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Inflammation Research

, Volume 66, Issue 11, pp 947–959 | Cite as

Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential

  • Daniele Tibullo
  • Giovanni Li Volti
  • Cesarina Giallongo
  • Sonia Grasso
  • Daniele Tomassoni
  • Carmelina Daniela Anfuso
  • Gabriella Lupo
  • Francesco Amenta
  • Roberto AvolaEmail author
  • Vincenzo Bramanti
Review

Abstract

Background

The molecular nature of lipoic acid (LA) clarifies its capability of taking part to a variety of biochemical reactions where redox state is meaningful. The pivotal action of LA is the antioxidant activity due to its ability to scavenge and inactivate free radicals. Furthermore, LA has been shown to chelate toxic metals both directly and indirectly by its capability to enhance intracellular glutathione (GSH) levels. This last property is due to its ability to interact with GSH and recycle endogenous GSH. LA exhibits significant antioxidant activity protecting against oxidative damage in several diseases, including neurodegenerative disorders. Interestingly, LA is unique among natural antioxidants for its capability to satisfy a lot of requirements, making it a potentially highly effective therapeutic agent for many conditions related with oxidative damage. In particular, there are evidences showing that LA has therapeutic activity in lowering glucose levels in diabetic conditions. Similarly, LA supplementation has multiple beneficial effects on the regression of the mitochondrial function and on oxidative stress associated with several diseases and aging.

Aim

The aim of the present review is to describe the molecular mechanisms underlying the beneficial effects of LA under various experimental conditions and disease and how to exploit such effect for clinical purposes.

Conclusion

LA has pleiotropic effects in different pathways related with several diseases, its use as a potential therapeutic agent is very promising.

Keywords

Alpha lipoic acid Antioxidant Chelation Free radical scavenger Glutathione Inflammation Therapeutic potential 

Abbreviations

LA

Lipoic acid

DHLA

Dihydrolipoic acid

R-LA or (+)LA

R-enantiomer lipoic acid

S-LA or (-)LA

S-enantiomer lipoic acid

(±)LA

Raceme lipoic acid

ROS

Reactive oxygen species

RNS

Reactive nitrogen species

SOD

Superoxide dismutase

GSH

Glutathione

GSSG

Disulfide form of glutathione

MAPK

Mitogen activated protein Kinases

PI3-K

Phosphatidyl inositide 3-kinase

αGPC

l-α-glycerylphosphorylcholine

GPCR

G protein coupled receptor

ERK

Extracellular regulated Kinases

JNK

c-Jun N-terminal kinase

AKT

The protein kinase B

NF-kB

Nuclear factor-KB

IGF-1

Insulin-like growth factor-1

IR

Insulin receptor

IRS1

Insulin receptor substrate 1

IRS-1

Insulin receptor substrate-1

AMPK

5′ Adenosine monophosphate-activated protein kinase

PTP1B

Cellular protein tyrosine phosphatases

LKB-1

Liver kinase B1

CaMKK

Ca/calmodulin dependent protein kinase

PGC-1-alpha

Proliferator activated receptor-gamma coactivator-1alpha

EAE

Experimental autoimmune encephalomyelitis

AD

Alzheimer’s disease

AChE

Acetylcholinesterase

AGEs

Advanced glycation end product

HNE

4-Hydroxy-2-nonenal

PKC

Protein kinase C

GLUT

Glucose transport protein

Notes

Acknowledgements

The authors acknowledged pharmaceutical MDM S.p.A. Via Volturno, 29/b—20900 Monza (MB), Italy, e-mail: mdm@mdmspa.com.

Author contributions

All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: RA and VB. Managing the literature searches: DT, SG, CG, DT. Drafting of the manuscript: RA and VB. Critical revision of the manuscript: DT, CG, CDA, GL, GLV, FA, RA and VB. Administrative and technical support: CG, DT. Supervision of the study: DT, RA and VB. Approving the final draft of manuscript: all the authors.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

