Protective Effect Of Lipoic Acid Research Articles

Manganese-induced neurotoxicity and the potential protective effects of lipoic acid and Spirulina platensis

Manganese (Mn) is essential for many physiological processes; however, its excessive accumulation in the brain causes severe dysfunctions in the nervous system. Oxidative stress is thought to be involved in Mn‐induced neurotoxicity. The aim of this study was to evaluate the neurotoxic effects of Mn and the potential protective effects of alpha lipoic acid (ALA) and Spirulina platensis (SP), each alone and in combination. Sixty-four male albino rats were divided into eight equal groups: group 1 was used as control, group 2 received saline, which used as a vehicle, group 3 received ALA (50 mg/kg/day), group 4 received SP (300 mg/kg/day), group 5 received Mn (74 mg/kg, 5 days/week), group 6 received Mn + ALA, group 7 received Mn + SP, group 8 received Mn + ALA + SP. Groups 6, 7 and 8 received the same previously mentioned doses. All treatments were orally gavaged for 8 weeks. Mn administration caused neurobehavioral changes, increases of brain and serum Mn and malondialdehyde (MDA), with decreased glutathione peroxidase (GPx), dopamine and acetylcholine levels. The co-treatment with ALA and SP revealed their ability to protect against oxidative damage, neurobehavioral and biochemical changes induced by Mn.

Protective effects of lipoic acid against acrylamide-induced neurotoxicity: involvement of mitochondrial energy metabolism and autophagy.

Acrylamide (ACR) is a chronic neurotoxin that is generated in high-starch foods during heat processing. Alpha-lipoic acid (LA) is an antioxidant that occurs in most plants and animals. The objective of this study was to reveal the mechanism of ACR-triggered neurotoxicity and identify the protective role of LA in SH-SY5Y cells. In this study, LA restored ACR-stimulated depletion of glutathione content and mitochondrial membrane potential, moderated the activation of inflammatory pathways, and recovered the Keap1/Nrf2 pathway. Moreover, LA upregulated the activities of oxidative phosphorylation complexes and diminished ACR-induced variation in AMPK/GSK3β, Ca2+ disturbance, and ATP depletion. The Sirt1/PGC-1α pathway was inhibited by ACR. Notably, autophagy was activated in the mitochondria-mediated apoptosis induced by ACR, which was also blocked by LA. Overall, our study demonstrated the pivotal roles of the mitochondrial energy metabolism and autophagy in the protective effects of LA and cytotoxicity of ACR in SH-SY5Y cells.

Functional and structural changes of the urinary bladder following spinal cord injury; treatment with alpha lipoic acid.

Alpha lipoic acid (LA) was shown to exert neuroprotection in trauma-induced spinal cord injury (SCI), which is frequently associated with urinary bladder complaints in patients with SCI. Accordingly, the protective effects of LA on biochemical and histological changes in bladder as well as functional studies were assessed. Wistar albino rats were divided as control, SCI, and LA (50 mg/kg/day, ip) treated SCI groups (SCI+LA). The standard weight-drop (100 g/cm force at T10) method was used to induce a moderately severe SCI. One week after the injury, neurological examination was performed and the rats were decapitated. Bladder samples were taken for histological examination, functional (isolated tissue bath) studies, and for the measurement of biochemical parameters (malondialdehyde, MDA; gluthathione, GSH; nerve growth factor, NGF; caspase-3, luminol and lucigenin chemiluminescences). SCI caused a significant (P < 0.001) increase in the detrusor muscle thickness. It increased the contractility responses to carbachol and relaxation responses to papaverine (P < 0.05-0.001). There were also significant alterations in MDA, caspase-3, luminol, and lucigenin chemiluminescences with concomitant decreases in NGF and GSH (P < 0.05). LA treatment reversed histological and functional (contraction and relaxation responses) changes induced by SCI (P < 0.05-0.001), but no significant recovery was observed in the impaired neurological functions. These results indicate that LA have a beneficial effect in improving the bladder tonus via its antioxidant and anti-inflammatory actions following SCI.

Effects of Lipoic Acid Supplementation on Activities of Cyclooxygenases and Levels of Prostaglandins E2 and F2α Metabolites, in the Offspring of Rats with Streptozotocin-Induced Diabetes.

