Skip to main content

Advertisement

SpringerLink
Log in

The Effects and Mechanisms of Mitochondrial Nutrient α-Lipoic Acid on Improving Age-Associated Mitochondrial and Cognitive Dysfunction: An Overview

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

We have identified a group of nutrients that can directly or indirectly protect mitochondria from oxidative damage and improve mitochondrial function and named them “mitochondrial nutrients”. The direct protection includes preventing the generation of oxidants, scavenging free radicals or inhibiting oxidant reactivity, and elevating cofactors of defective mitochondrial enzymes with increased Michaelis–Menten constant to stimulate enzyme activity, and also protect enzymes from further oxidation, and the indirect protection includes repairing oxidative damage by enhancing antioxidant defense systems either through activation of phase 2 enzymes or through increase in mitochondrial biogenesis. In this review, we take α-lipoic acid (LA) as an example of mitochondrial nutrients by summarizing the protective effects and possible mechanisms of LA and its derivatives on age-associated cognitive and mitochondrial dysfunction of the brain. LA and its derivatives improve the age-associated decline of memory, improve mitochondrial structure and function, inhibit the age-associated increase of oxidative damage, elevate the levels of antioxidants, and restore the activity of key enzymes. In addition, co-administration of LA with other mitochondrial nutrients, such as acetyl-l-carnitine and coenzyme Q10, appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial dysfunction. Therefore, administrating mitochondrial nutrients, such as LA and its derivatives in combination with other mitochondrial nutrients to aged people and patients suffering from neurodegenerative diseases, may be an effective strategy for improving mitochondrial and cognitive dysfunction.

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.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ames BN (2003) Delaying the mitochondrial decay of aging-a metabolic tune-up. Alzheimer Dis Assoc Disord 17(Suppl 2):S54–S57

    PubMed  CAS  Google Scholar 

  2. Ames BN, Shigenaga MK, Hagen TM (1995) Mitochondrial decay in aging. Biochim Biophys Acta 1271:165–170

    PubMed  Google Scholar 

  3. Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922

    Article  PubMed  CAS  Google Scholar 

  4. Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91:10771–10778

    Article  PubMed  CAS  Google Scholar 

  5. Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581

    PubMed  CAS  Google Scholar 

  6. Harman D (2002) Increasing healthy life span. The New York Academy of Sciences, New York

    Google Scholar 

  7. Roubertoux PL, Sluyter F, Carlier M, Marcet B, Maarouf-Veray F, Cherif C, Marican C, Arrechi P, Godin F, Jamon M et al (2003) Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet 35:65–69

    Article  PubMed  CAS  Google Scholar 

  8. Tritschler HJ, Packer L, Medori R (1994) Oxidative stress and mitochondrial dysfunction in neurodegeneration. Biochem Mol Biol Int 34:169–181

    PubMed  CAS  Google Scholar 

  9. Beal MF (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 31:119–130

    Article  PubMed  CAS  Google Scholar 

  10. Liu J, Mori A (1999) Stress, aging, and brain oxidative damage. Neurochem Res 24:1479–1497

    Article  PubMed  CAS  Google Scholar 

  11. Albers DS, Beal MF (2000) Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J Neural Transm Suppl 59:133–154

    PubMed  CAS  Google Scholar 

  12. Aliev G, Smith MA, Seyidov D, Neal ML, Lamb BT, Nunomura A, Gasimov EK, Vinters HV, Perry G, LaManna JC et al (2002) The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer’s disease. Brain Pathol 12:21–35

    Article  PubMed  CAS  Google Scholar 

  13. Rao AV, Balachandran B (2002) Role of oxidative stress and antioxidants in neurodegenerative diseases. Nutr Neurosci 5:291–309

    Article  PubMed  CAS  Google Scholar 

  14. Perry G, Nunomura A, Friedlich AL, Boswell MV et al (2000) Factors controlling oxidative damage in Alzheimer disease: metals and mitochondria. In: Yoshikawa T, Toyokuni S, Yamamato Y, Naito Y (eds) Free radicals in chemistry, biology and medicine. OICA International, London, pp 417–423

    Google Scholar 

  15. Beal MF (2003) Bioenergetic approaches for neuroprotection in Parkinson’s disease. Ann Neurol 53(Suppl 3):S39–S47; discussion S47–S-38

    Article  PubMed  CAS  Google Scholar 

  16. Butterfield D, Castegna A, Pocernich C, Drake J, Scapagnini G, Calabrese V (2002) Nutritional approaches to combat oxidative stress in Alzheimer’s disease. J Nutr Biochem 13:444

