Amino Acids

, Volume 40, Issue 5, pp 1305–1313 | Cite as

Neuroprotective effects of creatine

Review Article

Abstract

There is a substantial body of literature, which has demonstrated that creatine has neuroprotective effects both in vitro and in vivo. Creatine can protect against excitotoxicity as well as against β-amyloid toxicity in vitro. We carried out studies examining the efficacy of creatine as a neuroprotective agent in vivo. We demonstrated that creatine can protect against excitotoxic lesions produced by N-methyl-d-aspartate. We also showed that creatine is neuroprotective against lesions produced by the toxins malonate and 3-nitropropionic acid (3-NP) which are reversible and irreversible inhibitors of succinate dehydrogenase, respectively. Creatine produced dose-dependent neuroprotective effects against MPTP toxicity reducing the loss of dopamine within the striatum and the loss of dopaminergic neurons in the substantia nigra. We carried out a number of studies of the neuroprotective effects of creatine in transgenic mouse models of neurodegenerative diseases. We demonstrated that creatine produced an extension of survival, improved motor performance, and a reduction in loss of motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal atrophy in the R6/2 and the N-171-82Q transgenic mouse models of Huntington’s disease (HD), even when its administration was delayed until the onset of disease symptoms. We recently examined the neuroprotective effects of a combination of coenzyme Q10 (CoQ10) with creatine against both MPTP and 3-NP toxicity. We found that the combination of CoQ and creatine together produced additive neuroprotective effects in a chronic MPTP model, and it blocked the development of alpha-synuclein aggregates. In the 3-NP model of HD, CoQ and creatine produced additive neuroprotective effects against the size of the striatal lesions. In the R6/2 transgenic mouse model of HD, the combination of CoQ and creatine produced additive effects on improving survival. Creatine may stabilize mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition. Creatine, however, was still neuroprotective in mice, which were deficient in mitochondrial creatine kinase. Administration of creatine increases the brain levels of creatine and phosphocreatine. Due to its neuroprotective effects, creatine is now in clinical trials for the treatment of Parkinson’s disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement in Unified Parkinson’s Disease Rating Scale at one year, and the compound was judged to be non futile. Creatine is now in a phase III clinical trial being carried out by the NET PD consortium. Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine in HD patients phase II trial and was well-tolerated. Creatine is now being studied in a phase III clinical trial in HD, the CREST trial. Creatine, therefore, shows great promise in the treatment of a variety of neurodegenerative diseases.

