin against bisphenol A (BPA)‐induced apoptosis and oxidative damage in FLK‐BLV cells. The results showed that BPA reduced cell viability in a dose‐ and time‐dependent manner, caused cell shrinkage and induced oxidative stress and apoptosis in FLK‐BLV cells, which were effectively reversed by melatonin. In addition, BPA caused autophagy flux impairment, which was confirmed by the increased of LC3‐II and p62 levels, whereas melatonin treatment effectively reduced p62 levels under BPA treatment, and reversed apoptosis‐related protein expression patterns caused by BPA. However, inhibition of autophagy by CQ partially abolished the protective effect of melatonin on apoptosis, suggesting that melatonin against BPA‐induced oxidative injury and apoptosis by activating autophagy pathway. Moreover, we found that melatonin inhibited BPA‐induced the activation of p38 MAPK, which was comparable to SB203580 pretreatment, and companied by the activation of autophagy and decreases of apoptosis when compared to BPA alone, indicating that melatonin protected against BPA‐induced apoptosis partially through the p38 MAPK‐autophagy pathway. In conclusion, these results suggest that melatonin may prevent BPA‐induced FLK‐BLV cell damage by inhibiting p38/MAPK signaling pathway and activating autophagy, and it could be a potential therapeutic compound in preventing BPA‐induced cell damage.
Background: Renal ischemia-reperfusion (I/R) injury is one of the major causes related to acute kidney damage. Melatonin has been shown as a powerful antioxidant, with many animal experiments have been designed to evaluate the therapeutic effect of it to renal I/R injury.
Objectives: This systematic review aimed to assess the therapeutic effect of melatonin for renal I/R injury in animal models.
Methods and Results: The PubMed, Web of Science, Embase, and Science Direct were searched for animal experiments applying melatonin to treat renal I/R injury to February 2021. Thirty-one studies were included. The pooled analysis showed a greater reduction of blood urea nitrogen (BUN) (21 studies, weighted mean difference (WMD) = −30.00 [−42.09 to −17.91], p < 0.00001), and serum creatinine (SCr) (20 studies, WMD = −0.91 [−1.17 to −0.66], p < 0.00001) treated with melatonin. Subgroup analysis suggested that multiple administration could reduce the BUN compared with control. Malondialdehyde and myeloperoxidase were significantly reduced, meanwhile, melatonin significantly improved the activity of glutathione, as well as superoxide dismutase. The possible mechanism for melatonin to treat renal I/R injury is inhibiting endoplasmic reticulum stress, apoptosis, inflammation, autophagy, and fibrillation in AKI to chronic kidney disease.
Conclusions: From the available data of small animal studies, this systematic review demonstrated that melatonin could improve renal function and antioxidative effects to cure renal I/R injury through, then multiple administration of melatonin might be more appropriate. Nonetheless, extensive basic experiments are need to study the mechanism of melatonin, then well-designed randomized controlled trials to explore the protective effect of melatonin.
Background: Ischemia/reperfusion can cause injury to tissues and compromise functionality of organs due to inflammatory processes. Significantly, development of these effects in kidney tissue has been a challenging issue that leads to acute renal injury. In this study, anti-inflammatory, anti-oxidative, and protective features of dapsone on kidney ischemia/reperfusion injury were investigated.
Material and methods: Renal ischemia was induced in rats by bilateral renal arteries clamping for 45 min followed by 24 h reperfusion phase. The effects of different doses of dapsone (1, 3, 10 mg/kg) on ischemia/reperfusion injury in kidney tissue were investigated by targeting BUN, Creatinine, LDH, MDA, MPO, IL-1β, TNF-α, and NFκB. In addition histopathological examination was performed by H&E staining method.
Results and discussion: Comparing the findings of this study showed significant reduction in BUN and LDH in 10 mg/kg dapsone received groups, and Cr, MDA, and MPO in 3 mg/kg dapsone received groups. The serum level of TNF-α was significantly decreased with both doses of 3 and 10 mg/kg dapsone. The same results were observed in the serum level of IL-1β and NFκB. Besides, remarkable improvement in histological damages was also observed with dapsone treatment.
Conclusion: These results support the hypothesis that the positive effects of dapsone on the renal ischemia/reperfusion injury are mediated by modulating inflammatory cascades.
Renal ischemia/reperfusion injury (IRI), which occurs in many pathological conditions, is associated with high rate of morbidity and mortality. Activation of inflammatory responses and oxidative stress contribute to induce organ damage following IRI. Pantoprazole, a proton pump inhibitor, which is mostly prescribed for gastroesophageal reflux disease (GERD) has been shown to exert anti‐inflammation effects. In order to evaluate the effects of pantoprazole on renal ischemia/reperfusion injury, 4 different doses of pantoprazole (4.5mg/kg, 9mg/kg, 18mg/kg, and 36mg/kg) were administered 30 min before the induction of IRI in male Wistar rats. Serum concentration of creatinine and Blood Urea Nitrogen (BUN) were measured to assess renal function. Histopathological changes, MDA level and TLR‐4 expression in renal tissue were determined and compared to control group. The results revealed that pretreatment with 18 and 36mg/kg of pantoprazole leads to the significant decline in serum creatinine and BUN levels and the severity of necrosis grade in comparison with control group (P<0.05). Pantoprazole also reduced the MDA level and TLR‐4 expression in renal tissue. In summary, pantoprazole attenuates renal injury following ischemia/reperfusion. This effect is mediated partially through inhibition of oxidative stress and TLR‐4 signaling pathway.
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MicroRNAs (miRNAs) play important roles in kidney development and maintenance of kidney physiological functions. MiR-377 has been reported to regulate inflammation in cardiac and cerebral ischemia. However, it remains unclear whether it has a similar function in renal ischemia/reperfusion (I/R). Using I/R model mice, miR-377 expression was determined by qRT-PCR in the renal tissues. Renal function was assessed by detection of the concentrations of blood urea nitrogen (BUN) and serum creatinine (Cr). Oxidative stress was evaluated by ELISA analysis of oxidation-related enzymes and molecules. Inflammatory factor concentration and other protein levels were analyzed by the ELISA assay and Western blot, respectively. Our study found that renal I/R stimulated miR-377 expression, while the inhibition of miR-377 attenuated renal I/R injury, and blocked renal I/R-induced oxidative stress and inflammation. Meantime, NF-κB and MAPK signaling were activated by renal I/R, which could also be reversed by miR-377 inhibitor. Furthermore, vascular endothelial growth factor (VEGF) depletion by siRNA completely abrogated the impact of miR-377 on renal I/R-induced oxidative stress, inflammation and renal dysfunction. In conclusion, renal I/R induced miR-377 expression, which upregulated VEGF expression to attenuate renal I/R-induced oxidative stress and inflammation, and finally ameliorated renal dysfunction.