Background. Our aim was to evaluate the protective effect of lipoic acid (LA) on fetal outcome of diabetic mothers. Methods. Diabetes was induced in female rats using streptozotocin and rats were made pregnant. Pregnant control (group 1; n = 9; and group 2; n = 7) or pregnant diabetic (group 3; n = 10; and group 4; n = 8) rats were treated daily with either LA (groups 2 and 4) or vehicle (groups 1 and 3) between gestational days 0 and 15. On day 15 of gestation, the fetuses, placentas, and membranes were dissected, examined morphologically, and then homogenized, to measure cyclooxygenase (COX) activities and metabolisms of prostaglandin (PG) E2 (PGEM) and PGF2 α (PGFM) levels. The level of total glutathione was measured in the maternal liver and plasma and in all fetuses. Results. Supplementation of diabetic rats with LA was found to significantly (p < 0.05) reduce resorption rates in diabetic rats and led to a significant (p < 0.05) increase in liver, plasma, and fetuses total glutathione from LA-TD rats as compared to those from V-TD. Decreased levels of PGEM and elevated levels of PGFM in the fetuses, placentas, and membranes were characteristic of experimental diabetic gestation associated with malformation. The levels of PGEM in malformed fetuses from LA-TD mothers was significantly (p < 0.05) higher than those in malformed fetuses from V-TD rats. Conclusions. LA treatment did not completely prevent the occurrence of malformations. Thus, other factors may be involved in the pathogenesis of the diabetes-induced congenital malformations.

Evidence for protective effect of lipoic acid and desvenlafaxine on oxidative stress in a model depression in mice.

Oxidative stress is implicated in the neurobiology of depression. Here we investigated oxidative alterations in brain areas of animals submitted to the model of depression induced by corticosterone (CORT) and the effects of the antioxidant compound alpha-lipoic acid (ALA) alone or associated with the antidepressant desvenlafaxine (DVS) in these alterations. Female mice received vehicle or CORT (20 mg/kg) during 14 days. From the 15th to 21st days different animals received further administrations of: vehicle, DVS (10 or 20 mg/kg), ALA (100 or 200 mg/kg), or the combinations of DVS10+ALA100, DVS20+ALA100, DVS10+ALA200, or DVS20+ALA200. Twenty-four hours after the last drug administration prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were dissected for the determination of the activity of superoxide dismutase (SOD), reduced glutathione (GSH) and lipid peroxidation (LP) levels. CORT significantly increased SOD activity in the PFC and HC, decreased GSH levels in the HC and increased LP in all brain areas studied when compared to saline-treated animals. Decrements of SOD activity were observed in all groups and brain areas studied when compared to controls and CORT. The hippocampal decrease in GSH was reversed by ALA100, DVS10+ALA100, DVS20+ALA100 and DVS20+ALA200. The same DVS+ALA combination groups presented increased levels of GSH in the PFC and ST. The greater GSH levels were observed in the PFC, HC and ST of DVS20+ALA200 mice. LP was reversed in the groups ALA200 (PFC), DVS10+ALA100, DVS20+ALA100 (PFC, HC and ST), and DVS20+ALA200 (PFC, HC). Our findings contribute to the previous preclinical evidences implicating ALA as a promising agent for augmentation therapy in depression.

Lipoic acid and pentoxifylline mitigate nandrolone decanoate-induced neurobehavioral perturbations in rats via re-balance of brain neurotransmitters, up-regulation of Nrf2/HO-1 pathway, and down-regulation of TNFR1 expression