Keywords

Parkinson’s Huntington’s ALS Mitochondria 

References

  1. Adhihetty PJ, Beal MF (2008) Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromol Med 10:275–290CrossRefGoogle Scholar
  2. Adhihetty PJ, Irrcher I, Joseph AM, Ljubicic V, Hood DA (2003) Plasticity of skeletal muscle mitochondria in response to contractile activity. Exp Physiol 88:99–107PubMedCrossRefGoogle Scholar
  3. Aksenov M, Aksenova M, Butterfield DA, Markesbery WR (2000) Oxidative modification of creatine kinase BB in Alzheimer’s disease brain. J Neurochem 74:2520–2527PubMedCrossRefGoogle Scholar
  4. Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M et al (2001) Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis 8:479–491PubMedCrossRefGoogle Scholar
  5. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR (2008) Functions and effects of creatine in the central nervous system. Brain Res Bull 76:329–343PubMedCrossRefGoogle Scholar
  6. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431:805–810PubMedCrossRefGoogle Scholar
  7. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hanbleton MA et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662PubMedCrossRefGoogle Scholar
  8. Beal MF (1996) Mitochondria, free radicals, and neurodegeneration. Curr Opin Neurobiol 6:661–666PubMedCrossRefGoogle Scholar
  9. Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2:325–334PubMedCrossRefGoogle Scholar
  10. Beal MF (2009) Therapeutic approaches to mitochondrial dysfunction in Parkinson’s disease. Parkinsonism Relat Disord 15:S189–S194PubMedCrossRefGoogle Scholar
  11. Beal MF, Ferrante RJ (2004) Experimental therapeutics in transgenic mouse models of Huntington's Disease. Nat Rev Neurosci 5:373–384Google Scholar
  12. Beal MF, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM, Storey E, Srivastava R, Rosen BR, Hyman BT (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropionic acid. J Neurosci 13:4181–4192Google Scholar
  13. Bindoff LA, Birch-Machin M, Cartlidge NE, Parker WD Jr, Turnbull DM (1989) Mitochondrial function in Parkinson’s disease. Lancet 2:49Google Scholar
  14. Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X et al (2010) Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 59:290–294PubMedCrossRefGoogle Scholar
  15. Brewer GJ, Wallimann TW (2000) Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J Neurochem 74:1968–1978PubMedCrossRefGoogle Scholar
  16. Brouillet E, Jenkins BG, Hyman BT, Ferrante RJ, Kowall NW, Srivastava R, Roy DS, Rosen BR, Beal MF (1993) Age-dependent vulnerability of the striatum to the mitochondrial toxin 3-nitropropionic acid. J Neurochem 60:356–359Google Scholar
  17. Brouillet E, Hantraye P, Ferrante RJ, Dolan R, Leroy-Willig A, Kowall NW, Beal ME (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc Natl Acad Sci USA 92:7105–7109Google Scholar
  18. Browne SE, Beal MF (2006) Oxidative damage in Huntington’s disease pathogenesis. Antioxid Redox Signal 8:2061–2073PubMedCrossRefGoogle Scholar
  19. Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM, Bird ED, Beal MF (1997) Oxidative damage and metabolic dysfunction in Huntington’s disease: selective vulnerability of the basal ganglia. Ann Neurol 41:646–653Google Scholar
  20. Ceddia RB, Sweeney G (2004) Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells. J Physiol 555:409–421PubMedCrossRefGoogle Scholar
  21. Chaturvedi RK, Adhietty P, Shukla S, Hennessy T, Calingasan N, Yang L et al (2009) Impaired PGC-1alpha function in muscle in Huntington’s disease. Hum Mol Genet 18:3048–3065PubMedCrossRefGoogle Scholar
  22. Csukly K, Ascah A, Matas J, Gardner PF, Fontaine E, Burelle Y (2006) Muscle denervation promotes opening of the permeability transition pore and increases the expression of cyclophilin D. J Physiol 574:319–327PubMedCrossRefGoogle Scholar
  23. 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 127:59–69PubMedCrossRefGoogle Scholar
  24. David S, Shoemaker M, Haley BE (1998) Abnormal properties of creatine kinase in Alzheimer’s disease brain: correlation of reduced enzyme activity and active site photolabeling with aberrant cytosol-membrane partitioning. Brain Res Mol Brain Res 54:276–287PubMedCrossRefGoogle Scholar
  25. de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL et al (2010) Caspase activation precedes and leads to tangles. Nature 464:1201–1204PubMedCrossRefGoogle Scholar
  26. Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK et al (2000) Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 20:4389–4397PubMedGoogle Scholar
  27. Gallant M, Rak M, Szeghalmi A, Del Bigio MR, Westaway D, Yang J et al (2006) Focally elevated creatine detected in amyloid precursor protein (APP) transgenic mice and Alzheimer disease brain tissue. J Biol Chem 281:508Google Scholar
  28. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312PubMedCrossRefGoogle Scholar
  29. Groeneveld GJ, Van Kan HJ, Kalmijn S, Veldink JH, Guchelaar HJ, Wokke JH et al (2003) Riluzole serum concentrations inpatients with ALS: associations with side effects and symptoms. Neurology 61:1141–1143PubMedGoogle Scholar
  30. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775PubMedCrossRefGoogle Scholar
  31. Hensley K, Butterfield DA, Mattson M, Aksenova M, Harris M, Wu JF et al (1995) A model for beta-amyloid aggregation and neurotoxicity based on the free radical generating capacity of the peptide: implications of “molecular shrapnel” for Alzheimer’s disease. Proc West Pharmacol Soc 38:113–120PubMedGoogle Scholar
  32. Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M et al (2006) Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG. Neurology 66:250–252PubMedCrossRefGoogle Scholar
