Many people who come to try DCA may have already been treated with Cisplatin, an effective anti-cancer agent that is limited in application because of its extreme side effects on heart, liver and kidney. The following is an attempt to achieve three things:
1. Discover and detail the mechanism by which Cisplatin causes side effects;
2. Research the latest medical hypotheses and in vitro, vivo and human trials to find ways to reduce Cisplatin’s damage to kidneys, heart and liver;
3. Work out a way in which persons previously treated with Cisplatin can use DCA without fatally increasing the side effects on compromised heart, liver and kidney function. This may involve time between usage, dosage reductions and supplementation specifically targeting renal/heart/liver protective pathways.
Until there is a clearer picture of the above we should be aware that DCA therapy following Cisplatin may trigger toxic tumour lysis syndrome due to weakened heart/kidney function- if this occurs ideally you will be in a hospital and being aggressively treated by medical professionals for TLS in advance of taking DCA in case your tumour is killed aggressively by DCA- this may include uric acid reducing medication and even dialysis where appropriate. We want to win the war with cancer and not just the battle of killing the tumour.
From what I have collected to date: Cisplatin toxicity may be lessened by forms of carnitine (many mention this propionyl form) amongst other substances mentioned such as melatonin, alpha lipoic acid and even statins. These are non-human studies for the most part so it is uncertain if the protective effects translate to humans. However while forms of carnitine might reduce cisplatin toxicity we also don’t know if Tumour lysis syndrome does occurs whether carnitine would be helpful or harmful at that point.
Sorry for the size of the post but its better to have all the resources in the one place.
All the best
“Cisplatin toxicity prevented by propionyl - carnitine but side effects worsened by D-carnitine.”
“Although cis-diamminedichloroplatinum (II) (cisplatin) is a potent anticancer drug, clinical use of this agent is highly limited predominantly because of its strong side effects on the kidney and gastrointestinal tracts. We found that cisplatin impaired respiratory function and DNA of mitochondria in renal proximal tubules and small intestinal mucosal cells, thereby inducing apoptosis of epithelial cells. Cisplatin-induced mitochondrial dysfunction and DNA (mtDNA) injury, lipid peroxidation, and apoptosis of epithelial cells in the kidney and small intestine were strongly inhibited by carnitine. However, carnitine had no appreciable effect on the tumoricidal action of cisplatin against cancer cells inoculated in the peritoneal cavity. These results indicate that carnitine may have therapeutic potential for inhibiting the side effects of cisplatin and other anticancer agents in the kidney and small intestine.”
Extract re acetyl l carnitine improving Cisplatin Neuropathy
“Cisplatin is an alkylating agent that induces peripheral sensory axonal neuropathy affecting large and small diameter sensory fibers. It accumulates in the dorsal root ganglia, inducing axonal changes secondary to neuronal damage8. The drug binds tightly and irreversibly to nerve tissue.
Clinical symptoms are represented by the loss of deep tendon reflexes, a decrease in vibratory sensation and paresthesia and numbness of fingers and toes which progress in a glove/stocking fashion. Continuation of therapy may lead to the loss of fine motor coordination and gait disturbance due to proprioceptive sensory loss. Lhermitte’s sign is often present. Nerve conduction studies have suggested a greater involvement of sensory nerves than motor nerves9-11.
Cisplatin neurotoxicity generally arises after a total cumulative dose of 300 mg/m2, and it may progress after cisplatin discontinuation. Such toxicity can even persist for years. In a study of 69 patients with gynecological cancer treated with 50 to 100 mg/m2 cisplatin at 4-week intervals, 70% of the patients who received a cumulative dose of 600 mg/m2 of the drug experienced peripheral neuropathy12.
Acetyl-L-carnitine (ALC) is an ester of the trimethylated amino acid, L-carnitine, and is synthesized in the human brain, liver, and kidney by the enzyme ALCtransferase. Acetyl-L-carnitine’s primary biological function is that of facilitating the uptake of acetyl CoA
into the mitochondria during fatty acid oxidation. ALC exerts a protective and therapeutic effect in several models of chemotherapy-induced neuropathy without adversely affecting antitumor activity. Even though the ALC mechanism has not yet been fully elucidated, current
evidence suggests a pleiotropic action on the metabolism of nerve cells and a protective effect on cytotoxic-induced nerve growth factor (NGF), which is reduced by the enhancement of NGF signaling via NGFdependent histone hyperacetylation13.
