Skip to main content

Advertisement

SpringerLink
Log in

Protective effects of alpha lipoic acid on high glucose-induced neurotoxicity in PC12 cells

  • Research Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Hyperglycemia plays an important role in the development of diabetic neuropathy. In this study, we investigated the protective effects of alpha lipoic acid (ALA) against high glucose-induced neurotoxicity in PC12 cells as a suitable in vitro model for studying neuronal functions. PC12 cells were treated with high glucose (25 mg/ml for 24 h) in the absence and presence of ALA (100 μM for 24 h). The viability of PC12 cells was estimated by using MTT assay. The expression of pro- apoptotic Bax, anti- apoptotic Bcl-2 and caspase 3 protein were evaluated by western blotting. The reactive oxygen species (ROS) levels were determined with 2,7-dichlorodihydro- fluorescein diacetate (H2DCFDA). Biochemical markers of oxidative stress were assessed by using the total antioxidant power (TAP), lipid peroxidation (LPO), ADP/ATP ratio, activity of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Pretreatment of PC12 cells with ALA, significantly improved high glucose-induced toxicity by increasing activity of antioxidant enzymes CAT and SOD in the PC12 cell. It also increased the concentrations of TAP. An elevated level of cell death and ROS in high glucose conditions, diminished with ALA treatment. Over expression of Bax and caspase 3 protein, elevation of ADP/ATP ratio and LPO level in high glucose- treated PC12 cells, were significantly reduced by ALA. It was concluded that ALA attenuates neurotoxicity induced by high glucose in PC12 cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abdou RH, Abdel-Daim MM (2014) Alpha-lipoic acid improves acute deltamethrin-induced toxicity in rats. Can J Physiol Pharmacol 92:1–7

    Article  Google Scholar 

  • Abdul HM, Butterfield DA (2007) Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by co-treatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity. Implications Alzheimer’s Dis Free Radic Biol Med 42:371

    Article  Google Scholar 

  • Ahmed HH (2012) Modulatory effects of vitamin E, acetyl-l-carnitine and α-lipoic acid on new potential biomarkers for Alzheimer’s disease in rat model. Exp Toxicol Pathol 64:549–556

    Article  CAS  PubMed  Google Scholar 

  • Allen DA, Yaqoob MM, Harwood SM (2005) Mechanisms of high glucose-induced apoptosis and its relationship to diabetic complications. J Nutr Biochem 16:705–713

    Article  CAS  PubMed  Google Scholar 

  • Antonio AM, Gillespie RA, Druse–Manteuffel MJ (2011) Effects of lipoic acid on antiapoptotic genes in control and ethanol-treated fetal rhombencephalic neurons. Brain Res 1383:13–21

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Berg J, Hung YP, Yellen G (2009) A genetically encoded fluorescent reporter of ATP: ADP ratio. Nat Methods 6:161–166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bharath S, Cochran B, Hsu M, Liu J, Ames B, Andersen J (2002) Pre-treatment with < i > R</i > −Lipoic Acid Alleviates the Effects of GSH Depletion in PC12 Cells: Implications for Parkinson’s Disease Therapy. Neurotoxicology 23:479–486

    Article  CAS  Google Scholar 

  • Boyaci MG, Eser O, Kocogullari CU, Karavelioglu E, Tokyol C, Can Y (2014) Neuroprotective effect of alpha-lipoic acid and methylprednisolone on the spinal cord ischemia/reperfusion injury in rabbits British journal of neurosurgery:1–6

  • Castro MC, Francini F, Gagliardino JJ, Massa ML (2014) Lipoic acid prevents fructose-induced changes in liver carbohydrate metabolism: Role of oxidative stress. Biochimica et Biophysica Acta (BBA)-General Subjects 1840:1145–1151

    Article  CAS  Google Scholar 

  • Cunha-Oliveira T, Rego AC, Morgadinho MT, Macedo T, Oliveira CR (2006) Differential cytotoxic responses of PC12 cells chronically exposed to psychostimulants or to hydrogen peroxide. Toxicology 217:54–62

    Article  CAS  PubMed  Google Scholar 

  • Dalazen GR, Terra M, Jacques CED, Coelho JG, Freitas R, Mazzola PN, Dutra-Filho CS (2014) Pipecolic acid induces oxidative stress in vitro in cerebral cortex of young rats and the protective role of lipoic acid. Metab Brain Dis 29:175–183

    Article  CAS  PubMed  Google Scholar 

  • Demir R et al. (2014) Protective effects of alpha-lipoic acid on experimental sciatic nerve crush injury in rats: assessed with functional, molecular and electromicroscopic analyses International Journal of Neuroscience

  • Dwivedi N, Flora G, Kushwaha P, Flora SJ (2014) Alpha-lipoic acid protects oxidative stress, changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats. Environ Toxicol Pharmacol 37:7–23

    Article  CAS  PubMed  Google Scholar 

  • Emmez H et al (2010) Anti-apoptotic and neuroprotective effects of alpha-lipoic acid on spinal cord ischemia–reperfusion injury in rabbits. Acta Neurochir 152:1591–1601

