Insights on the Use of α-Lipoic Acid for Therapeutic Purposes

Bahare Salehi, Yakup Berkay Yılmaz, Gizem Antika, Tugba Boyunegmez Tumer, Mohamad Fawzi Mahomoodally, Devina Lobine, Muhammad Akram, Muhammad Riaz, Esra Capanoglu, Farukh Sharopov, Natália Martins, William C Cho, Javad Sharifi-Rad, Bahare Salehi, Yakup Berkay Yılmaz, Gizem Antika, Tugba Boyunegmez Tumer, Mohamad Fawzi Mahomoodally, Devina Lobine, Muhammad Akram, Muhammad Riaz, Esra Capanoglu, Farukh Sharopov, Natália Martins, William C Cho, Javad Sharifi-Rad

Abstract

α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant potential and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. However, the use of various innovative formulations has greatly improved ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found for gender. The present review aims to provide an updated on studies from preclinical to clinical trials assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related diseases and abnormalities in pregnancy.

Keywords: bioavailability; clinical trial; diabetic neuropathy; formulations; obesity; pregnancy; schizophrenia; sclerosis; α-lipoic acid.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The chemical structure of optical isomers of ALA.
Figure 2
Figure 2
From preclinical to clinical effects of ALA.

References

    1. Reed L.J., DeBusk B.G., Gunsalus I.C., Hornberger C.S. Crystalline α-lipoic acid: A catalytic agent associated with pyruvate dehydrogenase. Science. 1951;114:93–94. doi: 10.1126/science.114.2952.93.
    1. Bock E., Schneeweiss J. Ein Beitrag zur Therapie der Neuropathia diabetica. Munch. Med. Wochenschr. 1959;43:1911–1912.
    1. Brookes M.H., Golding B.T., Howes D.A., Hudson A.T. Proof that the absolute configuration of natural α-lipoic acid is R by the synthesis of its enantiomer [(S)-(–)-α-lipoic acid] from (S)-malic acid. J. Chem. Soc. Chem. Commun. 1983;19:1051–1053. doi: 10.1039/C39830001051.
    1. 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;54:391–398. doi: 10.1097/FJC.0b013e3181be7554.
    1. Brufani M. Acido α-lipoico farmaco o integratore. Una panoramica sulla farmacocinetica, le formulazioni disponibili e le evidenze cliniche nelle complicanze del diabete. Prog. Nutr. 2014;16:62–74.
    1. Singh U., Jialal I. Retracted: Alpha-lipoic acid supplementation and diabetes. Nutr. Rev. 2008;66:646–657. doi: 10.1111/j.1753-4887.2008.00118.x.
    1. Maglione E., Marrese C., Migliaro E., Marcuccio F., Panico C., Salvati C., Citro G., Quercio M., Roncagliolo F., Torello C., et al. Increasing bioavailability of (R)-alpha-lipoic acid to boost antioxidant activity in the treatment of neuropathic pain. Acta Bio-Medica Atenei Parm. 2015;86:226–233.
    1. Packer L., Cadenas E. Lipoic acid: Energy metabolism and redox regulation of transcription and cell signaling. J. Clin. Biochem. Nutr. 2010;48:26–32. doi: 10.3164/jcbn.11-005FR.
    1. Konrad D., Somwar R., Sweeney G., Yaworsky K., Hayashi M., Ramlal T., Klip A. The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: Potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes. 2001;50:1464–1471. doi: 10.2337/diabetes.50.6.1464.
    1. Chen W.-L., Kang C.-H., Wang S.-G., Lee H.-M. α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase. Diabetologia. 2012;55:1824–1835. doi: 10.1007/s00125-012-2530-4.
    1. Gorąca A., Huk-Kolega H., Piechota A., Kleniewska P., Ciejka E., Skibska B. Lipoic acid–biological activity and therapeutic potential. Pharmacol. Rep. 2011;63:849–858. doi: 10.1016/S1734-1140(11)70600-4.
    1. Han D., Handelman G., Marcocci L., Sen C.K., Roy S., Kobuchi H., Tritschler H.J., Flohé L., Packer L. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors. 1997;6:321–338. doi: 10.1002/biof.5520060303.
    1. Shay K.P., Moreau R.F., Smith E.J., Smith A.R., Hagen T.M. Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochim. Biophys. Acta. 2009;1790:1149–1160. doi: 10.1016/j.bbagen.2009.07.026.
    1. Ou P., Tritschler H.J., Wolff S.P. Thioctic (lipoic) acid: A therapeutic metal-chelating antioxidant? Biochem. Pharmacol. 1995;50:123–126. doi: 10.1016/0006-2952(95)00116-H.