The clinical safety profile of ALC in other neurological diseases (diabetic peripheral neuropathy, Alzheimer’s) has not given cause for serious concern14,15. Currently, there is no treatment which has a significant clinical impact leading to an improvement in CIPN symptoms and signs. Thus, ALC, in light of the existing preclinical evidence and its safety profile, appears to be a suitable candidate to be tested for the treatment of patients suffering from CIPN.”
“This study investigates whether or not carnitine deficiency is a risk factor and could contribute to cisplatin-induced liver toxicity. A total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, propionyl-l-carnitine (500 mg/kg), and d-carnitine (500 mg/kg), respectively, for 10 successive days. The fourth, fifth and sixth groups were injected intraperitoneally with the same doses of normal saline, propionyl-l-carnitine and d-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Administration of the standard nephrotoxic dose of cisplatin did not produce any changes in serum alanine transaminase and gamma-glutamyl transferase and no morphological changes in liver tissues. However, it did produce a significant increase in thiobarbituric acid reactive substances and total nitrate/nitrite and a significant decrease in reduced glutathione content in liver tissues. On the other hand, combined treatment with cisplatin and d-carnitine induced a dramatic increase in serum alanine transaminase and gamma-glutamyl transferase, as well as progressive reduction in total carnitine and ATP content in liver tissue. Moreover, histopathological examination of liver tissues confirmed the biochemical data, where cisplatin and d-carnitine combination showed signs of liver injury manifested as focal necro-inflammatory changes and portal inflammation. Interestingly, in carnitine supplemented rats using propionyl-l-carnitine, cisplatin did not produce any biochemical and histopathological changes in liver tissues. In conclusion, data from this study suggest for the first time that (1) carnitine deficiency is a risk factor and could precipitate cisplatin-induced hepatotoxicity, (2) oxidative stress is not the main cause of cisplatin-related hepatotoxicity and (3) propionyl-l-carnitine prevents the development of cisplatin-induced liver injury.”
“This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is a risk factor during development of cisplatin (CDDP)-induced cardiomyopathy and if so, whether carnitine supplementation by propionyl-L-carnitine (PLC) could offer protection against this toxicity. To achieve the ultimate goal of this study, a total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, PLC (500 mg kg(-1)), and d-carnitine (500 mg kg(-1)) respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, PLC and D-carnitine, respectively, for 5 successive days before and after a single dose of CDDP (7 mg kg(-1)). On day 6 after CDDP treatment, animals were sacrificed, serum as well as hearts were isolated and analyzed. CDDP resulted in a significant increase in serum creatine phosphokinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NO(x)) and a significant decrease in reduced glutathione (GSH), total carnitine, and adenosine triphosphate (ATP) content in cardiac tissues. In the carnitine-depleted rat model, CDDP induced dramatic increase in serum cardiomyopathy enzymatic indices, CK-MB and LDH, as well as progressive reduction in total carnitine and ATP content in cardiac tissue. Interestingly, PLC supplementation resulted in a complete reversal of the increase in cardiac enzymes, TBARS and NO(x), and the decrease in total carnitine, GSH and ATP, induced by CDDP, to the control values. Moreover, histopathological examination of cardiac tissues confirmed the biochemical data, where PLC prevents CDDP-induced cardiac degenerative changes while d-carnitine aggravated CDDP-induced cardiac tissue damage. In conclusion, data from this study suggest for the first time that carnitine deficiency and oxidative stress are risk factors and should be viewed as mechanisms during development of CDDP-related cardiomyopathy and that carnitine supplementation, using PLC, prevents the progression of CDDP-induced cardiotoxicity.”