    Article  PubMed  CAS  Google Scholar 

  17. Butterfield DA, Castegna A, Drake J, Scapagnini G, Calabrese V (2002) Vitamin E and neurodegenerative disorders associated with oxidative stress. Nutr Neurosci 5:229–239

    Article  PubMed  CAS  Google Scholar 

  18. Marriage B, Clandinin MT, Glerum DM (2003) Nutritional cofactor treatment in mitochondrial disorders. J Am Diet Assoc 103:1029–1038

    Article  PubMed  Google Scholar 

  19. McDaniel MA, Maier SF, Einstein GO (2003) “Brain-specific” nutrients: a memory cure? Nutrition 19:957–975

    Article  PubMed  CAS  Google Scholar 

  20. Baker SK, Tarnopolsky MA (2003) Targeting cellular energy production in neurological disorders. Expert Opin Investig Drugs 12:1655–1679

    Article  PubMed  CAS  Google Scholar 

  21. Black MM (2003) Micronutrient deficiencies and cognitive functioning. J Nutr 133:3927S–3931S

    PubMed  CAS  Google Scholar 

  22. Price MC (2002) Longevity Report 91: the role of enzymic cofactors in aging. Available at: http://www.quantium.cwe.net/lr91.htm#_Toc22709815

  23. Moini H, Packer L, Saris NE (2002) Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol 182:84–90

    Article  PubMed  CAS  Google Scholar 

  24. Packer L, Roy S, Sen CK (1997) Alpha-lipoic acid: a metabolic antioxidant and potential redox modulator of transcription. Adv Pharmacol 38:79–101

    PubMed  CAS  Google Scholar 

  25. Packer L, Tritschler HJ, Wessel K (1997) Neuroprotection by the metabolic antioxidant α-lipoic acid. Free Radic Biol Med 22:359–378

    Article  PubMed  CAS  Google Scholar 

  26. Packer L, Witt EH, Tritschler HJ (1995) Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med 19:227–250

    Article  PubMed  CAS  Google Scholar 

  27. Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH (1998) Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med 24:1023–1039

    Article  PubMed  CAS  Google Scholar 

  28. Fuchs J, Packer L, Zimmer G (1997) Lipoic acid in health and disease. Marcel Dekker Inc, New York

    Google Scholar 

  29. Sen CK, Roy S, Khanna S, Packer L (1999) Determination of oxidized and reduced lipoic acid using high- performance liquid chromatography and coulometric detection. Methods Enzymol 299:239–246

    Article  PubMed  CAS  Google Scholar 

  30. Ou P, Tritschler HJ, Wolff SP (1995) Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol 50:123–126

    Article  PubMed  CAS  Google Scholar 

  31. Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB (1999) (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J 13:411–418

    PubMed  CAS  Google Scholar 

  32. Hagen TM, Vinarsky V, Wehr CM, Ames BN (2000) (R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. Antioxid Redox Signal 2:473–483

    Article  PubMed  CAS  Google Scholar 

  33. Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, Hagen TM (2001) Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. FASEB J 15:700–706

    Article  PubMed  CAS  Google Scholar 

  34. Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147

    PubMed  CAS  Google Scholar 

  35. Hagen TM, Ingersoll RT, Wehr CM, Lykkesfeldt J, Vinarsky V, Bartholomew JC, Song MH, Ames BN (1998) Acetyl-l-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci USA 95:9562–9566

    Article  PubMed  CAS  Google Scholar 

  36. Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63

    Article  PubMed  CAS  Google Scholar 

  37. Cadenas E, Davies KJ (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29:222–230

    Article  PubMed  CAS  Google Scholar 

  38. Stadtman ER, Levine RL (2000) Protein oxidation. Ann N Y Acad Sci 899:191–208

    Article  PubMed  CAS  Google Scholar 

  39. Chen JJ, Yu BP (1994) Alterations in mitochondrial membrane fluidity by lipid peroxidation products. Free Radic Biol Med 17:411–418

    Article  PubMed  CAS  Google Scholar 

  40. Choi JH, Yu BP (1995) Brain synaptosomal aging: free radicals and membrane fluidity. Free Radic Biol Med 18:133–139

    Article  PubMed  CAS  Google Scholar 

  41. Paradies G, Ruggiero FM, Petrosillo G, Gadaleta MN, Quagliariello E (1994) Effect of aging and acetyl-l-carnitine on the activity of cytochrome oxidase and adenine nucleotide translocase in rat heart mitochondria. FEBS Lett 350:213–215

    Article  PubMed  CAS  Google Scholar 

  42. Stoll S, Hartmann H, Cohen SA, Muller WE (1993) The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits. Pharmacol Biochem Behav 46:799–805