    1. Bilska A., Wlodek L. Lipoic acid-the drug of the future. Pharmacol. Rep. 2005;57:570–577.
    1. Castro M.C., Villagarcía H.G., Massa M.L., Francini F. Alpha-lipoic acid and its protective role in fructose induced endocrine-metabolic disturbances. Food Funct. 2019;10:16–25. doi: 10.1039/C8FO01856A.
    1. Keith D.J., Butler J.A., Bemer B., Dixon B., Johnson S., Garrard M., Sudakin D.L., Christensen J.M., Pereira C., Hagen T.M. Age and gender dependent bioavailability of R- and R,S-alpha-lipoic acid: A pilot study. Pharmacol. Res. 2012;66:199–206. doi: 10.1016/j.phrs.2012.05.002.
    1. Packer L., Witt E.H., Tritschler H.J. alpha-Lipoic acid as a biological antioxidant. Free Radic. Boil. Med. 1995;19:227–250. doi: 10.1016/0891-5849(95)00017-R.
    1. Carreau J.-P. [32] Biosynthesis of lipoic acid via unsaturated fatty acids. Meth. Enzymol. 1979;62:152–158.
    1. Ziegler D. Thioctic acid for patients with symptomatic diabetic polyneuropathy: A critical review. Treat Endocrino. 2004;3:173–179. doi: 10.2165/00024677-200403030-00005.
    1. Henriksen E.J. Exercise training and the antioxidant alpha-lipoic acid in the treatment of insulin resistance and type 2 diabetes. Free Radic. Boil. Med. 2006;40:3–12. doi: 10.1016/j.freeradbiomed.2005.04.002.
    1. Ciftci H., Bakal U. The effect of lipoic acid on macro and trace metal levels in living tissues exposed to oxidative stress. Anti-Cancer Agents Med. Chem. 2009;9:560–568. doi: 10.2174/187152009788451815.
    1. Golbidi S., Badran M., Laher I. Diabetes and alpha lipoic acid. Front. Pharmacol. 2011;2:69. doi: 10.3389/fphar.2011.00069.
    1. Szeląg M., Mikulski D., Molski M. Quantum-chemical investigation of the structure and the antioxidant properties of α-lipoic acid and its metabolites. J. Mol. Modeling. 2012;18:2907–2916. doi: 10.1007/s00894-011-1306-y.
    1. Akiba S., Matsugo S., Packer L., Konishi T. Assay of protein-bound lipoic acid in tissues by a new enzymatic method. Anal. Biochem. 1998;258:299–304. doi: 10.1006/abio.1998.2615.
    1. Moura F.A., de Andrade K.Q., dos Santos J.C., Goulart M.O. Lipoic acid: Its antioxidant and anti-inflammatory role and clinical applications. Curr. Topics Med. Chem. 2015;15:458–483.
    1. Gomes M.B., Negrato C.A. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol. Metab. Syndr. 2014;6:80. doi: 10.1186/1758-5996-6-80.
    1. Smith A.R., Shenvi S.V., Widlansky M., Suh J.H., Hagen T.M. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr. Med. Chem. 2004;11:1135–1146. doi: 10.2174/0929867043365387.
    1. Liu J., Head E., Gharib A.M., Yuan W., Ingersoll R.T., Hagen T.M., Cotman C.W., Ames B.N. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-L-carnitine and/or R-α-lipoic acid. Proc. Natl. Acad. Sci. USA. 2002;99:2356–2361. doi: 10.1073/pnas.261709299.
    1. Han D., Sen C.K., Roy S., Kobayashi M.S., Tritschler H.J., Packer L. Protection against glutamate-induced cytotoxicity in C6 glial cells by thiol antioxidants. Am. J. Physiol. Integr. Comp. Physiol. 1997;273:1771–1778. doi: 10.1152/ajpregu.1997.273.5.R1771.
    1. Wray D.W., Nishiyama S.K., Harris R.A., Zhao J., McDaniel J., Fjeldstad A.S., Richardson R.S. Acute reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension. 2012;59:818–824. doi: 10.1161/HYPERTENSIONAHA.111.189456.
    1. McNeilly A.M., Davison G.W., Murphy M.H., Nadeem N., Trinick T., Duly E., McEneny J. Effect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance. Lipids Heal. Dis. 2011;10:217. doi: 10.1186/1476-511X-10-217.
    1. Ying Z., Kherada N., Farrar B., Kampfrath T., Chung Y., Simonetti O., Deiuliis J., Desikan R., Khan B., Villamena F., et al. Lipoic acid effects on established atherosclerosis. Life Sci. 2010;86:95–102. doi: 10.1016/j.lfs.2009.11.009.
    1. Park S., Karunakaran U., Jeoung N.H., Jeon J.-H., Lee I.-K. Physiological effect and therapeutic application of alpha lipoic acid. Curr. Med. Chem. 2014;21:3636–3645. doi: 10.2174/0929867321666140706141806.
    1. El Barky A.R., Hussein S.A., Mohamed T.M. The potent antioxidant alpha lipoic acid. J. Plant Chem. Ecophysiol. 2017;2:1016.