Lipopolysaccharide (LPS) administration in an in vivo experimental mice model causes oxidative damage in the liver, muscle and kidney. We aimed to determine specific mechanisms underlying melatonin's antioxidant protective role. Assays were carried out in quadruplicate in the control, melatonin (10 mg/kg, 10 days), acute LPS administration (once 150 μg) and LPS plus melatonin groups. LPS stimulated lipid peroxidation processes (dienes and malondialdehyde) and antioxidant enzyme concentrations (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) were assessed in all investigated tissues. Protein oxidation processes (measured as aldehyde and kenotic carbonyl protein derivatives) were enhanced by LPS in the kidney and liver but not in the muscle. Melatonin, reversed LPS-induced changes, with the exception of muscle protein oxidation. LPS-induced oxidative stress resulted in augmented early stage diene conjugated and end stage malondialdehyde lipid peroxidation processes and affected antioxidant activity in liver, kidney and muscle tissues. LPS activated protein oxidation processes in the kidney and liver. Melatonin ameliorated oxidative damage in the liver, kidney and partially in the muscle. Melatonin modulates the oxidative stress-induced states. Potential synergism between melatonin and systemic inflammation in terms of oxidative modification of muscle proteins needs to be clarified in further studies.
Acute kidney injury (AKI) is a common complication after severe burns. Melatonin has been reported to protect against multiple organ injuries by increasing the expression of SIRT1, a silent information regulator that regulates stress responses, inflammation, cellular senescence and apoptosis. This study aimed to investigate the protective effects of melatonin on renal tissues of burned rats and the role of SIRT1 involving the effects. Rat severely burned model was established, with or without the administration of melatonin and SIRT1 inhibitor. The renal function and histological manifestations were determined to evaluate the severity of kidney injury. The levels of acetylated-p53 (Ac-p53), acetylated-p65 (Ac-p65), NF-κB, acetylated-forkhead box O1 (Ac-FoxO1), Bcl-2 and Bax were analyzed to study the underlying mechanisms. Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling.
Objective:
Ischemia and reperfusion (IR) injury is an important complication of abdominal aortic surgery, and it mainly affects the lower extremities and remote organs. In the present study, we aimed to investigate the possible protective effect of crocin in IR-mediated kidney damage.
Materials and methods:
A total of 24 adult male Wistar-Albino rats were equally and randomly separated into three groups as follows: sham laparotomy, IR, and IR + crocin. Infrarenal aortic occlusion and reperfusion was applied for 1 and 2 h, respectively. Tissue samples were removed and collected. Biochemical and histopathologic analyses were performed.
Results:
Urea, blood urea nitrogen, creatinine, renal tissue tumor necrosis factor α, interleukin (IL)-6, IL-18, interferon gamma, IL-1β, total oxidant status, and oxidative stress index levels were significantly higher in IR group, when compared with other groups. These improvements were also demonstrated with some parameters including total score of histopathologic damage, Tunel, Bax, and Caspase-3 expression levels, and these parameters were prominently higher in the IR group, when compared with the other groups. Nevertheless, Bcl2 expression degree was prominently lower in the IR group than those in the other two groups.
Conclusions:
Data established from the present study suggest that crocin can preclude renal damage in infrarenal aortic occlusion models.
This study tests the hypothesis that combined melatonin and adipose-derived mesenchymal stem cell (ADMSC, 1.2 x 106 given intravenously) treatment offers superior protection against cyclophosphamide (CYP 150 mg/kg)-induced acute interstitial cystitis (AIC) in rats. Male adult Sprague-Dawley rats were treated as follows: sham controls, AIC alone, AIC + melatonin, AIC + ADMSC, and AIC + melatonin +ADMSC. When melatonin was used, it was given as follows: 20 mg/kg at 30 min after CYP and 50 mg/kg at 6 h and 18 h after CYP.Twenty-four-hour urine volume, urine albumin level, and severity of hematuria were highest in AIC rats and lowest in the controls; likewise urine volume was higher in AIC + melatonin rats than in AIC + ADMSC and AIC + melatonin + ADMSC treated rats; in all cases, p<0.001. The numbers of CD14+, CD74+, CD68+, MIP+, Cox-2+, substance-P+, cells and protein expression of IL-6, IL-12, RANTES, TNF-α, NF-κB, MMP-9, iNOS (i.e. inflammatory biomarkers), glycosaminoglycan level, expression of oxidized protein, and protein expression of reactive oxygen species (NOX-1, NOX-2, NOX-4) in the bladder tissue exhibited an identical pattern compared with that of hematuria among the five groups (all p<0.0001). The integrity of epithelial layer and area of collagen-deposition displayed an opposite pattern compared to that of hematuria among all groups (p<0.0001). The cellular expressions of antioxidants (GR, GPx, HO-1, NQO 1) showed a significant progressive increase form controls to AIC + melatonin + ADMSC (all p<0.0001). Combined regimen of melatonin and ADMSC was superior to either alone in protecting against CYP-induced AIC.This article is protected by copyright. All rights reserved.
Background:
Melatonin is released by pineal gland and maintains circadian rhythm in the body. It has been reported as renoprotective agent because of its antioxidant property. Recently, a cross talk between progesterone and melatonin has been observed in various preclinical studies. The present study investigated the involvement of progesterone receptors in melatonin-mediated protection against ischemia reperfusion induced acute kidney injury (AKI) in rats.
Materials and methods:
The rats were subjected to bilateral renal ischemia for 40 min followed by reperfusion for 24 h to induce AKI. The AKI was assessed by measuring creatinine clearance, serum urea, uric acid level, potassium level, fractional excretion of sodium, lactate dehydrogenase activity, and microproteinuria. The oxidative stress in renal tissues was assessed by quantification of myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, reduced glutathione level, and catalase activity. The hematoxylin-eosin staining was carried out to observe histopathologic changes in renal tissues. The melatonin (4 and 10 mg/kg, intraperitoneally) and progesterone receptor antagonist mifepristone (5 mg/kg, intraperitoneally) were used in the present study.
Results:
The renal ischemia reperfusion induced AKI as indicated by significant change in serum, urinary, and tissue parameters that was ameliorated by prior treatment with melatonin. No significant difference in serum progesterone level was observed between various groups used in the present study. The prior administration of mifepristone abolished melatonin-mediated protection against AKI.
Conclusions:
It is concluded that melatonin treatment affords protection against ischemia reperfusion induced AKI. Moreover, progesterone receptors are essentially involved in mediating protective role of melatonin against AKI in rats.
This study tested whether combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cells (A-ADMSCs) offered additional benefit in ameliorating sepsis-induced acute kidney injury. Adult male Sprague-Dawley rats (n=65) were randomized equally into five groups: Sham controls (SC), sepsis induced by cecal-ligation and puncture (CLP), CLP-melatonin, CLP-A-ADMSC, and CLP-melatonin-A-ADMSC. Circulating TNF-α level at post-CLP 6 hour was highest in CLP and lowest in SC groups, higher in CLP-melatonin than in CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups (all p<0.001). Immune reactivity as reflected in the number of splenic helper-, cytoxic-, and regulatory-T cells at post-CLP 72 hour exhibited the same pattern as that of circulating TNF-α among all groups (p<0.001). The histological scoring of kidney injury and the number of F4/80+ and CD14+ cells in kidney were highest in CLP and lowest in SC groups, higher in CLP-melatonin than in CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups, and higher in CLP-A-ADMSC than in CLP-melatonin-A-ADMSC groups (all p<0.001). Changes in protein expressions of inflammatory (RANTES, TNF-1α, NF-κB, MMP-9, MIP-1, IL-1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF-β) markers, reactive-oxygen-species (NOX-1, NOX-2), and oxidative stress displayed a pattern identical to that of kidney injury score among the five groups (all p<0.001). Expressions of antioxidants (GR+, GPx+, HO-1, NQO-1+) were lowest in SC group and highest in CLP-melatonin-A-ADMSC group, lower in CLP than in CLP-melatonin and CLP-A-ADMSC groups, and lower in CLP-melatonin- than in CLP-A-ADMSC-tretaed animals (all p<0.001). In conclusion, combined treatment with melatonin and A-ADMSC was superior to A-ADMSC alone in protecting the kidneys from sepsis-induced injury.This article is protected by copyright. All rights reserved.
Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated
as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort
to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin.
When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension,
metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia
and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent
on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute
renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious
effects of endotoxin.
Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. This heme enzyme uses hydrogen peroxide and chloride to catalyze the production of hypochlorous acid, which is the major strong oxidant generated by neutrophils in appreciable amounts. In addition to chlorination, myeloperoxidase displays several other activities. It readily oxidizes thiocyanate to hypothiocyanite, converts a myriad of organic substrates to reactive free radicals, and hydroxylates aromatic compounds. Depending on the concentration of its competing substrates and the conditions of the local environment, myeloperoxidase could substantially affect oxidant production by neutrophils. Superoxide is undoubtedly a physiological substrate for myeloperoxidase. Its interactions with the enzyme are key factors in determining how neutrophils use superoxide to kill pathogens and promote inflammatory tissue damage. Superoxide modulates the chlorination and peroxidation activities of myeloperoxidase. It also reacts with the enzyme to form oxymyeloperoxidase which is catalytically active and hydroxylates phenolic substrates. Myeloperoxidase reacts rapidly with nitric oxide and peroxynitrite so that at sites of inflammation there is a strong possibility that these reactions will impact on oxidative damage caused by neutrophils. Under certain conditions, many substrates of myeloperoxidase act as inhibitors and regulate oxidant production by the enzyme. Given the numerous reactions of myeloperoxidase, all its activities should be considered when assessing the injurious oxidants produced by neutrophils.
Abstract— Regarding the mechanisms of cisplatin (CP) nephrotoxicity, several hypotheses have been put forward, among which oxidative stress (including depletion of glutathione and production of lipid peroxide) is noticeable. This investigation elucidates the role of the antioxidant system in CP-induced nephrotoxicity and the nephroprotection by melatonin. Balb/c mice were injected i.p. with: 1) vehicle control; 2) a single dose of 6.5 mg/kg cisplatin, CP group; 3) melatonin in a dose of 10 mg/kg for 5 days after CP injection, CP-M group; 4) melatonin (10 mg/kg) for 5 days before and after CP injection, M-CP-M group; 5) melatonin in a dose of 10 mg/kg for 5 days, M group. Mice were sacrificed 5 days after CP injection to determine blood urea nitrogen (BUN) and serum creatinine. Renal lipid peroxidation (LP) and glutathione (GSH) levels were evaluated in kidney homogenates. Cisplatin administration resulted in increased LP, BUN and serum creatinine levels and decreased GSH levels, whereas melatonin reversed these effects. Morphological kidney damage was apparent in the CP group. Mentioned degeneration was moderate in the CP-M group, whereas morphological findings of the M-CP-M group implied a well preserved kidney tissue. When M was administered alone, it didn't cause any significant change in biochemical parameters. Both C and M groups exhibited similar biochemical and morphological findings in light and transmission electron microscope observation. In conclusion, the present study suggests that melatonin may be of therapeutic benefit when used with CP.
When the body responds to an infectious insult, it initiates an immune response to eliminate the pathogen. The hallmark of the immune response is an inflammatory cascade that can also do extensive damage to host tissues. Inflammation is a major contributing factor to many vascular events, including atherosclerotic plaque development and rupture, aortic aneurysm formation, angiogenesis, and ischemia/reperfusion damage. The immune response is mediated by both circulating and resident leukocytes and the cells with which they interact (e.g., vascular endothelium and smooth muscle cells). The process is orchestrated by the activity of a changing series of released and displayed mediators. These include the expression of adhesion molecules on leukocytes and underlying vascular endothelium and the release of cytokines, chemokines, and tissue-destructive metalloproteases and reactive oxygen species. This review focuses on the causes, the inflammatory processes involved, and possible strategies for decreasing vascular disease through regulation of the inflammatory response.
Previous results (Weinberg, J. M., J. A. David, M. Abarzua, and T. Rajan. 1987. J. Clin. Invest. 80:1446-1454) have shown that GSH and glycine (GLY) are cytoprotective during anoxia when added extracellularly. The present studies investigate the role that intracellular GSH plays in this cytoprotection. Proximal renal tubules in suspension prepared with either high (11 +/- 1 nmol/mg protein) or low (6 +/- 1 nmol/mg protein) GSH contents were subjected to 40 min of anoxia and 40 min of reoxygenation. Low GSH tubules were protected from plasma membrane damage during anoxia by exogenous addition of 1 mM GSH or GLY, reducing lactate dehydrogenase (LDH) release from 42 +/- 7 to 14 +/- 1 and 10 +/- 1%, respectively. High GSH tubules were equally protected from anoxic damage without exogenous additions. Since the high GSH content approximates the in vivo values, it may be concluded that GSH may be cytoprotective during anoxia in vivo. However, it is not the intracellular GSH itself that is cytoprotective; rather, this protection resides in the ability to produce GLY, which appears to be the cytoprotective agent. Alanine was also shown to have similar cytoprotective properties, although higher concentrations were required. Sulfhydryl reducing agents such as cysteine and dithiothreitol offered less, but significant protection from anoxic damage. Protection by GSH, GLY, or alanine was not associated with higher ATP levels during anoxia. Tubules that were protected from membrane damage during anoxia recovered oxygen consumption and K and ATP contents significantly better during reoxygenation than unprotected tubules.
Liver ischaemia was induced by cross clamping the hilar pedicle for 30 minutes in groups of rats with or without treatment with the iron chelating agent desferrioxamine (deferoxamine, DFR). The groups included eight animals each and were divided into the following treatment categories: control; ischaemia alone; ischaemia with subsequent reperfusion; ischaemia preceded by DFR, 60 mg/kg body weight; and reperfusion preceded by 20, 40, or 60 mg/kg DFR. The drug was given intravenously five minutes before either ischaemia or reperfusion. Malondialdehyde (MDA), a product of lipid peroxidation, and histopathological changes of liver tissue samples were used as indicators of hepatocellular injury. Lipid peroxidation (MDA concentration in mumol/kg liver tissue) was highest (4.76 (1.19] after ischaemia without reperfusion and less pronounced (2.87 (0.34] after reperfusion. Both concentrations, however, were significantly (p less than 0.05) higher than basal (control) values (1.78 (0.27]. At 60 mg/kg body weight, DFR treatment reduced MDA to basal or even lower concentrations in both situations (1.98 (0.08) and 1.26 (0.06), respectively) with a corresponding improvement in liver histopathology. Lower DFR doses were less protective. The data suggest that liver ischaemia is associated with free radical initiated, and apparently iron catalysed lipid peroxidation, which can be significantly decreased by iron chelation.
