Lipoic Acid Treatment Research Articles

Role of lipoic acid on insulin resistance and leptin in experimentally diabetic rats

Objective We aimed to examine the changes in serum insulin and leptin levels in induced type 1 diabetes mellitus in relationship to glycemic state and lipid profiles and to clarify the role of lipoic acid (LA). Methods Ninety-six male rats were equally divided into the following: a control group (normal, nondiabetic), a diabetic group induced by subcutaneous injection of alloxan (non-LA-treated), and an LA-treated diabetic group (for 4 weeks). Body weight, serum lipid profile, glucose, insulin, homeostasis model assessment–insulin resistance (HOMA-IR), and leptin were measured. Results This study showed a significant increase in serum triacylglycerol (TG), total cholesterol, glucose levels, and HOMA-IR and a significant decrease in body weight gain, insulin, and leptin levels in the diabetic group compared to the control group. LA treatment induced a significant decrease in glucose, TG, and total cholesterol levels and significantly increased serum insulin and leptin levels in comparison with the diabetic group. Conclusion Induced diabetes resulted in insulin resistance, hyperlipidemia, and hypoleptinemia, while LA ameliorates these changes and improves insulin sensitivity.

Chronic lipoic acid treatment worsens energy imbalances in streptozotocin-induced diabetic rats

Aim Our objective was to verify the energy balance in streptozotocin-induced diabetic rats chronically treated with lipoic acid (LA). Methods Diabetes was induced in rats by streptozotocin and the animals divided into four groups, comprising controls and diabetic rats, with each group receiving either daily intraperitoneal LA (30 mg/kg) or a buffer solution for 30 days. Body weight, food intake and stool and urine collections were recorded daily. On day 30, animals were sacrificed and the carcasses, faeces and urine collected and processed for calorimetric analysis. Blood glucose and insulin were also determined. Results All parameters of energy balance were affected by diabetes. LA treatment reduced weight gain, energy gain and gross food efficiency in both control and diabetic animals. However, the LA-treated animals tended to show higher energy expenditure than non-treated animals. Body composition was also affected by diabetes: fat content was impaired by LA treatment in both control and diabetic animals. The latter also showed increased glycaemia and decreased insulinaemia, but LA had no effect on these parameters. Conclusion Our results indicate that chronic treatment with LA aggravates energy imbalances in diabetic animals. Moreover, our data suggest the need to reconsider the use of LA as an adjuvant in the prevention and treatment of type 1 diabetes.

Modulation of antioxidant and detoxification responses mediated by lipoic acid in the fish Corydoras paleatus (Callychthyidae)

Lipoic acid (LA) has been reported as a potential therapeutic agent due its antioxidants proprieties. It was considered its effect in different organs (gills, brain, muscle and liver) of the fish Corydoras paleatus (Callychthyidae). LA (70 mg/kg of body mass) was added to a commercial fish diet, organisms being fed daily (1% body weight). Sixty animals (mean mass: 2.37 ± 0.09 g) were placed randomly in aquariums and received (+ LA) or not (− LA) lipoic acid enriched diet during four weeks. After, fish were killed and the brain, muscle, gills and liver were dissected. LA treatment reduced significantly ( p < 0.05) reactive oxygen species concentration in brain and increased ( p < 0.05) glutamate-cysteine ligase activity in brain and liver of the same experimental group. LA fed organisms showed higher ( p < 0.05) brain glutathione-S-transferase activity, indicating that LA improves the detoxification and antioxidant capacity face components that waste glutathione in phase II reactions. A conspicuous reduction of protein oxidation was observed in muscle and liver of + LA organisms, indicating that the treatment was also effective in reducing oxidative stress parameters.

Regulation of cell cycle transition and induction of apoptosis in HL-60 leukemia cells by lipoic acid: role in cancer prevention and therapy