References

  1. 1.
    Abdul HM, Butterfield DA. Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Free Radic Biol Med. 2007;42(3):371–84.PubMedCrossRefGoogle Scholar
  2. 2.
    Al Abdan M. Alfa-lipoic acid controls tumor growth and modulates hepatic redox state in Ehrlich-ascites-carcinoma-bearing mice. Sci World J. 2012;2012:509838.CrossRefGoogle Scholar
  3. 3.
    Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O’Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D, S. T. S. Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003;26(3):770–776.Google Scholar
  4. 4.
    Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, Luther T, Berentshtein E, Tritschler H, Muller M, Wahl P, Ziegler R, Nawroth PP. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes. 1997;46(9):1481–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Bo L, Dawson TM, Wesselingh S, Mork S, Choi S, Kong PA, Hanley D, Trapp BD. Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol. 1994;36(5):778–86.PubMedCrossRefGoogle Scholar
  6. 6.
    Bramanti V, Tomassoni D, Bronzi D, Grasso S, Curro M, Avitabile M, Li Volsi G, Renis M, Ientile R, Amenta F, Avola R. Alpha-lipoic acid modulates GFAP, vimentin, nestin, cyclin D1 and MAP-kinase expression in astroglial cell cultures. Neurochem Res. 2010;35(12):2070–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Chang MY, Gwon TM, Lee HS, Lee JH, Oh SH, Kim SJ, Park MH. The effect of systemic lipoic acid on hearing preservation after cochlear implantation via the round window approach: a guinea pig model. Eur J Pharmacol. 2017;799:67–72.PubMedCrossRefGoogle Scholar
  8. 8.
    Cho KJ, Moon HE, Moini H, Packer L, Yoon DY, Chung AS. Alpha-lipoic acid inhibits adipocyte differentiation by regulating pro-adipogenic transcription factors via mitogen-activated protein kinase pathways. J Biol Chem. 2003;278(37):34823–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Cromheeke KM, Kockx MM, De Meyer GR, Bosmans JM, Bult H, Beelaerts WJ, Vrints CJ, Herman AG. Inducible nitric oxide synthase colocalizes with signs of lipid oxidation/peroxidation in human atherosclerotic plaques. Cardiovasc Res. 1999;43(3):744–54.PubMedCrossRefGoogle Scholar
  10. 10.
    Diesel B, Kulhanek-Heinze S, Holtje M, Brandt B, Holtje HD, Vollmar AM, Kiemer AK. Alpha-lipoic acid as a directly binding activator of the insulin receptor: protection from hepatocyte apoptosis. Biochemistry. 2007;46(8):2146–55.PubMedCrossRefGoogle Scholar
  11. 11.
    Duby JJ, Campbell RK, Setter SM, White JR, Rasmussen KA. Diabetic neuropathy: an intensive review. Am J Health Syst Pharm. 2004;61(2):160–173 (quiz 175–166).Google Scholar
  12. 12.
    Durand M, Mach N. Alpha lipoic acid and its antioxidant against cancer and diseases of central sensitization. Nutr Hosp. 2013;28(4):1031–8.PubMedGoogle Scholar
  13. 13.
    El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, Cooper ME, Brownlee M. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205(10):2409–17.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Estrada DE, Ewart HS, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H, Klip A. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes. 1996;45(12):1798–804.PubMedCrossRefGoogle Scholar
  15. 15.
    Evans JL, Goldfine ID. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther. 2000;2(3):401–13.PubMedCrossRefGoogle Scholar
  16. 16.
    Feuerecker B, Pirsig S, Seidl C, Aichler M, Feuchtinger A, Bruchelt G, Senekowitsch-Schmidtke R. Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo. Cancer Biol Ther. 2012;13(14):1425–35.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Gasic-Milenkovic J, Loske C, Munch G. Advanced glycation endproducts cause lipid peroxidation in the human neuronal cell line SH-SY5Y. J Alzheimers Dis. 2003;5(1):25–30.PubMedCrossRefGoogle Scholar
  18. 18.