Behavioral perturbations associated with nandrolone decanoate abuse by athletes and adolescents may be attributed to oxidative stress and inflammation. However, the underlying mechanisms are not yet fully explored. On the other hand, the natural antioxidant lipoic acid can pass the blood brain barrier and enhance Nrf2/HO-1 (nuclear factor erythroid-2 related factor 2/heme oxygenase-1) pathway. In addition, the phosphodiesterase-IV inhibitor xanthine derivative pentoxifylline has a remarkable inhibitory effect on tumor necrosis factor-alpha (TNF-α). Therefore, this study aimed at investigation of the possible protective effects of lipoic acid and/or pentoxifylline against nandrolone-induced neurobehavioral alterations in rats. Accordingly, male albino rats were randomly distributed into seven groups and treated with either vehicle, nandrolone (15mg/kg, every third day, s.c.), lipoic acid (100mg/kg/day, p.o.), pentoxifylline (200mg/kg/day, i.p.), or nandrolone with lipoic acid and/or pentoxifylline. Rats were challenged in the open field, rewarded T-maze, Morris water maze, and resident–intruder aggression behavioral tests. The present findings showed that nandrolone induced hyperlocomotion, anxiety, memory impairment, and aggression in rats. These behavioral abnormalities were accompanied by several biochemical changes, including altered levels of brain monoamines, GABA, and acetylcholine, enhanced levels of malondialdehyde and TNF-α, elevated activity of acetylcholinesterase, and up-regulated expression of TNF-α receptor-1 (TNFR1). In addition, inhibited catalase activity, down-regulated Nrf2/HO-1 pathway, and suppressed acetylcholine receptor expression were observed. Lipoic acid and pentoxifylline combination significantly mitigated all the previously mentioned deleterious effects mainly via up-regulation of Nrf2/HO-1 pathway, inhibition of TNF-α and down-regulation of TNFR1 expression. In conclusion, the biochemical and histopathological findings of this study revealed the protective mechanisms of lipoic acid and pentoxifylline against nandrolone-induced behavioral changes and neurotoxicity in rats.

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

Excess of saturated free fatty acids, such as palmitic acid (PA), in hepatocytes has been implicated in nonalcoholic fatty liver disease. α-Lipoic acid (LA) is an antioxidant that protects against oxidative stress conditions. We have investigated the effects of LA in the early activation of oxidative and endoplasmic reticulum stress, lipid accumulation, and Nrf2-mediated antioxidant defenses in hepatocytes treated with PA or in rats fed a high-fat diet. In primary human hepatocytes, a lipotoxic concentration of PA triggered endoplasmic reticulum stress, induced the apoptotic transcription factor CHOP, and increased the percentage of apoptotic cells. Cotreatment with LA prevented these effects. Similar results were found in mouse hepatocytes in which LA attenuated PA-mediated activation of caspase 3 and reduced lipid accumulation by decreasing PA uptake and increasing fatty acid oxidation and lipophagy, thereby preventing lipoapoptosis. Moreover, LA augmented the proliferation capacity of hepatocytes after PA challenge. Antioxidant effects of LA ameliorated reactive oxygen species production and endoplasmic reticulum stress and protected against mitochondrial apoptosis in hepatocytes treated with PA. Cotreatment with PA and LA induced an early nuclear translocation of Nrf2 and activated antioxidant enzymes, whereas reduction of Nrf2 by siRNA abolished the benefit of LA on PA-induced lipoapoptosis. Importantly, posttreatment with LA reversed the established damage induced by PA in hepatocytes, as well as preventing obesity-induced oxidative stress and lipoapoptosis in rat liver. In conclusion, our work has revealed that in hepatocytes, Nrf2 is an essential early player in the rescue of oxidative stress by LA leading to protection against PA-mediated lipoapoptosis.

The protective effect of lipoic acid on selected cardiovascular diseases caused by age-related oxidative stress.

Oxidative stress is considered to be the primary cause of many cardiovascular diseases, including endothelial dysfunction in atherosclerosis and ischemic heart disease, hypertension, and heart failure. Oxidative stress increases during the aging process, resulting in either increased reactive oxygen species (ROS) production or decreased antioxidant defense. The increase in the incidence of cardiovascular disease is directly related to age. Aging is also associated with oxidative stress, which in turn leads to accelerated cellular senescence and organ dysfunction. Antioxidants may help lower the incidence of some pathologies of cardiovascular diseases and have antiaging properties. Lipoic acid (LA) is a natural antioxidant which is believed to have a beneficial effect on oxidative stress parameters in relation to diseases of the cardiovascular system.

Influence of lipoic acid on testicular toxicity induced by bi-n-butyl phthalate in rats