The effects of antioxidant therapy with probucol were evaluated in rats subjected to 1 h renal ischemia and to 24 h reperfusion. Probucol exerted significant antioxidant effects in renal cortical tubules in vitro when exposed to a catalase-resistant oxidant. At 24 h probucol treatment (IP) improved single nephron glomerular filtration rate (SNGFR) (28.1 +/- 3.3 nl/min) in comparison to untreated ischemic (I) rats (15.2 +/- 3.0), primarily as a result of improving SNGFR in a population of low SNGFR, low flow and/or obstructed nephrons. However, absolute proximal reabsorption remained abnormally low in IP rats at 24 h (5.9 +/- 0.8 nl/min), and cell necrosis was greater than in I rats. Kidney GFR remained low in IP rats due to extensive tubular backleak of inulin measured by microinjection studies. Evaluations after 2 h of reperfusion revealed a higher SNGFR in IP (36 +/- 3.1 nl/min) than I rats (20.8 +/- 2.7 nl/min). Absolute proximal reabsorption was essentially normal (11.6 +/- 1.3 nl/min) in IP rats, which was higher than IP rats at 24 h and the concurrent I rats. Administration of the lipophilic antioxidant, probucol, increased SNGFR and proximal tubular reabsorption within 2 h after ischemic renal failure. Although SNGFR remained higher than I rats at 24 h, absolute reabsorption fell below normal levels and tubular necrosis was more extensive in IP rats. Early improvement in nephron filtration with antioxidants may increase load dependent metabolic demand upon tubules and increase the extent of damage and transport dysfunction.
This survey summarizes the findings, accumulated within the last 2 years, concerning melatonin's role in defending against toxic free radicals. Free radicals are chemical constituents that have an unpaired electron in their outer orbital and, because of this feature, are highly reactive. Inspired oxygen, which sustains life, also is harmful because up to 5% of the oxygen (O2) taken in is converted to oxygen-free radicals. The addition of a single electron to O2 produces the superoxide anion radical (O2-.); O2-. is catalytic-reduced by superoxide dismutase, to hydrogen peroxide (H2O2). Although H2O2 is not itself a free radical, it can be toxic at high concentrations and, more importantly, it can be reduced to the hydroxyl radical (.OH). The .OH is the most toxic of the oxygen-based radicals and it wreaks havoc within cells, particularly with macromolecules. In recent in vitro studies, melatonin was shown to be a very efficient neutralizer of the .OH; indeed, in the system used to test its free radical scavenging ability it was found to be significantly more effective than the well known antioxidant, glutathione (GSH), in doing so. Likewise, melatonin has been shown to stimulate glutathione peroxidase (GSH-Px) activity in neural tissue; GSH-PX metabolizes reduced glutathione to its oxidized form and in doing so it converts H2O2 to H2O, thereby reducing generation of the .OH by eliminating its precursor. More recent studies have shown that melatonin is also a more efficient scavenger of the peroxyl radical than is vitamin E. The peroxyl radical is generated during lipid peroxidation and propagates the chain reaction that leads to massive lipid destruction in cell membranes. In vivo studies have demonstrated that melatonin is remarkably potent in protecting against free radical damage induced by a variety of means. Thus, DNA damage resulting from either the exposure of animals to the chemical carcinogen safrole or to ionizing radiation is markedly reduced when melatonin is co-administered. Likewise, the induction of cataracts, generally accepted as being a consequence of free radical attack on lenticular macromolecules, in newborn rats injected with a GSH-depleting drug are prevented when the animals are given daily melatonin injections. Also, paraquat-induced lipid peroxidation in the lungs of rats is overcome when they also receive melatonin during the exposure period. Paraquat is a highly toxic herbicide that inflicts at least part of its damage by generating free radicals.(ABSTRACT TRUNCATED AT 400 WORDS)
The protective effect of allopurinol, an inhibitor of the enzyme, xanthine oxidase, against the renal ischaemia-reperfusion of the rat was investigated. Rats were subjected to renal ischaemia by clamping of the left renal artery and vein for 45 min, and were then reperfused for 24 h; these animals were randomized to receive either saline (n = 10) or allopurinol (n = 10) at a dose of 50 mg/kg bolus intraperitoneally 5 min before reperfusion. The control group comprised seven healthy rats not exposed to ischaemia or reperfusion. The blood urea nitrogen and plasma creatinine levels were increased in the allopurinol group, but the increase was less than that in the placebo group, compared with the controls. The kidney glutathione level was significantly reduced in the placebo group but not in the allopurinol group compared with the controls. The glutathione peroxidase activity in the kidney tissues was reduced more than two-fold in the placebo group compared with the controls, but the reduction in glutathione peroxidase was considerably less in the allopurinol group. Renal tissue lactate dehydrogenase, aspartate amino-transferase, gamma-glutamyl transferase and alkaline phosphatase activities were reduced almost two-fold in the placebo group, but allopurinol treatment maintained these enzyme activities close to the control activities. These results provide evidence that allopurinol treatment may have beneficial effects on antioxidant defences against ischaemia-reperfusion injury of rat kidneys.
Purpose: Remnant kidneys may be susceptible to injury during positioning for a contralateral flank incision. We document renal dysfunction in a remnant kidney after staged partial nephrectomies. Materials and Methods: We review a case of renal dysfunction associated with staged bilateral partial nephrectomy. Pertinent data and radiographic findings are presented. Results: A man with multiple bilateral solid enhancing renal masses underwent left partial nephrectomy, resulting in sparing of 50% of the renal parenchyma. Postoperatively nuclear renography showed excellent flow and 33% function on that side. Right partial nephrectomy was then performed via the standard flank approach through the bed of the 11th rib, sparing 50% of the renal parenchyma. Cold ischemia time was 40 minutes. Serum creatinine increased to 4.9 mg./dl. within 48 hours. Nuclear renography immediately postoperatively showed poor flow and 13% function in the left kidney. Conclusions: Limited published data imply detrimental hemodynamic and myocutaneous consequences due to use of the kidney rest. Table flexion with elevation of the kidney rest may also cause ischemic damage in a previously operated contralateral kidney. Careful positioning is critical for preventing undue injury to the remnant kidney and in such cases elevation of the kidney rest should be avoided. Alternatively stage 2 may be approached via an anterior incision.
Background: Acute changes in renal function after elective coronary bypass surgery are incompletely characterized and represent a challenging clinical problem. Objective: To determine the incidence and characteristics of postoperative renal dysfunction and failure, perioperative predictors of dysfunction, and the effect of renal dysfunction and failure on in-hospital resource utilization and patient disposition after discharge. Design: Prospective, observational, multicenter study. Setting: 24 university hospitals. Patients: 2222 patients having myocardial revascularization with or without concurrent valvular surgery. Measurements: Prospective histories, physical examinations, and electrocardiographic and laboratory studies. The main outcome measure was renal dysfunction (defined as a postoperative serum creatinine level ≥ 177 μmol/L with a preoperative-to-postoperative increase ≥ 62 μmol/L). Results: 171 patients (7.7%) had postoperative renal dysfunction; 30 of these (1.4% overall) had oliguric renal failure that required dialysis. In-hospital mortality, length of stay in the intensive care unit, and hospitalization were significantly increased in patients who had renal failure and those who had renal dysfunction compared with those who had neither (mortality: 63%, 19%, and 0.9%; intensive care unit stay: 14.9 days, 6.5 days, and 3.1 days; hospitalization: 28.8 days, 18.2 days, and 10.6 days, respectively). Patients with renal dysfunction were three times as likely to be discharged to an extended-care facility. Multivariable analysis identified five independent preoperative predictors of renal dysfunction: age 70 to 79 years (relative risk [RR], 1.6 [95% Cl, 1.1 to 2.3]) or age 80 to 95 years (RR, 3.5 [Cl, 1.9 to 6.3]); congestive heart failure (RR, 1.8 [Cl, 1.3 to 2.6]); previous myocardial revascularization (RR, 1.8 [Cl, 1.2 to 2.7]); type 1 diabetes mellitus (RR, 1.8 [Cl, 1.1 to 3.0]) or preoperative serum glucose levels exceeding 16.6 mmol/L (RR, 3.7 [Cl, 1.7 to 7.8]); and preoperative serum creatinine levels of 124 to 177 μmol/L (RR, 2.3 [Cl, 1.6 to 3.4]). Independent perioperative factors that exacerbated risk were cardiopulmonary bypass lasting 3 or more hours and three measures of ventricular dysfunction. Conclusions: Many patients having elective myocardial revascularization develop postoperative renal dysfunction and failure, which are associated with prolonged intensive care unit and hospital stays, significant increases in mortality, and greater need for specialized long-term care. Resources should be redirected to mitigate renal injury in high-risk patients.