“The present study examined whether propionyl-L-carnitine (PLC) could prevent the development of cisplatin (CDDP)-induced acute renal failure in rats. 2. Forty adult male Wistar albino rats were divided into four groups. Rats in the first group were injected daily with normal saline (2.5 mL/kg, i.p.) for 10 consecutive days, whereas the second group received PLC (250 mg/kg, i.p.) for 10 consecutive days. Animals in the third group were injected daily with normal saline for 5 consecutive days before and after a single dose of CDDP (7 mg/kg, i.p.). Rats in the fourth group received a combination of PLC (250 mg/kg, i.p.) for 5 consecutive days before and after a single dose of CDDP (7 mg/kg, i.p.). On Day 6 following CDDP treatment, animals were killed and serum and kidneys were isolated for analysis. 3. Injection of CDDP resulted in a significant increase in serum creatinine, blood urea nitrogen (BUN), thiobarbituric acid-reactive substances (TBARS) and total nitrate/nitrite (NO(x)), as well as a significant decrease in reduced glutathione (GSH), total carnitine, ATP and ATP/ADP in kidney tissues. 4. Administration of PLC significantly attenuated the nephrotoxic effects of CDDP, manifested as normalization of the CDDP-induced increase in serum creatinine, BUN, TBARS and NO(x) and the CDDP-induced decrease in total carnitine, GSH, ATP and ATP/ADP in kidney tissues. 5. Histopathological examination of kidney tissues from CDDP-treated rats showed severe nephrotoxicity, in which 50-75% of glomeruli and renal tubules exhibited massive degenerative changes. Interestingly, administration of PLC to CDDP-treated rats resulted in a significant improvement in glomeruli and renal tubules, in which less than 25% of glomeruli and renal tubules exhibited focal necrosis. 6. Data from the present study suggest that PLC prevents the development of CDDP-induced acute renal injury by a mechanism related, at least in part, to the ability of PLC to increase intracellular carnitine content, with a consequent improvement in mitochondrial oxidative phosphorylation and energy production, as well as its ability to decrease oxidative stress. This will open new perspectives for the use of PLC in the treatment of renal diseases associated with or secondary to carnitine deficiency.”
“Background: This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is an additional risk factor and/or a mechanism in cisplatin-induced nephrotoxicity and to gain insights into the possibility of a mechanism-based protection by L-carnitine against this toxicity. Methods: 60 male Sprague-Dawley rats were divided into six groups of 10 animals each and received one of the following treatments: The first three groups were injected intraperitoneally with normal saline, L-carnitine (500 mg/kg), and D-carnitine (750 mg/kg), respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, L-carnitine and D-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Six days after cisplatin treatment, the animals were sacrificed, and serum as well as kidneys were isolated and analyzed. Results: A single dose of cisplatin resulted in a significant increase in blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) and nitric oxide (NO) and a significant decrease in total carnitine, reduced glutathione (GSH) and adenosine triphosphate (ATP) content in kidney tissues. Interestingly, L-carnitine supplementation attenuated cisplatin-induced nephrotoxicity manifested by normalizing the increase of serum creatinine, BUN, MDA and NO and the decrease in total carnitine, GSH and ATP content in kidney tissues. In the carnitine-depleted rat model, cisplatin induced a progressive increase in serum creatinine and BUN as well as a progressive reduction in total carnitine and ATP content in kidney tissue. Histopathological examination of kidney tissues confirmed the biochemical data, i.e. L-carnitine supplementation protected against cisplatin-induced kidney damage, whereas D-carnitine aggravated cisplatin-induced renal injury. Conclusion: Data from this study suggest that: (1) oxidative stress plays an important role in cisplatin-induced kidney damage; (2) carnitine deficiency should be viewed as an additional risk factor and/or a mechanism in cisplatin-induced renal dysfunction, and (3) L-carnitine supplementation attenuates cisplatin-induced renal dysfunction.”
“Cisplatin in normal saline of pH 2.5 caused haemolysis of rat erythrocytes, whereas cisplatin in normal saline of pH 3.5 did not. Even a difference of 0.2 pH units appeared to be of significant importance: haemolysis of rat erythrocytes was observed with cisplatin in saline of pH 3.0 but not with cisplatin in saline of pH 3.2. The LD in mice was 15.4 mg/kg for cisplatin in saline of pH 2.5 versus 24.0 mg/kg for cisplatin in saline of pH 3.5. Experiments with cisplatin should include careful control of pH.”