BackgroundLipoic acid (LA), a potent antioxidant, has been used as a dietary supplement to prevent and treat many diseases, including stroke, diabetes, neurodegenerative and hepatic disorders. Recently, potent anti-tumorigenic effects induced by LA were also reported and evident as assayed by suppression of cell proliferation and induction of apoptosis in malignant cells. However, the mechanism by which LA elicits its chemopreventive effects remains unclear.Methods and ResultsHerein, we investigated whether LA elicits its anti-tumor effects by inducing cell cycle arrest and cell death in human promyelocytic HL-60 cells. The results showed that LA inhibits both cell growth and viability in a time- and dose-dependent manner. Disruption of the G1/S and G2/M phases of cell cycle progression accompanied by the induction of apoptosis was also observed following LA treatment. Cell cycle arrest by LA was correlated with dose-dependent down regulation of Rb phosphorylation, likely via suppression of E2F-dependent cell cycle progression with an accompanying inhibition of cyclin E/cdk2 and cyclin B1/cdk1 levels. Evidence supporting the induction of apoptosis by LA was based on the appearance of sub-G1 peak in flow cytometry analysis and the cleavage of poly(ADP-ribose) polymerase (PARP) from its native 112-kDa form to the 89-kDa truncated product in immunoblot assays. Apoptosis elicited by LA was preceded by diminution in the expression of anti-apoptotic protein bcl-2 and increased expression of apoptogenic protein bax, and also the release and translocation of apoptosis inducing factor AIF and cytochrome c from the mitochondria to the nucleus, without altering the subcellular distribution of the caspases.ConclusionThis study provides evidence that LA induces multiple cell cycle checkpoint arrest and caspase-independent cell death in HL-60 cells, in support of its efficacious potential as a chemopreventive agent.

Efficacy of DL-α lipoic acid against systemic inflammation-induced mice: antioxidant defense system

Inflammation can activate macrophages or monocytes and sequentially release several inflammatory cytokines and reactive oxygen species (ROS). Oxidative stress-induced acute inflammatory response plays an important role in several diseases. This study was designed to investigate the prophylactic effect of the antioxidant lipoic acid (LA) during inflammation-induced mice. Mice were divided in to three groups (n = 8 in each): control, systemic inflammation, and LA treated mice with systemic inflammation. Results show that ROS was significantly higher in lymphocytes, hepatocytes, and astrocytes (P < 0.05) of inflammation induced mice when compared with control but no significant changes were observed in the LA treated group. Increased levels of lipid peroxidation (LPO) and decreased activities of oxidants such as superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione, and ATPase were observed in the inflammation-induced mice, which returned to near normalcy following LA therapy. In vitro study has shown that LA treatment not only suppresses the increased LPO levels but also inhibits the lipid break down resulting from autoxidation. In addition, increased immunoreactivity of the astrocyte marker glial fibrillary acidic protein (GFAP) was observed in the neocortex region of inflammation-induced mice, whereas nuclear factor kappa B p65 (NFkappaB) immunoreactivity was observed in both the neocortex and liver of the same group which were effectively controlled by LA therapy suggesting that LA can efficiently manage systemic inflammation.

Protective Effect of Lipoic Acid against Methylglyoxal-Induced Oxidative Stress in LLC-PK1 Cells

Methylglyoxal (MG), a reactive dicarbonyl compound, is a metabolic byproduct of glycolysis often found at high levels in blood from diabetic patients. The effect of lipoic acid on MG-induced oxidative stress was investigated using LLC-PK(1) renal tubular epithelial cells, which are susceptible to oxidative stress. MG (500 microM) treatment induced LLC-PK(1) cell death to nearly 50% compared with non-treated control cells, but lipoic acid significantly inhibited the MG-induced cytotoxicity in a concentration-dependent manner. In addition, lipoic acid treatment dose-dependently reduced the intracellular reactive oxygen species level increased by 500 microM MG. The nitric oxide level was also increased by 500 microM MG treatment, but it was significantly inhibited by lipoic acid. Furthermore, lipoic acid treatment at 50 microM inhibited the nuclear translocation of nuclear factor-kappa B induced by MG treatment in LLC-PK(1) cells. These findings indicate that lipoic acid has potential as a therapeutic agent against the development of diabetic complications related to MG-induced oxidative stress in diabetes.