Bi-n-butyl phthalate (BNBP) is an environmental pollutant. The aim of this study was to evaluate the protective effect of lipoic acid (LA) against testicular dysfunction associated with the intake of to BNBP- intoxicated rats. Adult male Wistar rats were divided into 4 groups of 6 animals each, and received medication orally for 14days. Group I rats received 0.5ml corn oil. Group II rats received LA (20mg/kgB.W./day). Group III rats received BNBP (250mg/kgB.W./day). Group IV rats received LA 24h prior to BNBP intake. Testes weight, cauda sperm count and sperm motility were decreased significantly by 18.15%, 13.83% and 13.5%, respectively, after BNBP treatment. Significant increase by 12.1%, 10.20% and 11.51%, respectively, was observed in LA–BNBP rats. Significant increase by 1.53%, 1.5% and 1.8%, for serum follicle stimulating hormone, testosterone and total antioxidant status, respectively, were observed in LA–BNBP rats. Testicular lipid peroxides and lactate dehydrogenase enzyme were significantly decreased by 1.5 and 1.6 folds, respectively, in LA–BNBP rats were decreased after BNBP treatment. Testicular superoxide dismutase, catalase and glutathione reductase enzymes were significantly increased in LA–BNBP rats. LA–BNBP rats, decreased the damage to seminiferous tubules produced by BNBP intake. In conclusion, LA mitigated BNBP-induced testicular toxicity through antioxidant mechanism and by direct free radical scavenging activity.

Protective effects of lipoic acid and mesna on cyclophosphamide‐induced haemorrhagic cystitis in mice

The protective roles of lipoic acid (LA)/vitamin C (VC) and mesna on preventing cyclophosphamide (CYP)-induced haemorrhagic cystitis (HC) were investigated. Swiss mice were divided into five groups randomly. HC was induced by a single dose of CYP injection (150-mg kg(-1) bodyweight). Group I was injected with saline (four times in total) throughout as control group. Group II received CYP and three equal doses of saline. Group III received CYP and three doses of mesna, whereas Group IV (or Group V) received CYP, mesna + two doses of VC (or LA). All injections were performed intraperitoneally. After 24 h of cystitis induction, the bladders were collected for all the experiments. Histological characterization showed that CYP injection resulted in severe HC. Reactive oxygen species (ROS) and thiobarbituric acid reactive substances' levels were increased in CYP group. The activities of antioxidant enzymes, e.g. superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase, were inhibited significantly in CYP groups, respectively. In addition, activation of c-jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in the mechanism of CYP-induced HC but not extracellular signal regulated kinases (ERK). Significant suppression of p38 phosphorylation on Group V suggests that LA and mesna may have synergistic beneficial effect. In Groups III-V, all the parameters of HC and oxidative stress were inhibited significantly. Taking together, we found that these results illustrated that ROS play an important role on CYP-induced HC and the administration of LA/VC with mesna may have therapeutic potential against CYP-induced bladder HC.

Protective effect of lipoic acid against oxidative stress is mediated by Keap1/Nrf2-dependent heme oxygenase-1 induction in the RGC-5 cellline

Oxidative stress plays a key role in neurodegeneration of CNS neurons such as in Alzheimer disease, Parkinson's disease and glaucoma. R-α-lipoic acid (R-LA) has been shown to have a neuroprotective effect through its antioxidant activity. However, the mechanism underlying its neuroprotection is totally unknown in retinal neurons. In this study, we show that R-LA has a dramatic neuroprotective effect against oxidative stress-induced death of the retinal neuronal RGC-5 cell line. We observed that R-LA induces the expression of heme oxygenase-1 (HO-1) by promoting the translocation of NF-E2-related factor 2 (Nrf2) to the nucleus. We examined the mechanism underlying HO-1 induction by R-LA by focusing on downstream signaling pathways. We found that R-LA activates Akt, and HO-1 induction by R-LA (involving Nrf2 translocation to the nucleus) was suppressed by phosphoinositide 3-kinase (PI3K) inhibitors. In addition, R-LA produced reactive oxygen species (ROS), including hydrogen peroxide. Pretreatment with a ROS scavenger or a NADPH oxidase inhibitor suppressed R-LA-induced Nrf2 translocation to the nucleus and HO-1 induction. These results suggest that ROS production triggered by R-LA might modify Kelch-like ECH-associated protein (Keap1), which in turn induces HO-1 expression through the PI3K signaling pathway. Furthermore, R-LA significantly attenuated cell death and accumulation of 4-hydroxy-2-nonenal (4HNE) in the retina induced by optic nerve injury in vivo through an HO-1 activity-dependent mechanism. These data demonstrate for the first time that R-LA exerts a neuroprotective effect against oxidative stress in retinal neurons in vitro and in vivo by inducing HO-1 through Keap1/Nrf2 signaling.

Lipoic acid enhances survival of transplanted neural stem cells by reducing transplantation-associated injury.