Increasing clinical evidence suggests that delayed initial function secondary to ischemia/reperfusion injury alone, and particularly in combination with early episodes of acute rejection, reduces kidney allograft survival over time.
We investigated changes developing over the long term following a standardized ischemia/reperfusion insult in a Lewis rat model. The left kidney was isolated in a uninephrectomized host and cooled, and the pedicle was clamped for 45 min. Animals were followed for 48 weeks after initial renal injury. Organs were removed serially (4, 8, 16, 24, 32, 40, and 48 weeks) for immunohistology and reverse transcriptase polymerase chain reaction.
Progressive proteinuria developed after 8 weeks. By immunohistology, CD4+ leukocytes and ED-1+ macrophages infiltrated the ischemic organs in parallel with up-regulation of major histocompatibility complex class II antigen expression. Because macrophages have been shown to be critical in chronic changes in other models, they were examined primarily in these studies. By reverse transcriptase polymerase chain reaction, macrophage-derived, fibrosis-inducing factors (transforming growth factor-beta, interleukin 6, and tumor necrosis factor-alpha) remained highly and constantly expressed throughout the follow-up period. The long-term influence of initial treatment with the soluble form of P-selectin glycoprotein ligand-1, a soluble ligand for P- and E-selectin, was then examined. All functional and structural changes remained at relative baseline, similar to uninephrectomized controls.
These data suggest that blocking the initial selectin-mediated step after ischemia/reperfusion injury, which triggers significant early cellular and molecular events, also reduces later renal dysfunction and tissue damage over time. In part, the findings may be explained by the sparing of functioning nephron units, which if destroyed or compromised by the original insult, may contribute to long-term graft failure. This approach may be important clinically in the transplantation of kidneys from non-heart-beating or marginal donors or organs experiencing prolonged ischemic times.
Over three centuries ago, the French philosopher René Descartes described the pineal gland as “the seat of the soul.” However, it was not until the late 1950s that the chemical identity and biosynthesis of melatonin, the principal hormone secreted by the pineal body, were revealed. Melatonin, named from the Greek melanos, meaning black, and tonos, meaning color, is a biogenic amine with structural similarities to serotonin. The mechanisms mediating the synthesis of melatonin are transcriptionally regulated by the photoperiodic environment. Once synthesized, the neurohormone is a biologic modulator of mood, sleep, sexual behavior, reproductive alterations, immunologic function, and circadian rhythms. Moreover, melatonin exerts its regulatory roles through high-affinity, pertussis toxin-sensitive, G-protein (or guanine nucleotide binding protein) coupled receptors that reside primarily in the eye, kidney, gastrointestinal tract, blood vessels, and brain. Additional evidence also indicates a role for melatonin in aging and age-related diseases, probably related to its efficient free radical scavenger (or antioxidant) activity. The potential clinical benefit of melatonin as an antioxidant is remarkable, suggesting that it may be of use in the treatment of many pathophysiological disease states including various cancers, hypertension, pulmonary diseases, and a variety of neurodegenerative diseases such as Alzheimer’s disease. This review summarizes the biosynthesis of melatonin and its many endocrine and physiological functions, including its therapeutic potential in human disease states. Emphasis is placed on the recent speculations indicating that this pineal hormone serves as an endogenous antioxidant agent with proficient free radical scavenging activity.
Tubular leakage and obstruction after renal ischemia: Structural-functional correlations. These ischemic sequelae were evaluated in rats following relief of 60, 25, and 15 min of renal artery occlusion. Light/electron microscopy after 60 min's ischemia showed necrosis of isolated cells in both proximal convoluted (PCT) and proximal straight tubules (PST); necrosis was present only in PST with 25 min's ischemia. Thirty-five percent of 14C-inulin microinjected into ischemic PCT was recovered in contralateral urine after 60 min of ischemia; 11% was recovered after 25 min. Backleak was insignificant after 15 min of ischemia. Horseradish peroxidase (mol wt, 40,000), injected into PCT passed through the cytoplasm of tubular cells into the interstitium. Intravenous administration of peroxidase demonstrated that loss of selective permeability of tubular cells to large molecules was not an artefact of tubular injection techniques. Intrarenal inulin sequestration was used as an approximate index of obstruction. After 60 min of ischemia, 28% of microinjected inulin was not recovered in urine from either kidney; after 25 min of ischemia, non-recovery was 12%. About three-quarters of this missing inulin was recovered from the ischemic kidney itself. Recovery in urine was substantially complete in control and 15 min's-ischemic animals. Impacted swollen blebs of brush border were seen in > 75% of PST following 60 min of ischemia, whereas this phenomenon was much less frequent and evanescent after 25 min. We conclude that increasing duration of renal ischemia causes incremental tubular leakiness to large molecules, which diffuse through damaged cells. After 60 min of ischemia, most PST appear filled with impacted brush border, which may cause obstruction.
Publisher Summary This chapter discusses microsomal lipid peroxidation. Lipid peroxidation is a complex process known to occur in both plants and animals. It involves the formation and propagation of lipid radicals, the uptake of oxygen, a rearrangement of the double bonds in unsaturated lipids, and the eventual destruction of membrane lipids, producing a variety of breakdown products, including alcohols, ketones, aldehydes, and ethers. Biological membranes are often rich in unsaturated fatty acids and bathed in an oxygen-rich, metal-containing fluid. Lipid peroxidation begins with the abstraction of a hydrogen atom from an unsaturated fatty acid, resulting in the formation of a lipid radical. The formation of lipid endoperoxides in unsaturated fatty acids containing at least 3 methylene interrupted double bonds can lead to the formation of malondialdehyde as a breakdown product. Nonenzymic peroxidation of microsomal membranes also occurs and is probably mediated in part by endogenous hemoproteins and transition metals. The direct measurement of lipid hydroperoxides has an advantage over the thiobarbituric acid assay in that it permits a more accurate comparison of lipid peroxide levels in dissimilar lipid membranes.