    1. Biewenga G.P., Haenen G.R., Bast A. The pharmacology of the antioxidant lipoic acid. Gen. Pharmacol. Vasc. Syst. 1997;29:315–331. doi: 10.1016/S0306-3623(96)00474-0.
    1. Goralska M., Dackor R., Holley B., McGahan M.C. Alpha lipoic acid changes iron uptake and storage in lens epithelial cells. Exp. Eye Res. 2003;76:241–248. doi: 10.1016/S0014-4835(02)00307-X.
    1. Suzuki Y.J., Tsuchiya M., Packer L. Thioctic acid and dihydrolipoic acid are novel antioxidants which interact with reactive oxygen species. Free Radic. Res. Commun. 1991;15:255–263. doi: 10.3109/10715769109105221.
    1. Scott B.C., Aruoma O.I., Evans P.J., O’Neill C., Van der Vliet A., Cross C.E., Tritschler H., Halliwell B. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic. Res. 1994;20:119–133. doi: 10.3109/10715769409147509.
    1. Islam M.T. Antioxidant activities of dithiol alpha-lipoic acid. Bangladesh J. Med. Sci. 2009;8:34–49. doi: 10.3329/bjms.v8i3.3982.
    1. WHO . Diabetes. World Health Organization; Geneva, Switzerland: 2018.
    1. Moodley K., Joseph K., Naidoo Y., Islam S., Mackraj I. Antioxidant, antidiabetic and hypolipidemic effects of Tulbaghia violacea Harv. (wild garlic) rhizome methanolic extract in a diabetic rat model. BMC Complement. Altern. Med. 2015;15:408. doi: 10.1186/s12906-015-0932-9.
    1. Beckman J.A., Creager M.A., Libby P. Diabetes and atherosclerosis: Epidemiology, pathophysiology, and management. J. Am. Med. Assoc. 2002;287:2570–2581. doi: 10.1001/jama.287.19.2570.
    1. Giacco F., Brownlee M. Oxidative stress and diabetic complications. Circ. Res. 2010;107:1058–1070. doi: 10.1161/CIRCRESAHA.110.223545.
    1. Pitocco D., Tesauro M., Alessandro R., Ghirlanda G., Cardillo C. Oxidative Stress in Diabetes: Implications for Vascular and Other Complications. Int. J. Mol. Sci. 2013;14:21525–21550. doi: 10.3390/ijms141121525.
    1. Asmat U., Abad K., Ismail K. Diabetes mellitus and oxidative stress-A concise review. Saudi Pharm. J. 2016;24:547–553. doi: 10.1016/j.jsps.2015.03.013.
    1. Eason R.C., Archer H.E., Akhtar S., Bailey C.J. Lipoic acid increases glucose uptake by skeletal muscles of obesediabetic ob/ob mice. Diabetes Obes. Metab. 2002;4:29–35. doi: 10.1046/j.1463-1326.2002.00171.x.
    1. García-Osta A., Cuadrado-Tejedor M., García-Barroso C., Oyarzábal J., Franco R. Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem. Neurosci. 2012;3:832–844. doi: 10.1021/cn3000907.
    1. Wu Y., Li Z., Huang Y.Y., Wu D., Luo H.B. Novel phosphodiesterase inhibitors for cognitive improvement in Alzheimer’s disease. J. Med. Chem. 2018;61:5467–5483. doi: 10.1021/acs.jmedchem.7b01370.
    1. Perry G., Cash A.D., Smith M.A. Alzheimer disease and oxidative stress. J. Biomed. Biotechnol. 2002;2:120–123. doi: 10.1155/S1110724302203010.
    1. Chen Z., Zhong C. Oxidative stress in Alzheimer’s disease. Neurosci. Bull. 2014;30:271–281. doi: 10.1007/s12264-013-1423-y.
    1. Huang W.-J., Zhang X., Chen W.-W. Role of oxidative stress in Alzheimer’s disease. Biomed. Rep. 2016;4:519–522. doi: 10.3892/br.2016.630.
    1. Cacciatore I., Marinelli L., Fornasari E., Cerasa L.S., Eusepi P., Türkez H., Pomilio C., Reale M., D’Angelo C., Costantini E., et al. Novel NSAID-derived drugs for the potential treatment of Alzheimer’s disease. Int. J. Mol. Sci. 2016;17:1035. doi: 10.3390/ijms17071035.
    1. Hagen T.M., Ingersoll R.T., Lykkesfeldt J., Liu J., Wehr C.M., Vinarsky V., Bartholomew J.C., Ames A.B. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999;13:411–418. doi: 10.1096/fasebj.13.2.411.
    1. Farr S.A., Poon H.F., Dogrukol-Ak D., Drake J., Banks W.A., Eyerman E., Allan Butterfield D., Morley J.E. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J. Neurochem. 2003;84:1173–1183. doi: 10.1046/j.1471-4159.2003.01580.x.