    Gerthoffer WT, Singer CA. MAPK regulation of gene expression in airway smooth muscle. Respir Physiol Neurobiol. 2003;137(2–3):237–50.PubMedCrossRefGoogle Scholar
  19. 19.
    Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, Rochette L. Antioxidant properties of an endogenous thiol: alpha-lipoic acid, useful in the prevention of cardiovascular diseases. J Cardiovasc Pharmacol. 2009;54(5):391–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic acid. Front Pharmacol. 2011;2:69.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr. 2014;6(1):80.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Grasso S, Bramanti V, Tomassoni D, Bronzi D, Malfa G, Traini E, Napoli M, Renis M, Amenta F, Avola R. Effect of lipoic acid and alpha-glyceryl-phosphoryl-choline on astroglial cell proliferation and differentiation in primary culture. J Neurosci Res. 2014;92(1):86–94.PubMedCrossRefGoogle Scholar
  23. 23.
    Guais A, Baronzio G, Sanders E, Campion F, Mainini C, Fiorentini G, Montagnani F, Behzadi M, Schwartz L, Abolhassani M. Adding a combination of hydroxycitrate and lipoic acid (METABLOC) to chemotherapy improves effectiveness against tumor development: experimental results and case report. Invest New Drugs. 2012;30(1):200–11.PubMedCrossRefGoogle Scholar
  24. 24.
    Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999;13(2):411–8.PubMedGoogle Scholar
  25. 25.
    Hedges JC, Singer CA, Gerthoffer WT. Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. Am J Respir Cell Mol Biol. 2000;23(1):86–94.PubMedCrossRefGoogle Scholar
  26. 26.
    Henriksen EJ, Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ. Stimulation by alpha-lipoic acid of glucose transport activity in skeletal muscle of lean and obese Zucker rats. Life Sci. 1997;61(8):805–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Hiller S, DeKroon R, Hamlett ED, Xu L, Osorio C, Robinette J, Winnik W, Simington S, Maeda N, Alzate O, Yi X. Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress. Biochim Biophys Acta. 2016;1860(1 Pt A):36–45.Google Scholar
  28. 28.
    Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Munch G. Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias. Pharmacol Ther. 2007;113(1):154–64.PubMedCrossRefGoogle Scholar
  29. 29.
    Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes. 1996;104(3):284–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med. 1999;27(3–4):309–14.PubMedCrossRefGoogle Scholar
  31. 31.
    Kates SA, Casale RA, Baguisi A, Beeuwkes R 3rd. Lipoic acid analogs with enhanced pharmacological activity. Bioorg Med Chem. 2014;22(1):505–12.PubMedCrossRefGoogle Scholar
  32. 32.
    Khanna S, Roy S, Packer L, Sen CK. Cytokine-induced glucose uptake in skeletal muscle: redox regulation and the role of alpha-lipoic acid. Am J Physiol. 1999;276(5 Pt 2):R1327–33.PubMedGoogle Scholar
  33. 33.
    Kim JI, Cho SR, Lee CM, Park ES, Kim KN, Kim HC, Lee HY. Induction of ER stress-mediated apoptosis by alpha-lipoic acid in A549 cell lines. Korean J Thorac Cardiovasc Surg. 2012;45(1):1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK, Viollet B, Youn JH, Lee HK, Lee KU. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004;10(7):727–33.PubMedCrossRefGoogle Scholar
  35. 35.
    Koh G, Yang EJ, Kim MK, Lee SA, Lee DH. Alpha-lipoic acid treatment reverses 2-deoxy-d-ribose-induced oxidative damage and suppression of insulin expression in pancreatic beta-cells. Biol Pharm Bull. 2013;36(10):1570–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Koprowski H, Zheng YM, Heber-Katz E, Fraser N, Rorke L, Fu ZF, Hanlon C, Dietzschold B. In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci USA. 1993;90(7):3024–7.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kwiecien B, Dudek M, Bilska-Wilkosz A, Knutelska J, Bednarski M, Kwiecien I, Zygmunt M, Iciek M, Sokolowska-Jezewicz M, Sapa J, Wlodek L. In vivo anti-inflammatory activity of lipoic acid derivatives in mice. Postepy Hig Med Dosw (Online). 2013;67:331–8.CrossRefGoogle Scholar