Alpha - Lipoic Acid Decreases DNA Damage and Oxidative Stress Induced by Alcohol in the Developing Hippocampus and Cerebellum of Rat

Background / aims: The present study was initiated in order to investigate the protective effects of α-lipoic acid upon ethanol-induced DNA damage, lipid peroxidation and protein oxidation in the developing rat hippocampus and cerebellum. Methods: Pregnant Wistar rats received ethanol with, or without lipoic acid from gestation day (GD) 7 throughout lactation. The changes in DNA damage, protein carbonyl, lipid hydroperoxide, catalase and superoxide dismutase activities were measured in the hippocampus and cerebellum of male offspring at the end of the lactation period. Results: The results indicated that DNA damage, lipid peroxidation and protein oxidation in the hippocampus and cerebellum were significantly elevated in animals that received alcohol. However, the catalase and superoxide dismutase activity results showed patterns that differed from those of DNA damage, lipid peroxidation and protein oxidation. Lipoic acid treatment significantly decreased DNA damage compared with the group that were administered alcohol alone, and restored the elevated protein carbonyl and lipid hydroperoxide levels to the levels of the control group. Conclusions: Our findings confirm that oxidative stress and DNA damage occur in the developing hippocampus and cerebellum as a result of alcohol administration, and also suggest that lipoic acid has protective effects as an antioxidant against alcohol-induced disorders in the developing hippocampus and cerebellum.

Early lipoic acid intake protects retina of diabetic mice

The aim of this study was to test the effect of lipoic acid treatment on the retina after a short diabetic insult. Diabetes was induced by alloxan and mice were divided into sub-groups; control, diabetic, diabetic+insulin and all groups received±lipoic acid (100 mg/kg body weight) for 3 weeks. GSH content, MDA concentration, GPx activity were measured and electroretinograms (ERG) were recorded. Early administration of lipoic acid to diabetic mice prevented the statistically significant decreases of GSH content and GPx activity and normalized MDA concentration. Moreover, lipoic acid restored electroretinogram b-wave amplitude of diabetic animals to control values. Lipoic acid has a protective effect on the diabetic retina.

Therapeutic efficacy of dl-α-lipoic acid on cyclosporine A induced renal alterations

The present study was designed to evaluate the possible beneficial effect of lipoic acid in preventing the renal damage induced by cyclosporine A in rats. Male albino rats of Wistar strain were divided into four groups and treated as follows. Two groups received cyclosporine A by oral gavage (25 mg/kg/body weight) for 21 days to induce nephrotoxicity, one of which simultaneously received lipoic acid treatment (20 mg/kg body weight) for 21 days. A vehicle (olive oil) and a lipoic acid drug control were also included. Cyclosporine A induced renal damage was evident from the decreased activities of tissue marker enzymes (alkaline phosphatase, acid phosphatase, lactate dehydrogenase, aspartate transaminase and alanine transaminase) and decreased activities of ATPases (Na+, K+-ATPase, Ca2+-ATPase and Mg2+ ATPase). An apparent increase in the levels of serum constituents (urea, uric acid and creatinine) and urinary marker enzymes (N-acetyl-beta-D-glucosaminidase, beta-glucosidase, beta-galactosidase, cathepsin-D and gamma-glutamyl transpeptidase) along with significant decline in creatinine clearance were seen in the cyclosporine treated rats, which was reversed upon treatment with lipoic acid. Ultrastructural observations were also in agreement with the above abnormal changes. Lipoic acid effectively reverted these abnormal biochemical changes and minimized the morphological lesions in renal tissue. Hence, this study clearly exemplifies that lipoic acid might be an ideal choice against cyclosporine A induced cellular abnormalities.

Oxidative stress reduces renal dopamine D1 receptor-Gq/11α G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2

The dopamine D1 receptors (D1R), expressed in renal proximal tubules, participate in the regulation of sodium transport. A defect in the coupling of the D1R to its G protein/effector complex in renal tubules has been reported in various conditions associated with oxidative stress. Because G protein-coupled receptor kinases (GRKs) are known to play an important role in D1R desensitization, we tested the hypothesis that increased oxidative stress in obese Zucker rats may cause GRK2 upregulation and, subsequently, D1R dysfunction. Lean and obese rats were given normal diet or diet supplemented with antioxidant lipoic acid for 2 wk. Compared with lean rats, obese rats exhibited oxidative stress, D1R were uncoupled from G(q/11)alpha at basal level, and SKF-38393 failed to elicit D1R-G protein coupling, stimulate phospholipase C (PLC), and inhibit Na-K-ATPase activity. These animals showed increased basal protein kinase C (PKC) activity and membranous translocation of GRK2 and increased GKR2-G(q/11)alpha interaction and D1R serine phosphorylation. Enzymatic dephosphorylation of D1R restored SKF-38393-induced adenylyl cyclase stimulation but not PLC activation. Treatment of obese rats with lipoic acid restored D1R-G protein coupling and SKF-38393-induced PLC stimulation and Na-K-ATPase inhibition. Lipoic acid treatment also normalized PKC activity, GRK2 sequestration, and GKR2-G(q/11)alpha interaction. In conclusion, these data show that oxidative stress increases PKC activity causing GRK2 membranous translocation. GRK2 interacts with G(q/11)alpha and acts, at least in part, as a regulator of G protein signaling leading to the D1R-G(q/11)alpha uncoupling, causing inability of SKF-38393 to stimulate PLC and inhibit Na/K-ATPase. Lipoic acid, while reducing oxidative stress, normalized PKC activity and restored D1R-G(q/11)alpha-PLC signaling and the ability of SKF-38393 to inhibit Na-K-ATPase activity.