    1. Ono K., Hirohata M., Yamada M. α-Lipoic acid exhibits anti-amyloidogenicity for β-amyloid fibrils in vitro. Biochem. Biophys. Res. Commun. 2006;341:1046–1052. doi: 10.1016/j.bbrc.2006.01.063.
    1. Zhang W.-J., Frei B. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J. 2001;15:2423–2432. doi: 10.1096/fj.01-0260com.
    1. Lovell M.A., Xie C., Xiong S., Markesbery W. Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. J. Alzheimer’s Dis. 2003;5:229–239. doi: 10.3233/JAD-2003-5306.
    1. Holmquist L., Stauchbury G., Berbaum K., Muscat S., Young S., Hager K., Engel J., Münch G. Lipoic acid as a novel treatment for Alzheimer’s disease and related demenias. Pharmacol. Ther. 2007;113:154–164. doi: 10.1016/j.pharmthera.2006.07.001.
    1. Haugaard N., Levin R.M. Regulation of the activity of choline acetyl transferase by lipoic acid. Mol. Cell. Biochem. 2000;213:61–63. doi: 10.1023/A:1007156732662.
    1. Meraz-Ríos M.A., Toral-Rios D., Franco-Bocanegra D., Villeda-Hernández J., Campos-Peña V. Inflammatory process in Alzheimer’s disease. Front. Integr. Neurosci. 2013;7:59. doi: 10.3389/fnint.2013.00059.
    1. Ooi L., Patel M., Münch G. The thiol antioxidant lipoic acid and Alzheimer’s disease. In: Laher I., editor. Systems Biology of Free Radicals and Antioxidants. Springer; Berlin/Heidelberg, Germany: 2014. pp. 2275–2288.
    1. Suh J.H., Wang H., Liu R.-M., Liu J.K., Hagena T.M. (R)-α-Lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: Evidence for increased cysteine requirement for zGSH synthesis. Arch. Biochem. Biophys. 2015;423:126–135. doi: 10.1016/j.abb.2003.12.020.
    1. Hardas S.S., Sultana R., Clark A.M., Beckett T.L., Szweda L.I., Murphy P., Butterfielda D.A. Oxidative modification of lipoic acid by HNE in Alzheimer disease brain. Redox Biol. 2013;1:80–85. doi: 10.1016/j.redox.2013.01.002.
    1. Breitzig M., Bhimineni C., Lockey R., Kolliputi N. 4-Hydroxy-2-nonenal: A critical target in oxidative stress? Am. J. Physiol. Cell Physiol. 2016;311:537–543. doi: 10.1152/ajpcell.00101.2016.
    1. Wong A., Dukic-Stefanovic S., Gasic-Milenkovic J., Schinzel R., Wiesinger H., Riederer P., Münch G. Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia. Eur. J. Neurosci. 2001;14:1961–1967. doi: 10.1046/j.0953-816x.2001.01820.x.
    1. Dinicola S., Proietti S., Cucina A., Bizzarri M., Fuso A.J.A. Alpha-Lipoic Acid Downregulates IL-1β and IL-6 by DNA Hypermethylation in SK-N-BE Neuroblastoma Cells. Antioxidant. 2017;6:74. doi: 10.3390/antiox6040074.
    1. Schwartz L., Abolhassani M., Guais A., Sanders E., Steyaert J.M., Campion F., Israël M. A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results. Oncol. Rep. 2010;23:1407–1420. doi: 10.3892/or_00000778.
    1. Na M.H., Seo E.Y., Kim W.K. Effects of alpha-lipoic acid on cell proliferation and apoptosis in MDA-MB-231 human breast cells. Nutr. Res. Pract. 2009;3:265–271. doi: 10.4162/nrp.2009.3.4.265.
    1. Ganapathy-Kanniappan S., Geschwind J.F. Tumor glycolysis as a target for cancer therapy: Progress and prospects. Mol. Cancer. 2013;12:152. doi: 10.1186/1476-4598-12-152.
    1. Zhang C., Liu J., Liang Y., Wu R., Zhao Y., Hong X., Lin M., Yu H., Liu L., Levine A.J., et al. Tumour-associated mutant p53 drives the Warburg effect. Nat. Commun. 2013;4:2935. doi: 10.1038/ncomms3935.
    1. 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;13:1425–1435. doi: 10.4161/cbt.22003.
    1. Jeon M.J., Kim W.G., Lim S., Choi H.J., Sim S., Kim T.Y., Shong Y.K., Kim W.B. Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells. Mol. Cell. Endocrinol. 2016;419:113–123. doi: 10.1016/j.mce.2015.10.005.