The efficacy of stem cell-based therapy for neurological diseases depends highly on cell survival post-transplantation. One of the key factors affecting cell survival is the grafting procedure. The current study aims to determine whether needle insertion into intact rat spinal cords creates a hypoxic environment that is prone to lipid peroxidation damage upon reperfusion, and whether an antioxidant protects human neural stem cells (hNSCs) both in vitro and post-transplantation into rat spinal cords. We show here that a single needle injection creates a hypoxic environment within the rat spinal cord that peaks at approximately 12 hours before reperfusion occurs. Lipid peroxidation damage at the transplantation site is evident by 48 hours post-needle insertion. In an in vitro model, hypoxia-reperfusion results in apoptotic death of hNSCs. Pretreatment with the antioxidant, α-lipoic acid, protects hNSCs against hypoxia-reperfusion injury and oxidative stress–mediated cell death. Increasing glutathione, but not Akt signaling, contributes to the protective effect of lipoic acid. Pretreating hNSCs with lipoic acid also increases the cell survival rate 1 month post-transplantation. Further investigation is warranted to develop improved techniques to maximize the survival of transplanted stem cells.

Neuropharmacological effects of lipoic acid and ubiquinone on δ‐aminolevulinic dehydratase, Na+, K+‐ATPase, and Mg2+‐ATPase activities in rat hippocampus after pilocarpine‐induced seizures

In this study, we investigated the effects of lipoic acid (LA) in the hippocampus oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10mg/kg, i.p., LA group), ubiquinone [20mg/kg, i.p., ubiquinone (UQ) group], pilocarpine (400mg/kg, i.p., P400 group), and the association of LA (10mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.) or UQ (20mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.), 30min before of administration of P400 (LA plus P400 group and UQ plus P400 group, respectively). After the treatments, all groups were observed for 1h. The enzyme activities (δ-aminolevulinic dehydratase (δ-ALA-D), Mg(2+) -ATPase, and Na(+) , K(+) -ATPase) were measured using spectrophotometric methods, and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA and UQ were also evaluated on the same parameters. We reported here for the first time that Na(+) , K(+) -ATPase and δ-ALA-D activities inhibition and Mg(2+) -ATPase stimulation in the pilocarpine model are probably attributed to the oxidative stress caused by seizures in the rat hippocampus. The addition of the antioxidants LA and UQ may reverses the previously mentioned Na(+) , K(+) -ATPase and δ-ALA-D inhibitions and Mg(2+) -ATPase stimulation. The oxidative stress plays an important signaling role in pilocarpine-induced seizures, and antioxidant drugs might be considered as therapeutical tools in this pathology.

Modulatory effects of lipoic acid and selenium against cadmium‐induced biochemical alterations in testicular steroidogenesis

Exposure to toxic metals including cadmium has become an increasingly recognized source of illness worldwide. Cadmium (Cd(2+) ) is one of the environmental pollutants affecting various tissues and organs including testis. The protective effect of lipoic acid and selenium on Cd(2+) -induced testicular damage was investigated. Accordingly, male Wistar rats were allocated into four groups (n = 8; each). Gp I: (control), whereas the other 3 groups received CdCl(2) (2 mg/kg, i.p. for 28 days) alone or in combination with either (i) lipoic acid (35 mg/kg, p.o) or (ii) selenium (0.35 mg/kg, p.o) throughout the experiment. Serum testosterone, luteinizing hormone and follicle-stimulating hormone levels significantly decreased in the Cd(2+) -exposed rats. The activities of testicular key androgenic enzymes, 3β-hydroxysteroid dehydrogenase and 17 β-HSD significantly decreased in Cd(2) exposed rats compared to the control counterparts. In addition, the activities of testicular marker enzymes were significantly altered in cadmium-treated animals. Significant reductions in body and testicular weight as well as antioxidant status were also observed in Cd(2+) -exposed rats. Moreover, some testicular metal levels were altered. Lipoic acid and selenium significantly increased serum testosterone level and restored testicular activity of 3β-HSD and 17 β-HSD and were effective in modulation of most of the measured biochemical parameters. The biochemical parameters were further confirmed with histopathological findings. In conclusion, the present study demonstrated the beneficial influences of lipoic acid and selenium in reducing harmful effects of Cd(2+) in rats' testes.

Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress

Gastrointestinal dysfunction is very common in diabetic patients. We assessed the changes in the colonic enteric nervous system using colectomy specimens and intestinal biopsies from diabetic subjects and age-matched controls. In control and diabetic colons, we determined the total ganglion area (hematoxylin-eosin staining), changes in neuronal markers-protein gene product 9.5, peripherin, neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY), choline acetyl transferase (ChAT) and vasoactive intestinal peptide (by immunostaining), apoptosis (cleaved caspase-3 staining) and reduced glutathione levels. Superoxide dismutase mRNA was determined in enteric ganglia isolated by laser capture micro dissection. Isometric muscle recording was used to assess contraction and relaxation responses of colonic circular muscle strips. Apoptosis in enteric neurons under hyperglycemia in vitro was determined by cleaved caspase-3 Western blotting and protective effects of lipoic acid were evaluated. Diabetic subjects had higher incidence of lower gastrointestinal symptoms like constipation and diarrhea at baseline prior to surgery. Diabetic ganglia displayed significant decrease in ganglion size due to enhanced apoptosis and loss of peripherin, nNOS, NPY, and ChAT neurons. Reduced glutathione levels in the diabetic colon (HbA1C > 7%) were significantly less than the control, indicating increased oxidative stress. Colonic circular muscle strips from diabetic subjects showed impaired contraction and relaxation responses compared with the healthy controls. Hyperglycemia-induced cleaved caspase-3 in enteric neurons was reversed by lipoic acid. Our data demonstrate loss of enteric neurons in the colon due to increased oxidative stress and apoptosis which may cause the motility disturbances seen in human diabetes. Antioxidants may be of therapeutic value for preventing motility disorders in diabetes.

Protective effect of lipoic acid against methotrexate-induced oxidative stress in liver mitochondria

Methotrexate (MTX) is a folic acid antagonist widely used as a cytotoxic chemotherapeutic agent for leukemia and other malignancies. The purpose of this study was to investigate the damage caused by MTX on liver mitochondria and its protection by using antioxidant properties of lipoic acid. MTX substantially affects mitochondrial function by reducing glutathione levels leading to disturbances in antioxidant enzyme defense system. Lipoic acid occurs naturally in mitochondria as a coenzyme. In various studies lipoic acid has been convincingly shown to exhibit an antioxidant role when supplemented exogenously. We studied the effect of lipoic acid pre-treatment on the toxicity of MTX in mouse liver mitochondria focusing specifically on the oxidative stress. MTX caused a significant rise in the mitochondrial lipid peroxidation (LPO), protein carbonyl (PC) content and superoxide radical generation. It also affected the mitochondrial thiol profile. Pre-treatment of mice with lipoic acid (35mg/kg) markedly lowered mitochondrial LPO, PC content and superoxide radical generation. It also restored decreased enzymatic and non-enzymatic antioxidants of mitochondria. It is suggested that lipoic acid has a potential role in suppressing MTX-induced mitochondrial toxicity, and it affords protection either by reversing the decline of antioxidants or by the directly scavenging the free radicals.

Modulatory effects of lipoic acid and selenium against cadmium‐induced biochemical alteration in testicular steroidogenesis

Exposure to toxic metals, especially Cadmium (Cd), a major environmental pollutant, has become an increasingly recognized source of illness worldwideSince antioxidant therapy provides potential protective role against metal induced testicular damage, hence the current study aimed at investigating the protective effects of lipoic acid and selenium in Cd‐induced testicular damage. Accordingly, male Wistar rats were allocated into four groups (n=8; each). One group received saline and served as control, while the other three groups were given CdCl2 (2mg/kg, i.p. for 28 days) either alone or in combination with (i) lipoic acid (35mg/kg, p.o) or (ii) selenium (as sodium selenite, 0.35mg/kg, p.o) from the first day of Cd administration till the end of the experiment. Serum testosterone, luteinizing hormone and follicular stimulating hormone levels were significantly decreased in the Cd‐exposed rats as well as the activity of testicular key androgenic enzymes such as (Δ53β‐HSD) and 17 β‐HSD as compared the control counterparts. In addition, the activities of testicular marker enzymes were significantly altered in cadmium treated animals. Significant reduction in body weight, testis weight, and testicular antioxidant status was also observed in Cd‐exposed rats. Lipoic acid and selenium significantly restored serum testosterone level and testicular activity of Δ53β‐ HSD, 17 β‐HSD Moreover, we demonstrate alterations in some testicular metal concentrations that were corrected by either selenium or lipoic acid. The biochemical parameters were further confirmed with histopathologial findings. In conclusion, the present study demonstrated the beneficial influences of lipoic acid and selenium in reducing harmful effects of Cd in rats’ testes.