The toxic metabolites of oxygen, including those which are free radicals, have been found to constitute a fundamental common pathway of tissue injury in a wide variety of disease processes, including injury in many organs resulting from post-ischemic reperfusion. Research efforts designed to prevent or ameliorate tissue injury have therefore centered on the pharmacologic inhibition of free radical-mediated mechanisms. This approach has particular application to post-ischemic renal failure seen in renal transplantation, after a well-defined period of graft ischemia, followed by reperfusion.
A method to quantitate myeloperoxidase (MPO) activity from rat whole kidney is described. Polymorphonuclear leukocyte (PMN) infiltration into tissue is a hallmark of acute inflammation. Historically, the degree of inflammation has been quantified by the identification and enumeration of PMNs histologically or by some other means. More recently, the enzyme activity of MPO, a marker enzyme for PMN, and freshly emigrated monocytes in many inflamed tissues has replaced these methods. The kidney, however, has been identified as a tissue from which MPO cannot be measured. Indeed, kidney homogenized by a standard extraction procedure was devoid of MPO activity. We modified the established methodology so that kidney was homogenized in 5 mM potassium phosphate buffer (PB) first and then centrifuged at 30,000 g for 30 min at 4 degrees C prior to extraction. The resulting 30,000 g pellets expressed MPO activity after suspending them in 50 mM PB containing 0.5% hexadecyltrimethylammoniumbromide (HTAB). Interference in the assay was observed with supernatants from control and inflamed kidney, which appeared to be due to kidney-derived material forming a complex with HTAB. After washing the pellets twice, we noted that their extracts exhibited greater activity, and interference from supernatants was abolished. Using this method, we observed that acutely inflamed kidneys from rats treated with sheep nephrotoxic immunoglobulin G (IgG) had significantly elevated MPO activity over kidneys from control rats. Thus, the described technique allows for the routine assay of MPO in kidney tissue.
Publisher Summary This chapter discusses methods to determine carbonyl content in oxidatively modified proteins. The methods described are (1) reduction of the carbonyl group to an alcohol with tritiated borohydride; (2) reaction of the carbonyl group with 2,4-dinitrophenylhydrazine to form the 2,4-dinitrophenylhydrazone; (3) reaction of the carbonyl with fluorescein thiosemicarbazide to form the thiosemicarbazone; and (4) reaction of the carbonyl group with fluorescein amine to form a Schiff base followed by reduction to the secondary amine with cyanoborohydride. Van Poelje and Snell have also quantitated protein-bound pyruvoyl groups through formation of a Schiff base with p-aminobenzoic acid followed by reduction with cyanoborohydride. Although a systematic investigation has not appeared, this method should also be useful in detecting other protein-bound carbonyl groups. Carbonyl content of proteins is expressed as moles carbonyl/mole subunit for purified proteins of known molecular weight. For extracts, the results may be given as nanomoles carbonyl/milligram protein. For a protein having a molecular weight of 50,000, a carbonyl content of 1 mol carbonyl/mol protein corresponds to 20 nmol carbonyl/mg proteins.
The objective of this study was to determine whether hydrogen peroxide, iron, and/or hydroxyl radicals play a role in ischemia/reperfusion (I/R)-induced granulocyte infiltration in the feline small intestine and whether a chemoattractant is formed when superoxide or hydrogen peroxide reacts with feline extracellular fluid. In vivo determinations of granulocyte infiltration consisted of measurements of tissue myeloperoxidase activity in either the intestinal mucosa (I/R studies) or dermis (chemotaxis studies), whereas in vitro measurements of granulocyte migration were obtained using a Boyden chamber. Treatment with either catalase or the iron chelator deferoxamine significantly attenuated granulocyte infiltration into the mucosa induced by reperfusion of the ischemic intestine. Two hydroxyl radical scavengers, dimethyl sulfoxide (DMSO) and dimethylthiourea (DMTU), were also evaluated for their ability to modulate I/R-induced granulocyte infiltration. DMTU significantly attenuated the I/R-induced granulocyte accumulation, whereas DMSO had no effect. In other experiments, we were unable to stimulate granulocyte migration with feline plasma exposed to superoxide-generating systems using both in vitro and in vivo models of leukocyte chemotaxis. However, hydrogen peroxide in the presence of either ferrous iron or hemoglobin did significantly increase the chemotactic activity of cat plasma. The results obtained from our studies suggest that either hydrogen peroxide or radical species derived from the interaction of superoxide and hydrogen peroxide with iron elicit I/R-induced granulocyte infiltration in the intestine.
Toxic O2 metabolites have been postulated to contribute to renal ischemia-reperfusion injury, but their biochemical assessment and contribution as a function of the duration of ischemia is unclear. To address this issue we measured renal function and renal cortical glutathione levels following 20, 30, or 45 min of ischemia in situ and then 60 min of reperfusion by the isolated kidney technique. Increasing durations of ischemia were associated with progressive decreases in perfusion flow rate, glomerular filtration rate, tubular Na reabsorption, and renal cortical glutathione following reperfusion. However, reperfusion following simultaneous addition of the permeable O2 metabolite scavenger dimethylthiourea (DMTU; but not urea) prevented glutathione consumption and attenuated reperfusion-induced injury after 20 and 30 min of ischemia. In contrast, reperfusion with DMTU prevented glutathione consumption but did not improve renal function after 45 min of ischemia. Similarly, reperfusion with dimethyl sulfoxide also attenuated renal injury after 20 and 30 min, but not after 45 min of ischemia. Thus reperfusion of kidneys made ischemic for 20 or 30 min is associated with decreases in tissue glutathione and renal function that were both inhibitable by addition of O2 metabolite scavengers during reperfusion. In contrast, addition of O2 metabolite scavengers during reperfusion of kidneys previously made ischemic for 45 min prevented decreases in glutathione but did not improve renal function. We conclude that O2 metabolites formed during reperfusion contribute to functional impairment in kidneys made ischemic for short durations up to 30 min) but that after prolonged ischemia (greater than 30 min) injury is primarily mediated by non-O2 metabolite-dependent cellular events.
Studies were performed to determine whether renal glutathione (GSH) is an important free-radical scavenger following ischemia and reperfusion, whether alterations in renal transport work affect renal GSH levels, and whether a decrease in renal work decreases susceptibility to postischemic renal injury via the first two effects. Following administration of either intravenous GSH to increase renal GSH or intraperitoneal diethylmaleate to decrease renal GSH, Sprague-Dawley rats underwent 60 minutes of renal ischemia. In animals with high renal GSH following GSH infusion, GFR 24 hours after ischemia was 0.43 +/- 0.08 ml/min compared to 0.15 +/- 0.02 ml/min in saline-infused control animals (P less than 0.01). When renal GSH was decreased by the administration of diethylmaleate postischemic renal dysfunction was accentuated. Twenty-four hours after ischemia GFR was 0.05 +/- 0.02 ml/min in diethylmaleate-treated animals and 0.28 +/- 0.06 ml/min in control animals (P less than 0.005). To test whether a decrease in renal transport work alters renal GSH the filtered load of sodium was reduced by producing unilateral renal artery stenosis. Alternatively, renal work was lessened when sodium reabsorption was interfered with by the infusion of a combination of natriuretic agents. Renal artery stenosis produced a 37% decrease in GFR. Renal GSH was 0.435 +/- 0.089 nmol/mg protein in intact kidneys and 0.804 +/- 0.239 nmol/mg protein in stenotic kidneys (P less than 0.05). The infusion of natriuretic agents produced no change in GFR or renal plasma flow but resulted in a striking elevation in renal GSH.(ABSTRACT TRUNCATED AT 250 WORDS)
Hemorrhagic lesions in the small intestinal mucosa have been demonstrated in humans and experimental animals following hemorrhagic shock and intestinal ischemia. In order to define the role of superoxide radicals and xanthine oxidase in the pathogenesis of the mucosal lesions, we compared the microscopic mucosal changes produced by 3 h of regional hypotension (intestinal arterial pressure = 30 mmHg) in untreated cats and cats pretreated with either superoxide dismutase or allopurinol. In the untreated animals the mucosa was characterized by massive epithelial lifting down the sides of the villi, completely denuded villi, and most frequently by disintegration of the lamina propria, hemorrhage, and ulceration. Pretreatment with either superoxide dismutase or allopurinol significantly attenuated the necrosis of villus and crypt epithelium produced by 3 h of ischemia. The results of this study suggest that superoxide radicals are involved in the pathogenesis of ischemic mucosal lesions and that the enzyme xanthine oxidase is the source of superoxide radicals in the ischemic small bowel.