    Article  PubMed  CAS  Google Scholar 

  43. Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, Morley JE (2003) The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 84:1173–1183

    Article  PubMed  CAS  Google Scholar 

  44. Poon HF, Farr SA, Thongboonkerd V, Lynn BC, Banks WA, Morley JE, Klein JB, Butterfield DA (2005) Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: implications for aging and age-related neurodegenerative disorders. Neurochem Int 46:159–168

    Article  PubMed  CAS  Google Scholar 

  45. Poon HF, Frasier M, Shreve N, Calabrese V, Wolozin B, Butterfield DA (2005) Mitochondrial associated metabolic proteins are selectively oxidized in A30P alpha-synuclein transgenic mice–a model of familial Parkinson’s disease. Neurobiol Dis 18:492–498

    Article  PubMed  CAS  Google Scholar 

  46. Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, Packer L, Liu J (2006) Chronic systemic d-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. J Neurosci Res 83:1584–1590

    Article  PubMed  CAS  Google Scholar 

  47. Quinn JF, Bussiere JR, Hammond RS, Montine TJ, Henson E, Jones RE, Stackman RW Jr (2007) Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol Aging 28:213–225

    Article  PubMed  CAS  Google Scholar 

  48. Manda K, Ueno M, Moritake T, Anzai K (2007) Radiation-induced cognitive dysfunction and cerebellar oxidative stress in mice: protective effect of alpha-lipoic acid. Behav Brain Res 177:7–14

    Article  PubMed  CAS  Google Scholar 

  49. Evans JL, Goldfine ID (2000) Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther 2:401–413

    Article  PubMed  CAS  Google Scholar 

  50. Ziegler D, Gries FA (1997) Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes 46(Suppl 2):S62–S66

    PubMed  CAS  Google Scholar 

  51. Sharma M, Gupta YK (2003) Effect of alpha lipoic acid on intracerebroventricular streptozotocin model of cognitive impairment in rats. Eur Neuropsychopharmacol 13:241–247

    Article  PubMed  CAS  Google Scholar 

  52. Schreibelt G, Musters RJ, Reijerkerk A, de Groot LR, van der Pol SM, Hendrikx EM, Dopp ED, Dijkstra CD, Drukarch B, de Vries HE (2006) Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity. J Immunol 177:2630–2637

    PubMed  CAS  Google Scholar 

  53. Holmguist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Munch G (2007) Lipoic acid as a novel treatment for Alzheimer's disease and related dementias. Pharmacol Ther113:154–164

    Article  CAS  Google Scholar 

  54. Arivazhagan P, Ayusawa D, Panneerselvam C (2006) Protective efficacy of alpha-lipoic acid on acetylcholinesterase activity in aged rat brain regions. Rejuvenation Res 9:198–201

    Article  PubMed  CAS  Google Scholar 

  55. Arivazhagan P, Panneerselvam C (2004) Alpha-lipoic acid increases Na + K + ATPase activity and reduces lipofuscin accumulation in discrete brain regions of aged rats. Ann N Y Acad Sci 1019:350–354

    Article  PubMed  CAS  Google Scholar 

  56. Zhang L, Xing GQ, Barker JL, Chang Y, Maric D, Ma W, Li BS, Rubinow DR (2001) Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway. Neurosci Lett 312:125–128

    Article  PubMed  CAS  Google Scholar 

  57. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634

    Article  PubMed  CAS  Google Scholar 

  58. Choi DW (1992) Excitotoxic cell death. J Neurobiol 23:1261–1276

    Article  PubMed  CAS  Google Scholar 

  59. Dumuis A, Sebben M, Haynes L, Pin JP, Bockaert J (1988) NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature 336:68–70

    Article  PubMed  CAS  Google Scholar 

  60. Lafon CM, Pietri S, Culcasi M, Bockaert J (1993) NMDA-dependent superoxide production and neurotoxicity. Nature 364:535–537

    Article  Google Scholar 

  61. Henneberry RC, Novelli A, Cox JA, Lysko PG (1989) Neurotoxicity at the N-methyl-d-aspartate receptor in energy-compromised neurons. An hypothesis for cell death in aging and disease. Ann N Y Acad Sci 568:225–233

    CAS  Google Scholar 

  62. Morimoto BH, Koshland DE Jr (1990) Excitatory amino acid uptake and N-methyl-d-aspartate-mediated secretion in a neural cell line. Proc Natl Acad Sci USA 87:3518–3521