Alpha-Lipoic Acid Protects against Hepatic Ischemia-Reperfusion Injury in Rats

Background and Aim: To evaluate the protective effect of alpha-lipoic acid in reducing oxidative damage after severe hepatic ischemia/reperfusion (IR) injury. Methods: Wistar albino rats were subjected to 45 min of hepatic ischemia, followed by 60 min reperfusion period. Lipoic acid (100 mg/kg i.p.) was administered 15 min prior to ischemia and immediately before reperfusion period. At the end of the reperfusion period aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) activity, and cytokine, TNF-α and IL-1β levels were determined in serum samples. Malondialdehyde (MDA), and glutathione (GSH) levels and myeloperoxidase (MPO) activity were determined in the liver tissue samples while formation of reactive oxygen species was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Tissues were also analyzed histologically. Results: Serum ALT, AST, and LDH activities and TNF-α and IL-1β levels were elevated in the I/R group, while this increase was significantly lower in the group of animals treated concomitantly with lipoic acid. Hepatic GSH levels, significantly depressed by I/R, were elevated back to control levels in lipoic acid-treated I/R group. Furthermore, increases in tissue luminol and lucigenin CL, MDA levels and MPO activity due to I/R injury were reduced back to control levels with lipoic acid treatment. Conclusion: Since lipoic acid administration alleviated the I/R-induced liver injury and improved the hepatic structure and function, it seems likely that lipoic acid with its antioxidant and oxidant-scavenging properties may be of potential therapeutic value in protecting the liver against oxidative injury due to ischemia-reperfusion.

The Efficacy of α-lipoic Acid on the Endotoxin-induced Acute Lung Injury

Background: Oxidative stress may play an important role in the pathogenesis of endotoxin-induced acute lung injury (ALI). This study evaluated the therapeutic effect of -lipoic acid, a nonenzymatic antioxidant, in a rat model of lipopolysaccharide (LPS) induced ALI. Materials and Methods: ALI was induced in Sprague-Dawley rats by instilling LPS (E.coli, 3mg/Kg) into the trachea. The rats were classified into the control, control+-lipoic acid, LPS, and LPS+-lipoic acid groups.The lung lavage neutrophil count, cytokine-induced neutrophil chemoattractant (CINC), lung myeloperoxidase (MPO), and cytokine concentrations (TNF-, IL-, IL-6 and IL-10) were measured at 2 h and 6 h after LPS administration. Results: The total cell and neutrophil counts of the LPS+-lipoic acid groups were significantly lower than the LPS groups. The protein concentration in the BAL fluid was similar in the LPS groups and LPS+-lipoic acid groups. The TNF-, IL-, and IL-6 concentrations in the BAL fluid were not decreased by the -lipoic acid treatment in the LPS treated rats. Conclusions: Although -lipoic acid decreased the level of LPS-induced neutrophil infiltration into the lung, it could not attenuate the LPS-induced ALI at the dose administered in this study.