Human neutrophils have been studied for their ability to respond with production of O(2) and H2O2 by human neutrophils contain a 1:2 weight ratio of antigen and antibody (molar ratio of 1.5:1). The metabolic stimulation of leukocytes is a linear function of the total amount of complex used. Complexes containing F(ab')2 are ineffective in stimulating leukocytes to produce O(2) and H2O2. The complexes that maximally stimulate production of O(2) by neutrophils differ from those complexes that are 1) most effective in complement fixation, 2) maximally taken up by neutrophils, and 3) most effective in the induction of enzyme release. These findings suggest that immune complex-induced damage in tissues may reflect the effects of a heterogeneous population of immune complexes.
During renal ischemia, ATP is degraded to hypoxanthine. When xanthine oxidase converts hypoxanthine to xanthine in the presence of molecular oxygen, superoxide radical (O-2) is generated. We studied the role of O-2 and its reduction product OH X in mediating renal injury after ischemia. Male Sprague-Dawley rats underwent right nephrectomy followed by 60 min of occlusion of the left renal artery. The O-2 scavenger superoxide dismutase (SOD) was given 8 min before clamping and before release of the renal artery clamp. Control rats received 5% dextrose instead. Plasma creatinine was lower in SOD treated rats: 1.5, 1.0, and 0.8 mg/dl vs. 2.5, 2.5, and 2.1 mg/dl at 24, 48, and 72 h postischemia. 24 h after ischemia inulin clearance was higher in SOD treated rats than in controls (399 vs. 185 microliter/min). Renal blood flow, measured after ischemia plus 15 min of reflow, was also greater in SOD treated than in control rats. Furthermore, tubular injury, judged histologically in perfusion fixed specimens, was less in SOD treated rats. Rats given SOD inactivated by prior incubation with diethyldithiocarbamate had plasma creatinine values no different from those of control rats. The OH X scavenger dimethylthiourea (DMTU) was given before renal artery occlusion. DMTU treated rats had lower plasma creatinine than did controls: 1.7, 1.7, and 1.3 mg/dl vs. 3.2, 2.2, and 2.4 mg/dl at 24, 48, and 72 h postischemia. Neither SOD nor DMTU caused an increase in renal blood flow, urine flow rate, or solute excretion in normal rats. The xanthine oxidase inhibitor allopurinol was given before ischemia to prevent the generation of oxygen free radicals. Plasma creatinine was lower in allopurinol treated rats: 2.7, 2.2, and 1.4 mg/dl vs. 3.6, 3.5, and 2.3 mg/dl at 24, 48, and 72 h postischemia. Catalase treatment did not protect against renal ischemia, perhaps because its large size limits glomerular filtration and access to the tubular lumen. Superoxide-mediated lipid peroxidation was studied after renal ischemia. 60 min of ischemia did not increase the renal content of the lipid peroxide malondialdehyde, whereas ischemia plus 15 min reflow resulted in a large increase in kidney lipid peroxides. Treatment with SOD before renal ischemia prevented the reflow-induced increase in lipid peroxidation in renal cortical mitochondria but not in crude cortical homogenates. In summary, the oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia. Reperfusion after ischemia resulted in lipid peroxidation; SOD decreased lipid peroxidation in cortical mitochondria after renal ischemia and reflow. We concluded that restoration of oxygen supply to ischemic kidney results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.
To determine whether the renal response to ischemia could be modified by the choice and/or amount of anesthetic agent, clearance and micropuncture studies were performed after 60 min of unilateral renal artery occlusion in rats anesthetized intraperitoneally with either the thiobarbiturate Inactin, 150 mg/kg BW (group I), or the oxybarbiturate sodium pentobarbital, 60 mg/kg BW (group II). Significant differences were noted in the mean values of V, UNaV and CIn of the postischemic kidneys. The group I vs. group II average values were V 25.0 vs. 2.6 μl/min, UNaV 2.83 vs. 0.36 μEq/min, and CIn 303 vs. 24 μl/min. The kidney surface of group I animals was heterogeneous in appearance. Approximately two thirds of the proximal convolutions were dilated without evidence of tubular fluid flow. Their PITPs averaged 28.0 mm Hg (control 11.0). The remaining one third of the proximal convolutions was of normal caliber, and spontaneous flow of tubular fluid could be demonstrated; PITP averaged 9.9 mm Hg. Moreover, blood flow in peritubular capillaries adjacent to these proximal convolutions appeared greater than that in peritubular capillaries adjacent to the distended convolutions. In contrast, the kidney surface of group II animals was homogeneous in appearance. Proximal convolutions were uniformly dilated, tubular fluid flow was absent, and PITP averaged 30.1 mm Hg. In a group of nephrons in which PITP was markedly elevated and adjacent peritubular capillary blood flow was absent, reduction of the PITP by aspiration of the tubular fluid resulted in the re-establishment of peritubular capillary blood flow. These data indicate that (1) the functional abnormalities due to ischemia are variable and depend in part on the nature of the anesthetic agent; (2) polyuria occurs in association with a subset of nephrons without evidence of intratubular obstruction; and (3) peritubular capillary blood flow may be reduced due to compression by distended proximal convolutions with markedly elevated PITPs.
One hour of total renal ischemia in the rat is associated with diminished glomerular filtration rate, a reduction in renal flow, and oliguira. A number of mechanisms including back-leakage of tubular filtrate, obstruction, and hemodynamic alterations have been postulated to be responsible for the reduced glomerular filtration rate in acute renal failure. Most emphasis has been placed on tubular changes following renal ischemia, and little attention has been focused on glomerular changes during early reflow. Since glomerular damage may account for a portion of function impairment during reflow, studies were performed to examine glomerular morphology in this model of acute renal failure. Glomerular alterations, as noted by scanning and transmission electron microscopy, were progressive spring reflow. At 30 minutes following 1 hour of renal ischemia, scanning electron microscopy revealed focal spreading of podocyte cell bodies associated with loss of foot processes and increased numbers of microvillous projections. Also, numerous cytoplasmic protuberances were observed on the epithelial cell surface. Transmission electron microscopy confirmed these changes and revealed displacement and duplication of slit diaphragms. In addition, endothelial fenestrae were reduced in number and appeared unduly wide. At 30 minutes, glomerular polyanion, determined by colloidal iron staining, was unchanged in ischemic kidneys when compared with the untouched contralateral control. At 1 hour of reflow, the above described glomerular morphologic changes were diffuse and global in distribution. However, cytoplasmic protuberances were uncommon. Changes in the glomerular epithelial slit pore complex at this time included loss of slit diaphragms and abnormal widening of slit pores. Also, glomerular polyanion was markedly diminished when compared with controls. These glomerular changes have not been previously described during early reflow in the ischemic model of acute renal failure. The role these alterations have in loss of renal function is not known; however, a loss of surface area available for ultrafiltration is suggested. In addition, loss of the glomerular polyanion suggests an increased permeability to macromolecules.