  38. 38.
    Li Volti G, Salomone S, Sorrenti V, Mangiameli A, Urso V, Siarkos I, Galvano F, Salamone F. Effect of silibinin on endothelial dysfunction and ADMA levels in obese diabetic mice. Cardiovasc Diabetol. 2011;10:62.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lovell MA, Markesbery WR. Oxidative damage in mild cognitive impairment and early Alzheimer’s disease. J Neurosci Res. 2007;85(14):3036–40.PubMedCrossRefGoogle Scholar
  40. 40.
    Lovell MA, Xie C, Xiong S, Markesbery WR. Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. J Alzheimers Dis. 2003;5(3):229–39.PubMedCrossRefGoogle Scholar
  41. 41.
    Mantovani G, Maccio A, Madeddu C, Mura L, Gramignano G, Lusso MR, Murgia V, Camboni P, Ferreli L, Mocci M, Massa E. The impact of different antioxidant agents alone or in combination on reactive oxygen species, antioxidant enzymes and cytokines in a series of advanced cancer patients at different sites: correlation with disease progression. Free Radic Res. 2003;37(2):213–23.PubMedCrossRefGoogle Scholar
  42. 42.
    Merz PA, Wisniewski HM, Somerville RA, Bobin SA, Masters CL, Iqbal K. Ultrastructural morphology of amyloid fibrils from neuritic and amyloid plaques. Acta Neuropathol. 1983;60(1–2):113–24.PubMedCrossRefGoogle Scholar
  43. 43.
    Michikoshi H, Nakamura T, Sakai K, Suzuki Y, Adachi E, Matsugo S, Matsumoto K. alpha-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells. Cancer Lett. 2013;335(2):472–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Moini H, Tirosh O, Park YC, Cho KJ, Packer L. R-alpha-lipoic acid action on cell redox status, the insulin receptor, and glucose uptake in 3T3-L1 adipocytes. Arch Biochem Biophys. 2002;397(2):384–91.PubMedCrossRefGoogle Scholar
  45. 45.
    Moura FA, de Andrade KQ, dos Santos JC, Goulart MO. Lipoic Acid: its antioxidant and anti-inflammatory role and clinical applications. Curr Top Med Chem. 2015;15(5):458–83.PubMedCrossRefGoogle Scholar
  46. 46.
    Muller U, Krieglstein J. Prolonged pretreatment with alpha-lipoic acid protects cultured neurons against hypoxic, glutamate-, or iron-induced injury. J Cereb Blood Flow Metab. 1995;15(4):624–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Nagamatsu M, Nickander KK, Schmelzer JD, Raya A, Wittrock DA, Tritschler H, Low PA. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care. 1995;18(8):1160–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Newsholme P, Rebelato E, Abdulkader F, Krause M, Carpinelli A, Curi R. Reactive oxygen and nitrogen species generation, antioxidant defenses, and beta-cell function: a critical role for amino acids. J Endocrinol. 2012;214(1):11–20.PubMedCrossRefGoogle Scholar
  49. 49.
    Nickander KK, McPhee BR, Low PA, Tritschler H. Alpha-lipoic acid: antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Radic Biol Med. 1996;21(5):631–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Ou P, Tritschler HJ, Wolff SP. Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol. 1995;50(1):123–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Packer L. alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug Metab Rev. 1998;30(2):245–75.PubMedCrossRefGoogle Scholar
  52. 52.
    Packer L, Kraemer K, Rimbach G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition. 2001;17(10):888–95.PubMedCrossRefGoogle Scholar
  53. 53.
    Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22(1–2):359–78.PubMedCrossRefGoogle Scholar
  54. 54.
    Palmer RM, Smith RE. Commentary on viewpoint article by AH Henderson, MJ Lewis, AM Shah, and JA Smith (April, pp 305–308). Cardiovasc Res. 1992;26(6):638.Google Scholar
  55. 55.
    Patrick L. Mercury toxicity and antioxidants: part 1: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. Altern Med Rev. 2002;7(6):456–71.PubMedGoogle Scholar
  56. 56.