    1. Yang L., Wen Y., Lv G., Lin Y., Tang J., Lu J., Zhang M., Liu W., Sun X. a-Lipoic acid inhibits human lung cancer cell proliferation through Grb2-mediated EGFR down regulation. Biochem. Biophys. Res. Commun. 2017;494:325–331. doi: 10.1016/j.bbrc.2017.10.030.
    1. Moungjaroen J., Nimmannit U., Callery P.S., Wang L., Azad N., Lipipun V., Chanvorachote P., Rojanasakul Y. Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation. J. Pharmacol. Exp. Ther. 2006;319:1062–1069. doi: 10.1124/jpet.106.110965.
    1. Dozio E., Ruscica M., Passafaro L., Dogliotti G., Steffani L., Marthyn P., Pagani A., Demartini G., Esposti D., Fraschini F., et al. The natural antioxidant alpha-lipoic acid induces p27(Kip1)-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cells. Eur. J. Pharmacol. 2010;641:29–34. doi: 10.1016/j.ejphar.2010.05.009.
    1. Wenzel U., Nickel A., Daniel H. α-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation. Apoptosis. 2005;10:359–368. doi: 10.1007/s10495-005-0810-x.
    1. Trivedi P.P., Jena G.B. Role of α-lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice: Studies on inflammation, oxidative stress, DNA damage and fibrosis. Food Chem. Toxicol. 2013;59:339–355. doi: 10.1016/j.fct.2013.06.019.
    1. Tripathy J., Tripathy A., Thangaraju M., Suar M., Elangovan S. alpha-Lipoic acid inhibits the migration and invasion of breast cancer cells through inhibition of TGFbeta signaling. Life Sci. 2018;207:15–22. doi: 10.1016/j.lfs.2018.05.039.
    1. Lee W.J., Song K.H., Koh E.H., Won J.C., Kim H.S., Park H.S., Kim M.S., Kim S.W., Lee K.U., Park J.Y. Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem. Biophys. Res. Commun. 2005;332:885–891. doi: 10.1016/j.bbrc.2005.05.035.
    1. Bitar M.S., Ayed A.K., Abdel-Halim S.M., Isenovic E.R., Al-Mulla F. Inflammation and apoptosis in aortic tissues of aged type II diabetes: Amelioration with lipoic acid through phosphatidylinositol 3-kinase/Akt-dependent mechanism. Life Sci. 2010;86:844–853. doi: 10.1016/j.lfs.2010.03.019.
    1. Rochette L., Ghibu S., Muresan A., Vergely C. Alpha-lipoic acid: Molecular mechanisms and therapeutic potential in diabetes1. Can. J. Physiol. Pharmacol. 2015;93:1021–1027. doi: 10.1139/cjpp-2014-0353.
    1. Smith A.R., Hagen T.M. Vascularendothelialdys- function inaging: Loss of Akt- dependent endothelial nitricoxide synthase phosphorylation and partial restoration by (R)-alpha-lipoic acid. Biochem. Soc. Trans. 2003;31:1447–1449. doi: 10.1042/bst0311447.
    1. Artwohl M., Muth K., Kosulin K., de Martin R., Holzenbein T., Rainer G., Freudenthaler A., Huttary N., Schmetterer L., Waldhausl W.K., et al. R-(+)-alpha-lipoic acid inhibits endothelial cell apoptosis and proliferation: Involvement of Akt and retinoblastoma protein/E2F-1. Am. J. Physiol. Endocrinol. Metab. 2007;293:681–689. doi: 10.1152/ajpendo.00584.2006.
    1. Zhang W.J., Wei H., Hagen T., Frei B. Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc. Natl. Acad. Sci. USA. 2007;104:4077–4082. doi: 10.1073/pnas.0700305104.
    1. Kawabata T., Packer L. Alpha-lipoate can protect against glycation of serum albumin, but not low density lipoprotein. Biochem. Biophys. Res. Commun. 1994;203:99–104. doi: 10.1006/bbrc.1994.2154.
    1. Thirunavukkarasu V., Nandhini A.A.T., Anuradha C.V. Lipoic acid improves glucose utilisation and prevents protein glycation and AGE formation. Die Pharm. 2005;60:772–775.
    1. Quinn J.F., Bussiere J.R., Hammond R.S., Montine T.J., Henson E., Jones R.E., Stackman R.W. Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol. Aging. 2007;28:213–225. doi: 10.1016/j.neurobiolaging.2005.12.014.
    1. Suh J.H., Zhu B.Z., de Szoeke E., Frei B., Hagen T.M. Dihydrolipoic acid lowers the redox activity of transition metal ions but does not remove them from the active site of enzymes. Redox Rep. 2004;9:57–61. doi: 10.1179/135100004225003923.
    1. Micili S.C., Goker A., Kuscu K., Ergur B.U., Fuso A.J.R.S. α-Lipoic Acid Vaginal Administration Contrasts Inflammation and Preterm Delivery in Rats. Reprod. Sci. 2019;26:128–138. doi: 10.1177/1933719118766266.