The debilitating consequences of age-related brain deterioration are widespread and extremely costly in terms of quality of life and longevity. One of the potential major causes of age-related destruction of neuronal tissue is toxic free radicals that are a natural result of aerobic metabolism. The brain is particularly susceptible to free radical attack because it generates more of these toxicants per gram of tissue than does any other organ. The major defense mechanisms the brain uses to combat reducing equivalents is via their enzymatic metabolism. The vitamin antioxidants, vitamin E (alpha-tocopherol in particular) and vitamin C (ascorbate), also aid in protecting the brain from oxidative stress by directly scavenging toxic radicals. A newly discovered, potentially highly important antioxidant in the brain is the indole melatonin. The pineal hormone melatonin is rapidly taken up by the brain. In vitro melatonin is more effective than glutathione in scavenging the highly toxic hydroxyl radical and also more efficient than vitamin E in neutralizing the peroxyl radical. Furthermore, it stimulates the main antioxidant enzyme of the brain, glutathione peroxidase. In vivo melatonin is a potent antioxidant and it lacks prooxidant actions.
We have compared the peroxyl radical scavenger ability to melatonin with that of vitamin E, vitamin C and reduced glutathione (GSH). In the assay system, beta-phycoerythrin (beta-PE) was used as fluorescent indicator protein, 2-2'-azo-bis(2-amidinopropane)dihydrochloride as a peroxyl radical generator and the water soluble vitamin E analogue. Trolox, as reference standard. Results are expressed as oxygen radical absorbing capacity (ORAC(perox)) units, where 1 ORAC unit equals the net protection produced by 1 microM Trolox. A linear correlation of ORAC values with concentration (0.5-4 microM) of all the substances tested has been observed. However, on molar basis, the relative ORAC(perox) of Trolox, vitamin C, GSH and melatonin was 1:1.12:0:68:2.04, respectively. Thus, melatonin, which is a lipid-soluble compound, was twice more active than vitamin E, believed to be the most effective lipophilic antioxidant.
Melatonin (in gum tragacanth as solvent) was administered to mice in the dose range of 100 to 450 mg/kg intraperitoneally. It prevented the increase in plasma glucose resulting from pancreatic toxicity caused by the intravenous administration of alloxan at 40 mg/kg. This action of melatonin was significant and dose-dependent. In parallel work using mouse brain homogenates, melatonin and more so its principal hepatic metabolite, 6-hydroxymelatonin, inhibited the formation of colored products reacting with thiobarbituric acid. Again, this inhibition was significant and dose-dependent. Alloxan-induced diabetes and lipoperoxidation induced by thiobarbituric acid are imputed to the production of oxygen free radicals. The consistent results obtained using these two experimental models show the antioxidant activity of melatonin, both in vivo and in vitro. This effect may be reasonably attributed to the indole structure of the molecule.
Oxygen-based free radicals produced by the enzyme xanthine oxidase may be involved in postischemic reperfusion injury. To determine whether oxypurinol, a xanthine oxidase inhibitor and the major metabolite of allopurinol, attenuates renal ischemic reperfusion injury, and, if so, to determine its most effective dose, oxypurinol 2.5, 5, 10 or 20 mg/kg BW was infused 20 min prior to 20 min of complete renal ischemia in uniephrectomized rats. Animals treated with 5 mg/kg BW oxypurinol had significantly higher creatinine clearances on the first and second days postischemia than did untreated animals. In other animals given either buffered saline or oxypurinol at 5 mg/kg BW i.v. 20 min before ischemia, the inulin clearance (CIn) returned to near-control values within 1 h after ischemia. At 24 h there was a secondary decline in the CIn in animals receiving buffered saline, whereas in the animals treated with oxypurinol, this decline was less evident. In animals given oxypurinol at 5 mg/kg BW 40 min after ischemia, the CIn was significantly greater than in those receiving buffered saline. No changes in renal blood flow or renal vascular resistance were observed, suggesting that the effect of oxypurinol was not hemodynamically mediated. Analysis of plasma hypoxanthine, xanthine, uric acid and oxypurinol levels by high-pressure liquid chromatography revealed that in the absence of oxypurinol, a significant increase in uric acid production occurred between 20 and 170 min after the period of ischemia. In the presence of oxypurinol, there was a marked reduction in the rate of production of uric acid for the first 3 h postischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
The protective effect of melatonin against lipopolysaccharide (LPS)-induced oxidative damage was examined in vitro. Lung, liver, and brain malonaldehyde (MDA) plus 4-hydroxyalkenals (4-HDA) concentrations were measured as indices of induced membrane peroxidative damage. Homogenates of brain, lung, and liver were incubated with LPS at concentrations of either 1, 10, 50, 200, or 400 micrograms/ml for 1 h and, in another study, LPS at a concentration of 400 micrograms/ml for either 0, 15, 30, or 60 min. Melatonin at increasing concentrations from 0.01-3 mM either alone or together with LPS (400 micrograms/ml) was used. Liver, brain, and lung MDA + 4-HDA levels increased after LPS at concentrations of 10, 50, 200 or 400 micrograms/ml; this effect was concentration-dependent. The highest levels of lipid peroxidation products were observed after tissues were incubated with an LPS concentration of 400 micrograms/ml for 60 min; in liver and lung this effect was totally suppressed by melatonin and partially suppressed in brain in a concentration-dependent manner. In addition, melatonin alone was effective in brain at concentrations of 0.1 to 3 mM, in lung at 2 to 3 mM, and in liver at 0.1 to 3 mM; in all cases, the inhibitory effects of melatonin on lipid peroxidation were always directly correlated with the concentration of melatonin in the medium. The results show that the direct effect of LPS on the lipid peroxidation following endotoxin exposure is markedly reduced by melatonin.
Ischaemia-reperfusion injury is a complex interrelated sequence of events that classically involves the vascular endothelium and activated leucocytes. During the ischaemic phase the endothelium is primed both to produce free radicals and to secrete chemoattractants. The resultant neutrophil sequestration serves to amplify the injury, but damage is not confined to the postischaemic area and more generalized effects typically follow. The situation in the kidney is complex for, while ischaemia primes the tissue for reperfusion damage, it also causes early and irreversible tubular injury. Furthermore, it appears that relatively less importance should be attached to the involvement of neutrophils than at other sites, and relatively more to a local postischaemic imbalance in the levels of nitric oxide and endothelin. Despite a greater understanding of the pathogenesis of ischaemia-reperfusion injury, effective treatment remains elusive and research is hampered by apparent species and organ-specific differences.