THE EFFECT OF LIPOIC ACID ON LIPID PEROXIDATION AND VISUAL EVOKED POTENTIALS (VEPS) IN RATS EXPOSED TO CHRONIC RESTRAINT STRESS

The purpose of the present study was to investigate the effect of lipoic acid on lipid peroxidation, nitric oxide production, and visual evoked potentials (VEPs) in rats exposed to chronic restraint stress and to examine whether lipoic acid could prevent VEP alterations that occurred in stress together with lipid peroxidation. Forty male wistar rats, aged three months, were used in the present study. They were equally divided into four groups: control (C), the group treated with lipoic acid (L), the group exposed to restraint stress (S), and the group exposed to stress and treated with lipoic acid (LS). Chronic restraint stress was applied for 21 days (1 h/day) and lipoic acid (100 mg/kg/day) was injected intraperitonally to the L and LS groups for the same period. Brain and retina TBARS levels were significantly increased in the S group compared with the C group. Lipoic acid reduced retina and brain TBARS levels in the L and LS groups compared with their corresponding control groups. Restraint stress significantly increased nitrite and nitrate levels in both brain and retina in the stress group with respect to the control group. Lipoic acid produced a significant decrease in brain and retina nitrite and nitrate levels of the L and LS groups comparing with their corresponding control groups. All latencies of VEP components were prolonged in the S group with respect to the C group. The study found significant correlations between VEPs latencies and TBARS and nitrite and nitrate levels of retina and brain. Lipoic acid decreased the latencies of all VEP components in the LS group whereas it did not affect them in the L group with respect to their control groups. In summary, lipoic acid treatment was found effective in preventing VEP and TBARS alterations caused by stress.

Protection Against Arsenic Trioxide-Induced Autophagic Cell Death in U118 Human Glioma Cells by Use of Lipoic Acid

P-698 Introduction: Exposure to toxic heavy metals has become an increasingly recognized source of illness worldwide. Arsenic is an environmental toxicant found naturally in ground water. Neurotoxic effects have been reported in clinical cases and animal experiments with chronic exposure to arsenic. Epidemiological studies also have suggested a correlation between arsenic exposure and potential neurotoxicity. Lipoic acid is a thiol-compound naturally occurring in plants and animals, which is thought to be a strong antioxidant and possess neuroprotective effects. The objective of this study was to determine if the AS2O3-induced neurotoxic effects could be prevented by lipoic acid. The U118 human glioma cell was selected as a research model. Methods: In this study, U118 cells were treated with As2O3 alone or in combination with lipoic acid, and the viability of the cells was determined with MTT assay. DNA fragmentation assay and flow cytometric analysis were performed to confirm the apoptotic cells with Annexin V-PI staining. Supravital cell staining with acridine orange was performed to detect the autophagic cell death. The regulatory proteins which were related to apoptosis was determined by immunoblotting analysis, using antibodies including HSP70, p53, p21/Cip1, Bax, and Bcl2. Results: The viability assays revealed that 50% mortality of the AS2O3-treated cells that died within 24 hrs was reversed by lipoic acid. The lipoic acid treatment promoted long-term survival in cells treated with AS2O3 and provided more than 80% protection during days 2–3. We also found that autophagic, but not apoptotic cell death was significantly induced by AS2O3 in U118 cells, and that AS2O3-mediated autophagic cell death was nearly completely attenuated by lipoic acid. The down-regulation of p53 and Bax proteins and the up-regulation of Bcl-2 and HSP-70 proteins were involved in AS2O3-mediated autophagic cell death. Discussion and Conclusions: The present study demonstrated for the first time that AS2O3-induced neurotoxicity could be completely attenuated by lipoic acid in U118 cells. Apoptotic neuronal cell death was suggested as a general mechanism underlying arsenic neurotoxicity. However, when U118 cells were exposed to AS2O3, autophagy but not apoptosis was induced. Such results implied that U118 cells response to AS2O3 must be regulated by different signaling mechanisms rather than the general apoptotic mechanism. Our results provide the molecular basis for the lipoic acid prevention of AS2O3-induced cell death in U118 cells; such observations may have significance in clinical application.

Protective effect of dl-α-lipoic acid on cyclophosphamide induced hyperlipidemic cardiomyopathy