    Article  PubMed  Google Scholar 

  • Gomes MB, Negrato CA (2014) Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr 6:80

    Article  PubMed Central  PubMed  Google Scholar 

  • Gorąca A, Huk-Kolega H, Kleniewska P, Piechota-Polańczyk A, Skibska B (2013) Effects of lipoic acid on spleen oxidative stress after LPS administration. Pharmacol Rep 65:179–186

    Article  PubMed  Google Scholar 

  • Goto M, Holgersson J, Kumagai‐Braesch M, Korsgren O (2006) The ADP/ATP ratio: a novel predictive assay for quality assessment of isolated pancreatic islets. Am J Transplant 6:2483–2487

    Article  CAS  PubMed  Google Scholar 

  • Henriksen EJ (2006) Exercise training and the antioxidant α-lipoic acid in the treatment of insulin resistance and type 2 diabetes. Free Radic Biol Med 40:3–12

    Article  CAS  PubMed  Google Scholar 

  • Hosseini A et al (2010) Benefit of magnesium-25 carrying porphyrin-fullerene nanoparticles in experimental diabetic neuropathy. Int J Nanomedicine 5:517

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hussein A, Ahmed A, Shouman SA, Sharawy S (2012) Ameliorating effect of DL-α-lipoic acid against cisplatin-induced nephrotoxicity and cardiotoxicity in experimental animals. Drug Discov Ther 6:147–156

    CAS  PubMed  Google Scholar 

  • Islam MT (2009) Antioxidant activities of dithiol alpha-lipoic acid Bangladesh Journal of Medical Science 8

  • Jalali-Nadoushan M, Roghani M (2013) Alpha-lipoic acid protects against 6-hydroxydopamine-induced neurotoxicity in a rat model of hemi-parkinsonism. Brain Res 1505:68–74

    Article  CAS  PubMed  Google Scholar 

  • Johansen JS, Harris AK, Rychly DJ, Ergul A (2005) Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol 4:5

    Article  PubMed Central  PubMed  Google Scholar 

  • Kang BP, Frencher S, Reddy V, Kessler A, Malhotra A, Meggs LG (2003) High glucose promotes mesangial cell apoptosis by oxidant-dependent mechanism. Am J Physiol-Ren Physiol 284:F455–F466

    Article  CAS  Google Scholar 

  • Lee KW (2011) High Glucose-induced ROS Production is Mediated by c-Src in Mesangial Cells. University of Toronto

  • Lelkes E, Unsworth BR, Lelkes PI (2001) Reactive oxygen species, apoptosis and alte1red NGF-induced signaling in PC12 pheochromocytoma cells cultured in elevated glucose: AnIn Vitro cellular model for diabetic neuropathy. Neurotox Res 3:189–203

    Article  CAS  PubMed  Google Scholar 

  • Li D-W et al (2013) α-lipoic acid protects dopaminergic neurons against MPP + −induced apoptosis by attenuating reactive oxygen species formation. Int J Molecular Med 32:108–114

    CAS  Google Scholar 

  • Li Y, Ma Q-G, Zhao L-H, Wei H, Duan G-X, Zhang J-Y, Ji C (2014) Effects of Lipoic Acid on Immune Function, the Antioxidant Defense System, and Inflammation-Related Genes Expression of Broiler Chickens Fed Aflatoxin Contaminated Diets. Int J Mol Sci 15:5649–5662

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Melli G et al (2008) Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol 214:276–284

    Article  CAS  PubMed  Google Scholar 

  • Moreira PI, Harris PL, Zhu X, Santos MS, Oliveira CR, Smith MA, Perry G (2007) Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts. J Alzheimers Dis 12:195–206

    CAS  PubMed  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  • Nakagami H et al (2001) Phosphorylation of p38 mitogen-activated protein kinase downstream of bax-caspase-3 pathway leads to cell death induced by high D-glucose in human endothelial cells. Diabetes 50:1472–1481

    Article  CAS  PubMed  Google Scholar 

  • Nishikawa T et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790

    Article  CAS  PubMed  Google Scholar 

  • Niu J, Azfer A, Rogers LM, Wang X, Kolattukudy PE (2007) Cardioprotective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy. Cardiovasc Res 73:549–559

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183

    Article  CAS  PubMed  Google Scholar 

  • Packer L, Kraemer K, Rimbach G (2001) Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17:888–895

    Article  CAS  PubMed  Google Scholar 

  • Park S, Karunakaran U, Jeoung N, Jeon J, Lee I (2014) Physiological Effect and Therapeutic Application of Alpha Lipoic Acid Current medicinal chemistry

  • Piconi L, Quagliaro L, Assaloni R, Da Ros R, Maier A, Zuodar G, Ceriello A (2006) Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction. Diabetes Metab Res Rev 22:198–203

    Article  CAS  PubMed  Google Scholar 

  • Pizzimenti S, Toaldo C, Pettazzoni P, Dianzani MU, Barrera G (2010) The “ two-faced” effects of reactive oxygen species and the lipid peroxidation product 4-hydroxynonenal in the hallmarks of cancer. Cancers 2:338–363

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Robertson RP (2004) Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 279:42351–42354