    1. Brufani M., Figliola R. (R)-α-lipoic acid oral liquid formulation: Pharmacokinetic parameters and therapeutic efficacy. Acta Bio-Medica: Atenei Parm. 2014;85:108–115.
    1. Gleiter C.H., Schug B.S., Hermann R., Elze M., Blume H.H., Gundert-Remy U. Influence of food intake on the bioavailability of thioctic acid enantiomers. Eur. J. Clin. Pharmacol. 1996;50:513–514. doi: 10.1007/s002280050151.
    1. Hermann R., Niebch G., Borbe H.O., Fieger-Büschges H., Ruus P., Nowak H., Riethmüller-Winzen H., Peukert M., Blume H. Enantioselective pharmacokinetics and bioavailability of different racemic α-lipoic acid formulations in healthy volunteers. Eur. J. Pharmacol. Sci. 1996;4:167–174. doi: 10.1016/0928-0987(95)00045-3.
    1. Teichert J., Tuemmers T., Achenbach H., Preiss C., Hermann R., Ruus P., Preiss R. Pharmacokinetics of alpha-lipoic acid in subjects with severe kidney damage and end-stage renal disease. J. Clin. Pharmacol. 2005;45:313–328. doi: 10.1177/0091270004270792.
    1. Breithaupt-Grogler K., Niebch G., Schneider E., Erb K., Hermann R., Blume H.H., Schug B.S., Belz G.G. Dose-proportionality of oral thioctic acid--coincidence of assessments via pooled plasma and individual data. Eur. J. Pharm. Sci. 1999;8:57–65. doi: 10.1016/S0928-0987(98)00061-X.
    1. Uchida R., Iwamoto K., Nagayama S., Miyajima A., Okamoto H., Ikuta N., Fukumi H., Terao K., Hirota T. Effect of gamma-Cyclodextrin Inclusion Complex on the Absorption of R-alpha-Lipoic Acid in Rats. Int. J. Mol. Sci. 2015;16:10105–10120. doi: 10.3390/ijms160510105.
    1. Uchida R., Okamoto H., Ikuta N., Terao K., Hirota T. Enantioselective Pharmacokinetics of alpha-Lipoic Acid in Rats. Int. J. Mol. Sci. 2015;16:22781–22794. doi: 10.3390/ijms160922781.
    1. Mignini F., Nasuti C., Gioventu G., Napolioni V., Martino P.D. Human bioavailability and pharmacokinetic profile of different formulations delivering alpha lipoic acid. Open Access Sci. Rep. 2012;1:418. doi: 10.4172/scientificreports.418.
    1. Hermann R., Mungo J., Cnota P.J., Ziegler D. Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms. Clin. Pharmacol. 2014;6:195–204. doi: 10.2147/CPAA.S71574.
    1. Reed L.J. The chemistry and function of lipoic acid. Adv. Enzymol. Related Areas Mol. Biol. 1957;18:319–347.
    1. Kim N.W., Song Y.M., Kim E., Cho H.S., Cheon K.A., Kim S.J., Park J.Y. Adjunctive α-lipoic acid reduces weight gain compared with placebo at 12 weeks in schizophrenic patients treated with atypical antipsychotics: A double-blind randomized placebo-controlled study. Int. Clin. Psychopharmacol. 2016;31:265–274. doi: 10.1097/YIC.0000000000000132.
    1. Sun H., Yao W., Tang Y., Zhuang W., Wu D., Huang S., Sheng H. Urinary exosomes as a novel biomarker for evaluation of α-lipoic acid’s protective effect in early diabetic nephropathy. J. Clin. Lab. Anal. 2017;31:e22129. doi: 10.1002/jcla.22129.
    1. De Sousa C.N.S., da Silva Leite C.M.G., da Silva Medeiros I., Vasconcelos L.C., Cabral L.M., Patrocínio C.F.V., Patrocínio M.L.V., Mouaffak F., Kebir O., Macedo D., et al. Alpha-lipoic acid in the treatment of psychiatric and neurological disorders: A systematic review. Metab. Brain Dis. 2019;34:39–52. doi: 10.1007/s11011-018-0344-x.
    1. The Emerging Risk Factors Collaboration Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–2222. doi: 10.1016/S0140-6736(10)60484-9.
    1. Fowler M.J. Microvascular and macrovascular complications of diabetes. Clin. Diabetes. 2008;26:77–82. doi: 10.2337/diaclin.26.2.77.
    1. Vinik A., Casellini C., Nevoret M.L. Diabetic Neuropathies. In: Feingold K.R., Anawalt B., Boyce A., Chrousos G., Dungan K., Grossman A., Hershman J.M., Kaltsas G., Koch C., Kopp P., et al., editors. South Dartmouth. , Inc.; South Dartmouth, MA, USA: 2000.