Cyclophosphamide is a potent alkylating agent used in cancer chemotherapy and immunosuppression. The present study is aimed at evaluating the role of a potent antioxidant lipoic acid in cyclophosphamide induced hyperlipidemic cardiomyopathy. Adult male Wistar rats were divided into four treatment groups. Two groups received single intraperitoneal injection of cyclophosphamide (200 mg/kg body weight) to induce cardiotoxicity, one of these groups received lipoic acid treatment (25 mg/kg body weight, orally for 10 days). A vehicle treated control group and a lipoic acid drug control were also included. Cyclophosphamide administration resulted in abnormal elevation of serum lipids. Similarly in the cardiac tissue, the levels of free cholesterol, esterified cholesterol, triglycerides were increased significantly ( P < 0.05) while the levels of phospholipids and free fatty acids were reduced significantly unlike serum ( P < 0.05). Serum Low Density Lipoprotein (LDL) and Very Low Density Lipoprotein (VLDL) cholesterol increased significantly ( P < 0.05) while High Density Lipoprotein (HDL) cholesterol ( P < 0.05) decreased significantly when compared to controls. These changes corroborated with the abnormal distortion in the activities of lipid metabolizing enzymes in cyclophosphamide treated group. Supplementation of lipoic acid reverted these abnormalities in the lipid levels and activities of lipid metabolizing enzymes to near normalcy after cyclophosphamide administration.

Role of lipoic acid in reducing the oxidative stress induced by cyclosporine A

Background Cyclosporine A (CsA) is the first choice immunosuppresant universally used for the prevention of allograft rejection in solid organ transplantation and immune-mediated diseases. However, with increasing use, evidence has accumulated that CsA therapy is associated with a variety of side effects, the most important being nephrotoxicity. We investigated the potential role of dl-α lipoic acid (LA), a universal antioxidant in combating the oxidative stress induced by CsA. Methods Adult male albino Wistar rats were divided into 4 treatment groups. Two groups received CsA (25 mg/kg body weight, orally for 21 days) to induce nephrotoxicity. One of these groups received LA treatment (20 mg/kg body weight, orally) for 21 days concurrently during CsA administration. A vehicle treated control group and a LA drug control were also included. Results CsA-induced nephrotoxicity was assessed in terms of increased activities of serum marker enzymes; alkaline phosphatase, acid phosphatase and lactate dehydrogenase. An apparent rise in the activities of N-acetyl-β- d-glucosaminidase, β-glucuronidase and cathepsin D were seen in the renal tissue of CsA given rats, which were reversed upon treatment with LA. CsA administration induced significant elevation in lipid peroxidation along with abnormal levels of enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione- S-transferase and glucose-6-phosphate dehydrogenase) and non-enzymic antioxidants (glutathione, vitamins C and E) in the rat kidney. LA administration improved renal function, by bringing about a significant decrease in peroxidative levels and increase in antioxidant status. Conclusion These results indicate that LA has a protective action against CsA nephrotoxicity and suggest that the LA may find clinical application against a variety of toxins where cellular damage is a consequence of reactive oxygen species.

Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: Prevention by lipoic acid treatment

BackgroundA reduction in the number of podocytes and podocyte density has been documented in the kidneys of patients with diabetes mellitus. Additional studies have shown that podocyte injury and loss occurs in both diabetic animals and humans. However, most studies in animals have examined relatively long-term changes in podocyte number and density and have not examined effects early after initiation of diabetes. We hypothesized that streptozotocin diabetes in rats and mice would result in an early reduction in podocyte density and that this reduction would be prevented by antioxidants.MethodsThe number of podocytes per glomerular section and the podocyte density in glomeruli from rats and mice with streptozotocin (STZ)-diabetes mellitus was determined at several time points based on detection of the glomerular podocyte specific antigens, WT-1 and GLEPP1. The effect of insulin administration or treatment with the antioxidant, α-lipoic acid, on podocyte number was assessed.ResultsExperimental diabetes resulted in a rapid decline in apparent podocyte number and podocyte density. A significant reduction in podocytes/glomerular cross-section was found in STZ diabetes in rats at 2 weeks (14%), 6 weeks (18%) and 8 weeks (34%) following STZ injection. Similar declines in apparent podocyte number were found in STZ diabetes in C57BL/6 mice at 2 weeks, but not at 3 days after injection. Treatment with α-lipoic acid substantially prevented podocyte loss in diabetic rats but treatment with insulin had only a modest effect.ConclusionSTZ diabetes results in reduction in apparent podocyte number and in podocyte density within 2 weeks after onset of hyperglycemia. Prevention of these effects with antioxidant therapy suggests that this early reduction in podocyte density is due in part to increased levels of reactive oxygen species as well as hyperglycemia.