“Hepatic drug metabolism is impaired in experimental animals and humans with renal diseases. An anticancer drug, cisplatin induces acute renal failure (ARF) in rats. Under the same experimental conditions, cisplatin causes down-regulation of hepatic cytochrome P450 (P450) enzymes in an isozyme selective manner. The present study examined the pathological role of ARF in the down-regulation of hepatic P450 enzymes in the cisplatin-treated rats. Male rats with single dose of intraperitoneally cisplatin (5 mg/kg) caused marked changes in renal parameters, BUN and serum creatinine but not hepatic parameters, serum alanine aminotransferase or aspartate aminotransferase. The rats also suffered from down-regulation of hepatic microsomal CYP2C11 and CYP3A2, male specific P450 isozymes, but not CYP1A2, CYP2E1, or CYP2D2. The decrease in serum testosterone level was also observed in injured rats, which was consistent with the selective effects on male specific P450 enzymes. Protection of rats against cisplatin-induced ARF by dimethylthiourea, a hydroxyl radical scavenger, also protected rats against the decrease in serum testosterone levels and the down-regulation of CYP2C11 and CYP3A2. Carboplatin, an analogue to cisplatin but no ARF inducer, did not cause decrease in serum testosterone levels and down-regulation of hepatic male specific P450 enzymes. These results suggest that down-regulation of hepatic P450 enzymes in male rats given cisplatin is closely related to the cisplatin-induced ARF and the resultant impairment of testis function.”
The present study examined whether the cisplatin-induced nephropathy could be ameliorated by administration of butein isolated from the stems of Rhus verniciflua STOCKS. The present study showed that polyuric profile was revealed in cisplatin-induced acute renal failure (ARF) rats associated with decreases in urinary sodium, potassium, chloride, and creatinine excretion, and osmolality. Among these renal functional parameters, urinary volume and osmolality were partially restored by administration of butein (10 mg/kg, i.p.), but electrolytes and creatinine excretion were not restored. Both solute-free water reabsorption and creatinine clearance were also significantly decreased in rats subjected to cisplatin. When butein was administered in rats with cisplatin-induced ARF for 4 d, solute-free water reabsorption was improved by 91% compared with that of cisplatin-induced ARF rats, but creatinine clearance was not restored. The expression levels of aquaporin 2 (AQP 2) in the inner, outer medulla, and cortex were significantly decreased in the kidney of ARF, which were partially reverted by administration of butein. In histological examination of the kidney, butein treatment partially prevented the lesions at tubules of renal cortex in cisplatin-induced ARF rats, while the lesions at glomeruli were not ameliorated. Taken together, butein ameliorates renal concentrating ability via up-regulation of renal AQP 2 water channel in rats with cisplatin-induced ARF without ameliorating effect on renal filtration defect.”
“The effects of cisplatin (5 mg/kg BW given intraperitoneally) on renal concentration mechanism were evaluated initially by clearance studies in rats 5-7 days after cisplatin administration and compared to normal rats. During hypotonic saline infusion, cisplatin rats showed a lower inulin clearance (0.56 +/- 0.07 vs. 1.12 +/- 0.09 ml/min/100 g BW, p less than 0.01), a higher fractional distal delivery (CNa + CH2O/Cin) (36.3 +/- 4.4 vs. 22.8 +/- 4.5%, p less than 0.05), and lower CH2O/CNa + CH2O (33.6 +/- 5.8 vs. 56.5 +/- 5.0%, p less than 0.01). During hypertonic saline infusion the TcH2O/Cosm was lower in cisplatin (18.3 +/- 1.1%) than in normal rats (33.4 +/- 3.5%, p less than 0.01). These results suggest a defect in NaCl transport in the thick ascending limb of Henle and proximal tubule. In order to characterize these tubular defects, we measured Na-K-ATPase activity (microM Pi/mg protein/h). In the renal cortex of cisplatin rats the ATPase activity was lower (18.1 +/- 3.2) than in normal rats (33.4 +/- 6.4, p less than 0.05), also in the inner strip of the outer medulla of cisplatin rats Na-K-ATPase was reduced (26.0 +/- 5.7) when compared with normal rats (67.3 +/- 9.2, p less than 0.01), presumably representing a decrease in enzyme activity in the thick ascending limb.”