    1. Ziegler D., Low P.A., Freeman R., Tritschler H.J., Vinik A.I. Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial. J. Diabetes Its Complicat. 2016;30:350–356. doi: 10.1016/j.jdiacomp.2015.10.018.
    1. Garcia-Alcala H., Santos Vichido C.I., Islas Macedo S., Genestier-Tamborero C.N., Minutti-Palacios M., Hirales Tamez O., Garcia C., Ziegler D. Treatment with alpha-Lipoic Acid over 16 Weeks in Type 2 Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading. J. Diabetes Res. 2015;2015:189857. doi: 10.1155/2015/189857.
    1. Agathos E., Tentolouris A., Eleftheriadou I., Katsaouni P., Nemtzas I., Petrou A., Papanikolaou C., Tentolouris N. Effect of α-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. J. Int. Med. Res. 2018;46:1779–1790. doi: 10.1177/0300060518756540.
    1. WHO . Obesity and Overweight. World Health Organization; Geneva, Switzerland: 2018.
    1. Flegal K.M., Graubard B.I., Williamson D.F., Gail M.H. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA. 2007;298:2028–2037. doi: 10.1001/jama.298.17.2028.
    1. Van Kruijsdijk R.C.M., Van Der Wall E., Visseren F.L.J. Obesity and cancer: The role of dysfunctional adipose tissue. Cancer Epidemiol. Biomarkers Prev. 2009;18:2569–2578. doi: 10.1158/1055-9965.EPI-09-0372.
    1. Escoté X., Félix-Soriano E., Gayoso L., Huerta A.E., Alvarado M.A., Ansorena D., Astiasarán I., Martínez J.A., Moreno-Aliaga M.J. Effects of EPA and lipoic acid supplementation on circulating FGF21 and the fatty acid profile in overweight/obese women following a hypocaloric diet. Food Funct. 2018;9:3028–3036. doi: 10.1039/C8FO00355F.
    1. Huerta A.E., Navas-Carretero S., Prieto-Hontoria P.L., Martínez J.A., Moreno-Aliaga M.J. Effects of α-lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss. Obesity. 2015;23:313–321. doi: 10.1002/oby.20966.
    1. Li N., Yan W., Hu X., Huang Y., Wang F., Zhang W., Wang Q., Wang X., Sun K. Effects of oral α-lipoic acid administration on body weight in overweight or obese subjects: A crossover randomized, double-blind, placebo-controlled trial. Clin. Endocrinol. 2017;86:680–687. doi: 10.1111/cen.13303.
    1. Hosseinpour-Arjmand S., Amirkhizi F., Ebrahimi-Mameghani M. The effect of alpha-lipoic acid on inflammatory markers and body composition in obese patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial. J. Clin. Pharm. Ther. 2019;44:258–267. doi: 10.1111/jcpt.12784.
    1. Romo-Hualde A., Huerta A.E., González-Navarro C.J., Ramos-López O., Moreno-Aliaga M.J., Martínez J.A. Untargeted metabolomic on urine samples after α-lipoic acid and/or eicosapentaenoic acid supplementation in healthy overweight/obese women. Lipids Health Dis. 2018;17:103. doi: 10.1186/s12944-018-0750-4.
    1. The American Psychiatric Association . Diagnostic and statistical manual of mental disorders. The American Psychiatric Association; Washington, DC, USA: 2013.
    1. Gold J.M. Cognitive deficits as treatment targets in schizophrenia. Schizophr. Res. 2004;72:21–28. doi: 10.1016/j.schres.2004.09.008.
    1. Friedman J.I., Wallenstein S., Moshier E., Parrella M., White L., Bowler S., Gottlieb S., Harvey P.D., McGinn T.G., Flanagan L. The effects of hypertension and body mass index on cognition in schizophrenia. Am. J. Psychiatry. 2010;167:1232–1239. doi: 10.1176/appi.ajp.2010.09091328.
    1. Goughari A.S., Mazhari S., Pourrahimi A.M., Sadeghi M.M., Nakhaee N. Associations between components of metabolic syndrome and cognition in patients with schizophrenia. J. Psychiatr. Pract. 2015;21:190–197. doi: 10.1097/PRA.0000000000000065.
    1. Sanders L.L.O., de Souza Menezes C.E., Chaves Filho A.J.M., de Almeida Viana G., Fechine F.V., de Queiroz M.G.R., da Cruz Fonseca S.G., Vasconcelos S.M.M., de Moraes M.E.A., Gama C.S. α-Lipoic acid as adjunctive treatment for Schizophrenia: An open-label trial. J. Clin. Psychopharmacol. 2017;37:697–701. doi: 10.1097/JCP.0000000000000800.
    1. Vidović B., Milovanović S., Stefanović A., Kotur-Stevuljević J., Takić M., Debeljak-Martačić J., Pantović M., Đorđević B. Effects of alpha-lipoic acid supplementation on plasma adiponectin levels and some metabolic risk factors in patients with schizophrenia. J. Med. Food. 2017;20:79–85. doi: 10.1089/jmf.2016.0070.