Protective effect of lipoic acid on cyclophosphamide-induced testicular toxicity

Background Cyclophosphamide (CP), a widely used anticancer and immunosuppressive drug causes severe testicular toxicity. We investigated the protective effect of lipoic acid in CP-induced testicular toxicity. Methods Two groups of male Wistar rats (140 ± 20 g) were administered CP (15 mg/kg body weight, oral gavage) once a week for 10 weeks to induce testicular toxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight, i.p., 24 h prior to CP administration) once a week for 10 weeks. A vehicle treated control and a lipoic acid control groups were also included. Results The untreated CP exposed rats showed a significant increase in testicular reactive oxygen species (ROS) level, along with a significant decrease in cellular thiol levels. The activities of testicular marker enzymes such as γ-glutamyl transferase, β-glucuronidase, acid phosphatase and alkaline phosphatase were increased whereas the activities of sorbitol dehydrogenase and lactate dehydrogenase-X were decreased significantly in the animals treated with CP. In contrast, rats pretreated with lipoic acid showed normal marker enzymic patterns and normal levels of ROS and thiols. Testicular protection by lipoic acid is further substantiated by the normal histologic findings as against shrunken seminiferous tubules with impaired spermatogenesis in the CP administered rats. Conclusions By the reversal of biochemical and morphological changes towards normalcy, the cytoprotective role of lipoic acid is illuminated in CP-induced testicular toxicity.

Chemoprotective effect of lipoic acid against cyclophosphamide-induced changes in the rat sperm

Treatment with cyclophosphamide (CP), a commonly used anticancer and immunosuppressive agent, may result in oligospermia and azoospermia. CP administration induces oxidative stress and is cytotoxic to normal cells. In this context, we have studied the effect of an established antioxidant, lipoic acid on its influence on CP-induced oxidative injury in rat sperm. In this study, we have assessed the possible protective efficacy of lipoic acid on the sperm characteristics, peroxidative damages and abnormal antioxidant levels in the epididymal sperm of CP-administered rats. Male Wistar rats of 140 ± 20 g were categorized into four groups. Two groups of rats were administered CP (15 mg/kg body weight once a week for 10 weeks by oral gavage) to induce testicular toxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight intraperitoneally once a week for 10 weeks; 24 h prior to CP administration). A vehicle treated control group and a lipoic acid drug control group were also included. CP-treated rats showed a significant decrease in sperm count and motility with an increase in dead and abnormal sperms. The epididymal sperm of untreated CP-exposed rats showed 1.9-fold increase in lipid peroxidation, along with a significant increase in protein carbonyl level. These changes were associated with significant increase in DNA damage in the sperm as evidenced by increased single strand breaks in fluorimetric analysis of DNA unwinding (FADU). In rats treated with CP, abnormal changes in the activities/levels of enzymic (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymic (reduced glutathione, ascorbate and α-tocopherol) antioxidants, were also observed. Pretreatment with lipoic acid improved the semen quality and reduced the oxidative stress and DNA damage induced by CP, thereby demonstrating the protection rendered by lipoic acid.

Mitigation of oxidative stress in cyclophosphamide-challenged hepatic tissue by DL-α-lipoic acid

The present study investigated the protective effect of DL-alpha-lipoic acid on the tissue peroxidative damage and abnormal antioxidant levels in cyclophosphamide (CP) induced hepatotoxicity. Male Wistar rats of 140 +/- 20 g were categorized into four groups. Two groups were administered CP (15 mg/kg body weight once a week for 10 weeks by oral gavage) to induce hepatotoxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight intraperitoneally once a week for 10 weeks; 24 h prior to the CP administration). A vehicle (saline) treated control group and a lipoic acid drug control group were also included. The extent of liver damage in CP-induced rats was evident from the increased activities of serum aminotransferases, alkaline phosphatase and lactate dehydrogenase; whereas lipoic acid pretreatment prevented the rise in these marker enzymes. We evaluated the changes in activities/levels of tissue enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase) and non-enzymic (reduced glutathione, ascorbate and a-tocopherol) antioxidants along with malondialdehyde levels in the experimental groups. In CP-administered rats the antioxidant enzymes showed significantly depressed activities (p < 0.001, p < 0.01) and the antioxidant molecules also showed depleted levels (p < 0.001, p < 0.01), in comparison with the control group. However the extent of lipid peroxidation and the abnormal antioxidant status were normalized in lipoic acid pretreated rats. The present work highlights the efficacy of lipoic acid as a cytoprotectant in CP-induced hepatic oxidative injury.