    Article  CAS  PubMed  Google Scholar 

  • Rochette L, Ghibu S, Richard C, Zeller M, Cottin Y, Vergely C (2013) Direct and indirect antioxidant properties of α‐lipoic acid and therapeutic potential. Mol Nutr Food Res 57:114–125

    Article  CAS  PubMed  Google Scholar 

  • Russell JW, Golovoy D, Vincent AM, Mahendru P, Olzmann JA, Mentzer A, Feldman EL (2002) High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 16:1738–1748

    Article  CAS  PubMed  Google Scholar 

  • Schütt F, Aretz S, Auffarth GU, Kopitz J (2012) Moderately reduced ATP levels promote oxidative stress and debilitate autophagic and phagocytic capacities in human RPE cells. Invest Ophthalmol Vis Sci 53:5354–5361

    Article  PubMed  Google Scholar 

  • Shahraki J, Motallebi A, Aghvami M, Pourahmad J (2013) Ichthyotoxic Cochlodinium polykrikoides Induces Mitochondrial Mediated Oxidative Stress and Apoptosis in Rat Liver Hepatocytes. Iran J Pharm Res 12:829–844

    PubMed Central  PubMed  Google Scholar 

  • Sharifi AM, Mousavi SH, Farhadi M, Larijani B (2007) Study of high glucose-induced apoptosis in PC12 cells: role of bax protein. J Pharmacol Sci 104:258–262

    Article  CAS  PubMed  Google Scholar 

  • Sharifi AM, Eslami H, Larijani B, Davoodi J (2009) Involvement of caspase-8,-9, and-3 in high glucose-induced apoptosis in PC12 cells. Neurosci Lett 459:47–51

    Article  CAS  PubMed  Google Scholar 

  • Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM (2009) Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochimica et Biophysica Acta (BBA)-General Subjects 1790:1149–1160

    Article  CAS  Google Scholar 

  • Shi H, Liu KJ (2006) Effects of glucose concentration on redox status in rat primary cortical neurons under hypoxia. Neurosci Lett 410:57–61

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Siddique YH, Ara G, Afzal M (2012) Estimation of lipid peroxidation induced by hydrogen peroxide in cultured human lymphocytes. Dose-Response 10:1–10

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smith A, Shenvi S, Widlansky M, Suh J, Hagen T (2004) Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem 11:1135–1146

    Article  CAS  PubMed  Google Scholar 

  • Steele ML, Fuller S, Patel M, Kersaitis C, Ooi L, Münch G (2013) Effect of Nrf2 activators on release of glutathione, cysteinylglycine and homocysteine by human U373 astroglial cells. Redox biology 1:441–445

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Veskovic M, Mladenovic D, Jorgacevic B, Stevanovic I, de Luka S, Radosavljevic T (2014) Alpha-lipoic acid affects the oxidative stress in various brain structures in mice with methionine and choline deficiency Experimental Biology and Medicine:1535370214549521

  • Vidović B et al (2014) Effect of alpha-lipoic acid supplementation on oxidative stress markers and antioxidative defense in patients with schizophrenia. Psychiatr Danub 26:205–213

    PubMed  Google Scholar 

  • Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368–383

    Article  CAS  PubMed  Google Scholar 

  • Vincent AM, McLean LL, Backus C, Feldman EL (2005) Short-term hyperglycemia produces oxidative damage and apoptosis in neurons. FASEB J 19:638–640

    CAS  PubMed  Google Scholar 

  • Vincent AM, Callaghan BC, Smith AL, Feldman EL (2011) Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 7:573–583

    Article  CAS  PubMed  Google Scholar 

  • Voloboueva LA, Liu J, Suh JH, Ames BN, Miller SS (2005) (R)-α-lipoic acid protects retinal pigment epithelial cells from oxidative damage. Invest Ophthalmol Vis Sci 46:4302–4310

    Article  PubMed Central  PubMed  Google Scholar 

  • Wollin SD, Jones PJ (2003) α-lipoic acid and cardiovascular disease. The J Nutr 133:3327–3330

    CAS  Google Scholar 

  • Xia X et al. (2014) Role of α-lipoic acid in LPS/d-GalN induced fulminant hepatic failure in mice: Studies on oxidative stress, inflammation and apoptosis International immunopharmacology

Download references

Acknowledgments

This study was supported by a grant from Iran University of Medical Sciences.

Conflict of interest

None to declare.

Author information

Authors and Affiliations

  1. Razi Drug Research Center, Iran University of Medical Sciences, Tehran, 1449614535, Iran

    Rezvan Najafi, Ali Mohammad Sharifi & Asieh Hosseini

  2. Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

    Rezvan Najafi

Authors
  1. Rezvan Najafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ali Mohammad Sharifi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Asieh Hosseini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Asieh Hosseini.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Najafi, R., Sharifi, A.M. & Hosseini, A. Protective effects of alpha lipoic acid on high glucose-induced neurotoxicity in PC12 cells. Metab Brain Dis 30, 731–738 (2015). https://doi.org/10.1007/s11011-014-9625-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-014-9625-1

Keywords

Search

Navigation