    1. Confavreux C., Vukusic S., Moreau T., Adeleine P. Relapses and progression of disability in multiple sclerosis. N. Engl. J. Med. 2000;343:1430–1438. doi: 10.1056/NEJM200011163432001.
    1. Marracci G.H., Jones R.E., McKeon G.P., Bourdette D.N. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J. Neuroimmunol. 2002;131:104–114. doi: 10.1016/S0165-5728(02)00269-2.
    1. Yadav V., Marracci G., Lovera J., Woodward W., Bogardus K., Marquardt W., Shinto L., Morris C., Bourdette D. Lipoic acid in multiple sclerosis: A pilot study. Mult. Scler. J. 2005;11:159–165. doi: 10.1191/1352458505ms1143oa.
    1. Dutta R., Trapp B.D. Relapsing and progressive forms of multiple sclerosis–insights from pathology. Curr. Opin. Neurol. 2014;27:271–278. doi: 10.1097/WCO.0000000000000094.
    1. Khalili M., Azimi A., Izadi V., Eghtesadi S., Mirshafiey A., Sahraian M.A., Motevalian A., Norouzi A., Sanoobar M., Eskandari G., et al. Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: A double-blind, placebo-controlled, randomized clinical trial. Neuroimmunomodulation. 2014;21:291–296. doi: 10.1159/000356145.
    1. Loy B.D., Fling B.W., Horak F.B., Bourdette D.N., Spain R.I. Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis. Complement. Ther. Med. 2018;41:169–174. doi: 10.1016/j.ctim.2018.09.006.
    1. Fiedler S.E., Yadav V., Kerns A.R., Tsang C., Markwardt S., Kim E., Spain R., Bourdette D., Salinthone S. Lipoic acid stimulates cAMP production in healthy control and secondary progressive MS subjects. Mol. Neurobiol. 2018;55:6037–6049. doi: 10.1007/s12035-017-0813-y.
    1. Yamada T., Atsuki Y., Wakasaya A., Kobayashi M., Hirano Y., Ohwada M. Characteristics of patients with subchorionic hematomas in the second trimester. J. Obstet. Gynaecol. Res. 2012;38:180–184. doi: 10.1111/j.1447-0756.2011.01665.x.
    1. Şükür Y.E., Göç G., Köse O., Açmaz G., Özmen B., Atabekoğlu C.S., Koç A., Söylemez F. The effects of subchorionic hematoma on pregnancy outcome in patients with threatened abortion. J. Turkish German Gynecol. Assoc. 2014;15:239. doi: 10.5152/jtgga.2014.14170.
    1. Carp H.J.A. Progestogens and pregnancy loss. Climacteric. 2018;21:380–384. doi: 10.1080/13697137.2018.1436166.
    1. Porcaro G., Brillo E., Giardina I., Di Iorio R. Alpha Lipoic Acid (ALA) effects on subchorionic hematoma: Preliminary clinical results. Eur. Rev. Med. Pharmacol. Sci. 2015;19:3426–3432.
    1. Grandi G., Pignatti L., Ferrari F., Dante G., Neri I., Facchinetti F. Vaginal alpha-lipoic acid shows an anti-inflammatory effect on the cervix, preventing its shortening after primary tocolysis. A pilot, randomized, placebo-controlled study. J. Matern. Fetal Neonatal Med. 2017;30:2243–2249. doi: 10.1080/14767058.2016.1245282.
    1. Costantino M., Guaraldi C., Costantino D. Resolution of subchorionic hematoma and symptoms of threatened miscarriage using vaginal alpha lipoic acid or progesterone: Clinical evidences. Eur. Rev. Med. Pharmacol. Sci. 2016;20:1656–1663.
    1. Ambrosi N., Arrosagaray V., Guerrieri D., Uva P.D., Petroni J., Herrera M.B., Iovanna J.L., Leon L., Incardona C., Chuluyan H.E., et al. alpha-Lipoic acid protects against ischemia-reperfusion injury in simultaneous kidney-pancreas transplantation. Transplantation. 2016;100:908–915. doi: 10.1097/TP.0000000000000981.
    1. Casciato P., Ambrosi N., Caro F., Vazquez M., Müllen E., Gadano A., de Santibañes E., de Santibañes M., Zandomeni M., Chahdi M. α-Lipoic acid reduces postreperfusion syndrome in human liver transplantation-a pilot study. Transpl. Int. 2018;31:1357–1368. doi: 10.1111/tri.13314.
    1. Guo Y., Jones D., Palmer J.L., Forman A., Dakhil S.R., Velasco M.R., Weiss M., Gilman P., Mills G.M., Noga S.J., et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled trial. Support. Care Cancer. 2014;22:1223–1231. doi: 10.1007/s00520-013-2075-1.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다