    Article  PubMed  CAS  Google Scholar 

  63. Liu J, Atamna H, Kuratsune H, Ames BN (2002) Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann N Y Acad Sci 959:133–166

    Article  PubMed  CAS  Google Scholar 

  64. Tirosh O, Sen CK, Roy S, Packer L (2000) Cellular and mitochondrial changes in glutamate-induced HT4 neuronal cell death. Neuroscience 97:531–541

    Article  PubMed  CAS  Google Scholar 

  65. Wolz P, Krieglstein J (1996) Neuroprotective effects of alpha-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia. Neuropharmacology 35:369–375

    Article  PubMed  CAS  Google Scholar 

  66. Marangon K, Devaraj S, Tirosh O, Packer L, Jialal I (1999) Comparison of the effect of alpha-lipoic acid and alpha-tocopherol supplementation on measures of oxidative stress. Free Radic Biol Med 27:1114–1121

    Article  PubMed  CAS  Google Scholar 

  67. Aksenova MV, Aksenov MY, Carney JM, Butterfield DA (1998) Protein oxidation and enzyme activity decline in old brown Norway rats are reduced by dietary restriction. Mech Ageing Dev 100:157–168

    Article  PubMed  CAS  Google Scholar 

  68. Suh JH, Moreau R, Heath SH, Hagen TM (2005) 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 10:52–60

    Article  PubMed  CAS  Google Scholar 

  69. Gao X, Dinkova-Kostova AT, Talalay P (2001) Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: the indirect antioxidant effects of sulforaphane. Proc Natl Acad Sci USA 98:15221–15226

    Article  PubMed  CAS  Google Scholar 

  70. Satoh T, Okamoto SI, Cui J, Watanabe Y, Furuta K, Suzuki M, Tohyama K, Lipton SA (2006) Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers. Proc Natl Acad Sci USA 103:768–773

    Article  PubMed  CAS  Google Scholar 

  71. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98:3410–3415

    Article  PubMed  CAS  Google Scholar 

  72. Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM (2004) Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem 11:1135–1146

    PubMed  CAS  Google Scholar 

  73. Reznick RM, Shulman GI (2006) The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol 574:33–39

    Article  PubMed  CAS  Google Scholar 

  74. Hardie DG (2004) AMP-activated protein kinase: a key system mediating metabolic responses to exercise. Med Sci Sports Exerc 36:28–34

    Article  PubMed  CAS  Google Scholar 

  75. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, Bracale R, Valerio A, Francolini M, Moncada S et al (2003) Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 299:896–899

    Article  PubMed  CAS  Google Scholar 

  76. Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, Bassel-Duby R, Williams RS (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296:349–352

    Article  PubMed  CAS  Google Scholar 

  77. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC et al (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124

    Article  PubMed  CAS  Google Scholar 

  78. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W et al (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408

    Article  PubMed  CAS  Google Scholar 

  79. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69

    Article  PubMed  CAS  Google Scholar 

  80. Prasad KN, Cole WC, Prasad KC (2002) Risk factors for Alzheimer’s disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. J Am Coll Nutr 21:506–522

    PubMed  CAS  Google Scholar 

  81. Hongu N, Sachan DS (2000) Caffeine, carnitine and choline supplementation of rats decreases body fat and serum leptin concentration as does exercise. J Nutr 130:152–157

    PubMed  CAS  Google Scholar 

  82. Gonzalez-Perez O, Gonzalez-Castaneda RE, Huerta M, Luquin S, Gomez-Pinedo U, Sanchez-Almaraz E, Navarro-Ruiz A, Garcia-Estrada J (2002). Beneficial effects of alpha-lipoic acid plus vitamin E on neurological deficit, reactive gliosis and neuronal remodeling in the penumbra of the ischemic rat brain. Neurosci Lett 321:100–104

    Article  PubMed  CAS  Google Scholar 

  83. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN (2002) Feeding acetyl-l-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA 99:1870–1875

    Article  PubMed  CAS  Google Scholar 

  84. Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN (2002) 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-alpha-lipoic acid. Proc Natl Acad Sci USA 99:2356–2361

    Article  PubMed  CAS  Google Scholar 

  85. Liu J, Killilea DW, Ames BN (2002) Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-l-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci USA 99:1876–1881

    Article  PubMed  CAS  Google Scholar 

  86. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60

    Article  PubMed  CAS  Google Scholar 

  87. Gharib A, Derby S, Roberts S (2001) Timing and the control of variation. J Exp Psychol Anim Behav Process 27:165–178

    Article  PubMed  CAS  Google Scholar 

  88. Muthuswamy AD, Vedagiri K, Ganesan M, Chinnakannu P (2006) Oxidative stress-mediated macromolecular damage and dwindle in antioxidant status in aged rat brain regions: role of l-carnitine and dl-alpha-lipoic acid. Clin Chim Acta 368:84–92