    Perez-Matos MC, Morales-Alvarez MC, Mendivil CO. Lipids: a suitable therapeutic target in diabetic neuropathy? J Diabetes Res. 2017;2017:6943851.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Pick U, Haramaki N, Constantinescu A, Handelman GJ, Tritschler HJ, Packer L. Glutathione reductase and lipoamide dehydrogenase have opposite stereospecificities for alpha-lipoic acid enantiomers. Biochem Biophys Res Commun. 1995;206(2):724–30.PubMedCrossRefGoogle Scholar
  58. 58.
    Quinn JF, Bussiere JR, Hammond RS, Montine TJ, Henson E, Jones RE, Stackman RW Jr. Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol Aging. 2007;28(2):213–25.PubMedCrossRefGoogle Scholar
  59. 59.
    Ramamurthy S, Ronnett G. AMP-activated protein kinase (AMPK) and energy-sensing in the brain. Exp Neurobiol. 2012;21(2):52–60.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Roman-Pintos LM, Villegas-Rivera G, Rodriguez-Carrizalez AD, Miranda-Diaz AG, Cardona-Munoz EG. Diabetic polyneuropathy in type 2 Diabetes Mellitus: inflammation, oxidative stress, and mitochondrial function. J Diabetes Res. 2016;2016:3425617.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Sacerdoti D, Colombrita C, Ghattas MH, Ismaeil EF, Scapagnini G, Bolognesi M, Li Volti G, Abraham NG. Heme oxygenase-1 transduction in endothelial cells causes downregulation of monocyte chemoattractant protein-1 and of genes involved in inflammation and growth. Cell Mol Biol (Noisy-le-grand). 2005;51(4):363–370.Google Scholar
  62. 62.
    Salinthone S, Yadav V, Bourdette DN, Carr DW. Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS. Endocr Metab Immune Disord Drug Targets. 2008;8(2):132–42.PubMedCrossRefGoogle Scholar
  63. 63.
    Salomone F, Barbagallo I, Puzzo L, Piazza C, Li Volti G. Efficacy of adipose tissue-mesenchymal stem cell transplantation in rats with acetaminophen liver injury. Stem Cell Res. 2013;11(3):1037–44.PubMedCrossRefGoogle Scholar
  64. 64.
    Shaw JE, Zimmet PZ, de Courten M, Dowse GK, Chitson P, Gareeboo H, Hemraj F, Fareed D, Tuomilehto J, Alberti KG. Impaired fasting glucose or impaired glucose tolerance. What best predicts future diabetes in Mauritius? Diabetes Care. 1999;22(3):399–402.PubMedCrossRefGoogle Scholar
  65. 65.
    Shen QW, Zhu MJ, Tong J, Ren J, Du M. Ca2+/calmodulin-dependent protein kinase is involved in AMP-activated protein kinase activation by alpha-lipoic acid in C2C12 myotubes. Am J Physiol Cell Physiol. 2007;293(4):C1395–403.PubMedCrossRefGoogle Scholar
  66. 66.
    Singer CA, Baker KJ, McCaffrey A, AuCoin DP, Dechert MA, Gerthoffer WT. p38 MAPK and NF-kappaB mediate COX-2 expression in human airway myocytes. Am J Physiol Lung Cell Mol Physiol. 2003;285(5):L1087–98.PubMedCrossRefGoogle Scholar
  67. 67.
    Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem. 2004;11(9):1135–46.PubMedCrossRefGoogle Scholar
  68. 68.
    Smith AR, Visioli F, Frei B, Hagen TM. Lipoic acid significantly restores, in rats, the age-related decline in vasomotion. Br J Pharmacol. 2008;153(8):1615–22.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev. 2009;89(3):1025–78.PubMedCrossRefGoogle Scholar
  70. 70.
    Suh JH, Moreau R, Heath SH, Hagen TM. Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Rep. 2005;10(1):52–60.PubMedCrossRefGoogle Scholar
  71. 71.
    Suh JH, Zhu BZ, deSzoeke E, Frei B, Hagen TM. Dihydrolipoic acid lowers the redox activity of transition metal ions but does not remove them from the active site of enzymes. Redox Rep. 2004;9(1):57–61.PubMedCrossRefGoogle Scholar
  72. 72.
    Targonsky ED, Dai F, Koshkin V, Karaman GT, Gyulkhandanyan AV, Zhang Y, Chan CB, Wheeler MB. alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells. Diabetologia. 2006;49(7):1587–98.PubMedCrossRefGoogle Scholar
  73. 73.
    Tibullo D, Barbagallo I, Giallongo C, La Cava P, Parrinello N, Vanella L, Stagno F, Palumbo GA, Li Volti G, Di Raimondo F. Nuclear translocation of heme oxygenase-1 confers resistance to imatinib in chronic myeloid leukemia cells. Curr Pharm Des. 2013;19(15):2765–70.PubMedCrossRefGoogle Scholar