Lipoic acid alters delta-aminolevulinic dehydratase, glutathione peroxidase and Na+,K+-ATPase activities and glutathione-reduced levels in rat hippocampus after pilocarpine-induced seizures.

In the present study, we investigated the effects of lipoic acid (LA) in the brain oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (10 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (10 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before the administration of LA (LA plus pilocarpine group). After the treatments, all groups were observed for 1 h. The enzyme activities [delta-aminolevulinic dehydratase (delta-ALA-D), glutathione peroxidase (GPx), glutathione reductase (GR), and Na+,K+-ATPase] as well as the glutathione-reduced (GSH) and ascorbic acid (AA) concentrations were measured using spectrophotometric methods, and the results were compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA were also evaluated on the same parameters. In pilocarpine group, no changes were observed in GPx and GR activities and AA content. Moreover, in the same group, decrease in GSH levels as well as a reduction in delta-ALA-D and Na+,K+-ATPase activities after seizures was observed. In turn, in LA plus pilocarpine group, the appearance of seizures was abolished, and the decreases in delta-ALA-D and Na+,K+-ATPase activities produced by seizures as well as increases in GSH levels and GPx activity were reversed, when compared to the pilocarpine seizing group. The results of the present study demonstrated that preadministration of LA abolished seizure episodes induced by pilocarpine in rat, probably by reducing oxidative stress in rat hippocampus caused by seizures.

Effects of lipoic acid on oxidative stress in rat striatum after pilocarpine-induced seizures

The relationship between free radical and scavenger enzymes has been found in the epilepsy and reactive oxygen species have been implicated in seizure-induced neurodegeneration. It has been suggested that pilocarpine-induced seizures is mediated by increases in oxidative stress. Current researches have suggested that antioxidant compounds may afford some level of neuroprotection against the neurotoxicity of seizures in cellular level. The objective of the present study was to evaluate the neuroprotective effects of lipoic acid (LA) in rats, against the observed oxidative stress during seizures induced by pilocarpine. Wistar rats were treated with 0.9% saline (i.p., control group), LA (20 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., P400 group), and the association of LA (20 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of LA (LA plus P400 group). After the treatments all groups were observed for 1 h. The enzyme activities as well as the lipid peroxidation and nitrite concentrations were measured using spectrophotometric methods and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA were also evaluated on the same parameters. In P400 group there was a significant increase in lipid peroxidation, nitrite level and glutathione peroxidase (GPx) activity. However, no alteration was observed in superoxide dismutase (SOD) and catalase activities. Antioxidant treatment significantly reduced the lipid peroxidation level and nitrite content as well as increased the SOD, catalase and GPx activities in rat striatum after seizures. Our findings strongly support the hypothesis that oxidative stress in striatum occurs during seizures induced by pilocarpine, proving that brain damage induced by the oxidative process plays a crucial role in seizures pathogenic consequences, and also imply that strong protective effect could be achieved using LA.

The evaluation of effects of lipoic acid on the lipid peroxidation, nitrite formation and antioxidant enzymes in the hippocampus of rats after pilocarpine-induced seizures

It has been suggested that pilocarpine-induced seizures is mediated by increases in oxidative stress. Current researches have suggested that antioxidant compounds may afford some level of neuroprotection against the neurotoxicity of seizures in cellular level. The objective of the present study was to evaluate the neuroprotective effects of lipoic acid (LA) in rats, against the observed oxidative stress during seizures induced by pilocarpine. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (10 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of LA (LA plus pilocarpine group). After the treatments all groups were observed for 6 h. The enzyme activities as well as the lipid peroxidation and nitrite concentrations were measured using spectrophotometric methods and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA were also evaluated on the same parameters. In pilocarpine group there was a significant increase in lipid peroxidation and nitrite level. However, no alteration was observed in superoxide dismutase and catalase activities. Antioxidant treatment significantly reduced the lipid peroxidation level and nitrite content as well as increased the superoxide dismutase and catalase activities in hippocampus of rats after seizures induced by pilocarpine. Our findings strongly support the hypothesis that oxidative stress in hippocampus occurs during seizures induced by pilocarpine, proving that brain damage induced by the oxidative process plays a crucial role in seizures pathogenic consequences, and also imply that strong protective effect could be achieved using lipoic acid as an antioxidant.