    Article  PubMed  CAS  Google Scholar 

  89. Abdul HM, Butterfield DA (2007) 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 42:371–384

    Article  PubMed  CAS  Google Scholar 

  90. Kozlov AV, Gille L, Staniek K, Nohl H (1999) Dihydrolipoic acid maintains ubiquinone in the antioxidant active form by two-electron reduction of ubiquinone and one-electron reduction of ubisemiquinone. Arch Biochem Biophys 363:148–154

    Article  PubMed  CAS  Google Scholar 

  91. Milgram NW, Head E, Zicker SC, Ikeda-Douglas CJ, Murphey H, Muggenburg B, Siwak C, Tapp D, Cotman CW (2005) Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiol Aging 26:77–90

    Article  PubMed  CAS  Google Scholar 

  92. Opii WO, Joshi G, Head E, Milgram NW, Muggenburg BA, Klein JB, Pierce WM, Cotman CW, Butterfield DA (2006) Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer’s disease. Neurobiol Aging, doi: 10.1016/j.neurobiolaging.2006.09.012

  93. Kayali R, Cakatay U, Akcay T, Altug T (2006) Effect of alpha-lipoic acid supplementation on markers of protein oxidation in post-mitotic tissues of ageing rat. Cell Biochem Funct 24:79–85

    Article  PubMed  CAS  Google Scholar 

  94. Tirosh O, Sen CK, Roy S, Kobayashi MS, Packer L (1999) Neuroprotective effects of alpha-lipoic acid and its positively charged amide analogue. Free Radic Biol Med 26:1418–1426

    Article  PubMed  CAS  Google Scholar 

  95. Korotchkina LG, Yang H, Tirosh O, Packer L, Patel MS (2001) Protection by thiols of the mitochondrial complexes from 4-hydroxy-2-nonenal. Free Radic Biol Med 30:992–999

    Article  PubMed  CAS  Google Scholar 

  96. Guo Q, Tirosh O, Packer L (2001) Inhibitory effect of alpha-lipoic acid and its positively charged amide analogue on nitric oxide production in RAW 264.7 macrophages. Biochem Pharmacol 61:547–554

    Article  PubMed  CAS  Google Scholar 

  97. Venkatachalam SR, Salaskar A, Chattopadhyay A, Barik A, Mishra B, Gangabhagirathi R, Priyadarsini KI (2006) Synthesis, pulse radiolysis, and in vitro radioprotection studies of melatoninolipoamide, a novel conjugate of melatonin and alpha-lipoic acid. Bioorg Med Chem 14:6414–6419

    Article  PubMed  CAS  Google Scholar 

  98. Dixit V, Van den Bossche J, Sherman DM, Thompson DH, Andres RP (2006) Synthesis and grafting of thioctic acid-PEG-folate conjugates onto Au nanoparticles for selective targeting of folate receptor-positive tumor cells. Bioconjug Chem 17:603–609

    Article  PubMed  CAS  Google Scholar 

  99. Di Stefano A, Sozio P, Cocco A, Iannitelli A, Santucci E, Costa M, Pecci L, Nasuti C, Cantalamessa F, Pinnen F (2006) l-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties. J Med Chem 49:1486–1493

    Article  PubMed  CAS  Google Scholar 

  100. Biessels GJ, Smale S, Duis SE, Kamal A, Gispen WH (2001) The effect of gamma-linolenic acid-alpha-lipoic acid on functional deficits in the peripheral and central nervous system of streptozotocin-diabetic rats. J Neurol Sci 182:99–106

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author thanks Dr. Carl W. Cotman for his encouragement and reading the manuscript and Dr Jiangang Long for help of drawing the figures. This work was supported by National Eye Institute, NIH grant EY0160101, and Macular Degeneration Research Award (MDR Grant 2005-038).

Author information

Authors and Affiliations

  1. Institute for Brain Aging and Dementia, University of California, 1261 Gillespie Neuroscience Research Facility, Irvine, CA, 92697, USA

    Jiankang Liu

Authors
  1. Jiankang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiankang Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, J. The Effects and Mechanisms of Mitochondrial Nutrient α-Lipoic Acid on Improving Age-Associated Mitochondrial and Cognitive Dysfunction: An Overview. Neurochem Res 33, 194–203 (2008). https://doi.org/10.1007/s11064-007-9403-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-007-9403-0

Keywords

Search

Navigation