  74. 74.
    Tibullo D, Giallongo C, Puglisi F, Tomassoni D, Camiolo G, Cristaldi M, Brundo MV, Anfuso CD, Lupo G, Stampone T, Li Volti G, Amenta F, Avola R, Bramanti V. Effect of lipoic acid on the biochemical mechanisms of resistance to Bortezomib in SH-SY5Y Neuroblastoma Cells. Mol Neurobiol. 2017.Google Scholar
  75. 75.
    Torella D, Leosco D, Indolfi C, Curcio A, Coppola C, Ellison GM, Russo VG, Torella M, Li Volti G, Rengo F, Chiariello M. Aging exacerbates negative remodeling and impairs endothelial regeneration after balloon injury. Am J Physiol Heart Circ Physiol. 2004;287(6):H2850–60.PubMedCrossRefGoogle Scholar
  76. 76.
    Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic acid and diabetic neuropathy. Rev Diabet Stud. 2009;6(4):230–6.PubMedCrossRefGoogle Scholar
  77. 77.
    van der Goes A, Brouwer J, Hoekstra K, Roos D, van den Berg TK, Dijkstra CD. Reactive oxygen species are required for the phagocytosis of myelin by macrophages. J Neuroimmunol. 1998;92(1–2):67–75.PubMedCrossRefGoogle Scholar
  78. 78.
    Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. 2000;43(8):957–73.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang Y, Li X, Guo Y, Chan L, Guan X. alpha-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling in the skeletal muscle of aged mice. Metabolism. 2010;59(7):967–76.PubMedCrossRefGoogle Scholar
  80. 80.
    Wenk GL. Neuropathologic changes in Alzheimer’s disease: potential targets for treatment. J Clin Psychiatry. 2006;67(Suppl 3):3–7 (quiz 23).Google Scholar
  81. 81.
    Winiarska K, Malinska D, Szymanski K, Dudziak M, Bryla J. Lipoic acid ameliorates oxidative stress and renal injury in alloxan diabetic rabbits. Biochimie. 2008;90(3):450–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Wong WS. Inhibitors of the tyrosine kinase signaling cascade for asthma. Curr Opin Pharmacol. 2005;5(3):264–71.PubMedCrossRefGoogle Scholar
  83. 83.
    Xing ZG, Yu GD, Qin L, Jiang F, Zhao WH. Effects and mechanism of lipoic acid on beta-amyloid-intoxicated C6 glioma cells. Genet Mol Res. 2015;14(4):13880–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest. 2001;107(2):135–42.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Yaworsky K, Somwar R, Ramlal T, Tritschler HJ, Klip A. Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia. 2000;43(3):294–303.PubMedCrossRefGoogle Scholar
  86. 86.
    Ying Z, Kampfrath T, Sun Q, Parthasarathy S, Rajagopalan S. Evidence that alpha-lipoic acid inhibits NF-kappaB activation independent of its antioxidant function. Inflamm Res. 2011;60(3):219–25.PubMedCrossRefGoogle Scholar
  87. 87.
    Zhang J, McCullough PA. Lipoic acid in the prevention of acute kidney injury. Nephron. 2016;134(3):133–40.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–70.PubMedCrossRefGoogle Scholar
  90. 90.
    Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999;22(8):1296–301.PubMedCrossRefGoogle Scholar
  91. 91.
    Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Daniele Tibullo
    • 1
  • Giovanni Li Volti
    • 1
  • Cesarina Giallongo
    • 1
  • Sonia Grasso
    • 1
  • Daniele Tomassoni
    • 2
  • Carmelina Daniela Anfuso
    • 1
  • Gabriella Lupo
    • 1
  • Francesco Amenta
    • 3
  • Roberto Avola
    • 1
    Email author
  • Vincenzo Bramanti
    • 1
    • 4
  1. 1.Section of Medical Biochemistry, Department of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly
  2. 2.School of Bioscience and Veterinary MedicineUniversity of CamerinoCamerinoItaly
  3. 3.School of Medicinal Sciences and Health ProductsUniversity of CamerinoCamerinoItaly
  4. 4.Division of Microbiology and Virology, Villa Sofia HospitalA.O.O.R. “Villa Sofia-Cervello”PalermoItaly

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