Abstract The present study was designed to investigate the protective effects of L-carnitine (LC) on changes in the levels of lipid peroxidation and endogenous antioxidants induced by cisplatin (cis-diamminedichloroplatinum II, CDDP) in the liver and kidney tissues of rats. Twenty-four Sprague Dawley rats were equally divided into four groups of six rats each: control, cisplatin, L-carnitine, and L-carnitine plus cisplatin. The degree of protection produced by L-carnitine was evaluated by determining the level of malondialdehyde (MDA). The activity of glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione S-transferase (GST), and superoxide dismutase (SOD) were estimated from liver and kidney homogenates, and the liver and kidney were histologically examined as well. L-carnitine elicited significant liver and kidney protective activity by decreasing the level of lipid peroxidation (MDA) and elevating the activity of GSH, GSHPx, GST, and SOD. Furthermore, these biochemical observations were supported by histological findings. In conclusion, the present study indicates a significant role for reactive oxygen species (ROS) and their relation to liver and kidney dysfunction, and points to the therapeutic potential of LC in CDDP-induced liver and kidney toxicity.
Protein-cisplatin interactions lie at the heart of both the effectiveness of cisplatin as a therapeutic agent and side effects associated with cisplatin treatment. Because a greater understanding of the protein-cisplatin interactions at the molecular level can inform the design of cisplatin-like agents for future use, mass spectrometric determination of the binding site of cisplatin on a model protein, cytochrome c, was undertaken in this paper. The monoadduct cytochrome c-Pt(NH(3))(2)(H(2)O) is found to be the primary adduct produced by the cytochrome c-cisplatin interactions under native conditions. To locate the primary binding site of cisplatin, both free cytochrome c and the cytochrome c adducts underwent trypsin digestion, followed by Fourier transform mass spectrometry (FT-MS) to identify unique fragments in the adduct digest. Four such fragments were found in the adduct digest. Tandem mass spectrometry (MS/MS and MS(3) indicates that two fragments are Pt(NH(3))(2)(H(2)O) bound peptides (Gly56-Glu104 and Asn54-Glu104) with one water associated at the peptide bond Lys79-Met80, and the other two fragments are heme containing peptides (acety1-Gly1-Lys53 and acety1-Gly1-Lys55). The product-ion spectra of the four fragments reveal that Met65 is the primary binding site of cisplatin on cytochrome c.
The mechanism of mitochondrial damage, a key contributor to renal tubular cell death during acute kidney injury, remains largely unknown. Here, we have demonstrated a striking morphological change of mitochondria in experimental models of renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to mitochondrial outer membrane permeabilization, release of apoptogenic factors, and consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome c release and apoptosis. This mitochondrial fragmentation was inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a critical mitochondrial fission protein, translocated to mitochondria early during tubular cell injury, and both siRNA knockdown of Drp1 and expression of a dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome c release, caspase activation, and apoptosis. Further in vivo analysis revealed that mitochondrial fragmentation also occurred in proximal tubular cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. Notably, both tubular cell apoptosis and acute kidney injury were attenuated by mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury and identifies mitochondrial fragmentation as what we believe to be a novel mechanism contributing to mitochondrial damage and apoptosis in vivo in mouse models of disease.
BACKGROUND: Cisplatin-induced renal damage was associated with an inflammatory process. ATP-sensitive potassium channels can be involved in neutrophil migration. This study evaluated the effects of glibenclamide, an ATP-sensitive potassium channel blocker, on cisplatin-induced renal damage. METHODS: A total of 48 Wistar rats received glibenclamide (20 mg/kg/day, s.c.) and 24 h later, these animals, and an additional group of 45 rats, were injected with cisplatin (5 mg/kg, i.p.). In addition, 38 control rats were injected with saline, i.p. Twenty-four hours and 5 days after saline or cisplatin injections blood and urine samples were collected to evaluate renal function and the kidneys were removed for analysis of neutrophil accumulation, tumor necrosis factor-alpha and interleukin-1beta and histological and immunohistochemical studies. RESULTS: Cisplatin injection induced neutrophil recruitment and increased tumor necrosis factor-alpha and interleukin-1beta contents in renal cortices and outer medullae tissues. Cisplatin-treated rats also presented reduction in the glomerular filtration rate, as well as greater immunostaining for ED1 (macrophages/monocytes) and acute tubular necrosis. All of these alterations were reduced by treatment with glibenclamide. These effects seem to be related, at least in part, to the restriction of neutrophil recruitment and inflammatory process observed in the kidneys from glibenclamide+cisplatin-treated rats. 2007 S. Karger AG, Basel
BACKGROUND: Cisplatin is a major antineoplastic drug for the treatment of solid tumors, but it has dose-dependent renal toxicity. METHODS: We reviewed clinical and experimental literature on cisplatin nephrotoxicity to identify new information on the mechanism of injury and potential approaches to prevention and/or treatment. RESULTS: Unbound cisplatin is freely filtered at the glomerulus and taken up into renal tubular cells mainly by a transport-mediated process. The drug is at least partially metabolized into toxic species. Cisplatin has multiple intracellular effects, including regulating genes, causing direct cytotoxicity with reactive oxygen species, activating mitogen-activated protein kinases, inducing apoptosis, and stimulating inflammation and fibrogenesis. These events cause tubular damage and tubular dysfunction with sodium, potassium, and magnesium wasting. Most patients have a reversible decrease in glomerular filtration, but some have an irreversible decrease in glomerular filtration. Volume expansion and saline diuresis remain the most effective preventive strategies. CONCLUSIONS: Understanding the mechanisms of injury has led to multiple approaches to prevention. Furthermore, the experimental approaches in these studies with cisplatin are potentially applicable to other drugs causing renal dysfunction.
Statins have anti-inflammatory effects that are not directly related to their cholesterol-lowering activity. This study aimed to investigate the effect of simvastatin on the extent of tissue damage in cisplatin-induced nephrotoxicity and hepatotoxicity. The rats received a single intravenous injection of 2.5mgkg(-1) cisplatin. Other groups received either simvastatin (1mgkg(-1)) or the vehicle (ethanol:saline) intraperitoneally for 10 days beginning 5 days prior to cisplatin injection. All animals were decapitated 5 days after cisplatin administration. Trunk blood was collected and analyzed for blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), albumin, and total bilirubin levels. The urine samples were used for the calculation of creatinine clearance levels. The kidney and liver samples were stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content or were processed for histopathological examinations. Formation of reactive oxygen species in tissue samples was monitored by using chemiluminescence method. Simvastation reduced the extent of both kidney and liver damage and preserved both kidney and liver functions (p<0.01-0.001). Increase in liver MDA level with a concomitant reduction in GSH in the cisplatin group was attenuated by simvastatin treatment (p<0.05-0.01). Increase in tissue collagen content and chemiluminescence levels in the kidney and liver samples of the cisplatin group was also reversed by simvastatin (p<0.001). In conclusion, simvastatin is beneficial in cisplatin-induced kidney and liver dysfunction and organ damage in rats via prevention of lipid peroxidation and tissue fibrosis, preservation of antioxidant glutathione, and suppression of neutrophil infiltration.
BACKGROUND: Cisplatin is a chemotherapeutic agent used in treatment of malignant tumours. However, cisplatin produces various side effects, such as nephrotoxicity, neurotoxicity, emetogenesis and ototoxicity. Inflammation is an important mechanism of cisplatin nephrotoxicity. Alpha-lipoic acid (alpha-LA) has anti-inflammatory effects that inhibit both adhesion molecule expression in human endothelial cells and monocyte adhesion by suppressing the nuclear factor-kappaB (NF-kappaB) signalling pathway. The goals of this study were to investigate the anti-inflammatory effects of alpha-LA during cisplatin-induced renal injury and to examine the mechanisms of protection. METHODS: C57BL/6 mice were given cisplatin (20 mg/kg) with or without alpha-LA treatment (100 mg/kg for 3 days). Renal function, histological changes, adhesion molecule expression and inflammatory cell infiltration were examined. The effect of alpha-LA on NF-kappaB activity was evaluated by examining nuclear translocation and phosphorylation of NF-kappaB p65 subunits in kidney tissue. RESULTS: Cisplatin-induced decreases in renal function, measured by blood urea nitrogen, serum creatinine level and renal tubular injury scores, were attenuated by alpha-LA treatment. alpha-LA decreased the tissue levels of tumour necrosis factor-alpha, the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), and suppressed the infiltration of CD11b-positive macrophages. alpha-LA also attenuated the cisplatin-induced increases in the phosphorylation and nuclear translocation of NF- kappaB p65 subunits in kidney tissue. CONCLUSIONS: These results suggest that alpha-LA treatment ameliorates cisplatin-induced acute kidney injury by reducing inflammatory adhesion molecule expression and NF-kappaB activity.