  33. Hervias I, Beal MF, Manfredi G (2006) Mitochondrial dysfunction and amyotrophic lateral sclerosis. Muscle Nerve 33:598–608PubMedCrossRefGoogle Scholar
  34. Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR (1993) Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localized 1H NMR spectroscopy. Neurology 43:2689–2695Google Scholar
  35. Juhn MS, Tarnopolsky M (1998a) Oral creatine supplementation and athletic performance. A critical review. Clin J Sport Med 8:286–297PubMedCrossRefGoogle Scholar
  36. Juhn MS, Tarnopolsky M (1998b) Potential side effects of creatine supplementation: a critical review. Clin J Sport Med 8:298–304PubMedCrossRefGoogle Scholar
  37. Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal MF, Ferrante RJ (2010) Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease. Hum Mol Genet 19(20):3919–3935Google Scholar
  38. Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA et al (1999) Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 5:347–350PubMedCrossRefGoogle Scholar
  39. Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF (1997) Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol 4:160–165Google Scholar
  40. Krige D, Carroll MT, Cooper JM, Marsden CD, Schapira AH, The Royal Kings and Queens Parkinson Disease Research Group (1992) Platelet mitochondrial function in Parkinson’s disease. Ann Neurol 32:782–788PubMedCrossRefGoogle Scholar
  41. Li X, Burklen T, Yuan X, Schlattner U, Desiderio DM, Wallimann T et al (2006) Stabilization of ubiquitous mitochondrial creatine kinase preprotein by APP family proteins. Mol Cell Neurosci 31:263–272PubMedCrossRefGoogle Scholar
  42. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795PubMedCrossRefGoogle Scholar
  43. Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R et al (1998) Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci 18:156–163PubMedGoogle Scholar
  44. Matthews RT, Ferrante RJ, Klivenyi P, Yang L, Klein AM, Mueller G et al (1999) Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol 157:142–149PubMedCrossRefGoogle Scholar
  45. McGill JK, Beal MF (2006) PGC-1alpha, a new therapeutic target in Huntington’s disease? Cell 127:465–468PubMedCrossRefGoogle Scholar
  46. Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751PubMedCrossRefGoogle Scholar
  47. Mihic S, MacDonald JR, McKenzie S, Tarnopolsky MA (2000) Acute creatine loading increases fat-free mass, but does not affect blood pressure, plasma creatinine, or CK activity in men and women. Med Sci Sports Exerc 32:291–296PubMedCrossRefGoogle Scholar
  48. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298PubMedCrossRefGoogle Scholar
  49. NINDS NET-PD Investigators (2006) A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 66:664–671CrossRefGoogle Scholar
  50. O’Gorman E, Beutner G, Dolder M, Koretsky AP, Brdiczka D, Wallimann T (1997) The role of creatine kinase in inhibition of mitochondrial permeability transition. FEBS Lett 414:253–257Google Scholar
  51. Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Vincent Chen HS, Tong G, Hayden MR, Lipton SA (2009) Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15:1407–1413Google Scholar
  52. Parker WD Jr, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 26:719–723Google Scholar
  53. Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D et al (2004) Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43:19–30PubMedCrossRefGoogle Scholar
  54. Pedrini S, Sau D, Guareschi S, Bogush M, Brown RH Jr, Naniche N et al (2010) ALS-linked mutant SOD1 damages mitochondria by promotion conformational changes in Bcl-2. Human Mol Genet 19:2974–2986CrossRefGoogle Scholar
  55. Peng TI, Greenamyre JT (1998) Privileged access to mitochondria of calcium influx through N-methyl-d-aspartate receptors. Mol Pharmacol 53:974–980PubMedGoogle Scholar
  56. Pettegrew JW, Panchalingam K, Klunk WE, McClure RJ, Muenz LR (1994) Alterations of cerebral metabolism in probable Alzheimer’s disease: a preliminary study. Neurobiol Aging 15:117–132PubMedCrossRefGoogle Scholar
  57. Poortmans JR, Auquier H, Renaut V, Durussel A, Saugy M, Brisson GR (1997) Effect of short-term creatine supplementation on renal responses in men. Eur J Appl Physiol 76:566–567CrossRefGoogle Scholar
  58. Poortsmans JR, Francaux M (2000) Adverse effects of creatine supplementation: fact or fiction? Sports Med 30:155–170CrossRefGoogle Scholar
  59. Primeau AJ, Adhihetty PJ, Hood DA (2002) Apoptosis in heart and skeletal muscle. Can J Appl Physiol 27:349–395PubMedCrossRefGoogle Scholar
  60. Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD et al (2009) PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 66:352–361PubMedCrossRefGoogle Scholar
  61. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N England J Med 362:329–344CrossRefGoogle Scholar
  62. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondria complex 1 deficiency in Parkinson’s disease. J Neurochem 54:823–827Google Scholar
  63. Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M et al (2004) A clinical trial of creatine in ALS. Neurology 63:1656–1661PubMedGoogle Scholar
  64. Sora I, Richman J, Santoro G, Wei H, Wang Y, Vanderah T et al (1994) The cloning and expression of a human creatine transporter. Biochem Biophys Res Commun 204:419–427. doi:10.1006/bbrc.1994.2475 PubMedCrossRefGoogle Scholar
  65. Steenge GR, Lambourne J, Casey A, Macdonald IA, Greenhaff PL (1998) Stimulatory effect of insulin on creatine accumulation in human skeletal muscle. Am J Physiol 275:E974–E979PubMedGoogle Scholar
  66. Stockler S, Hanefeld F (1997) Guanidinoacetate methyltransferase deficiency: a newly recognized inborn error of creatine biosynthesis. Wien Klin Wochenschr 109:86–88PubMedGoogle Scholar
  67. Stockler S, Marescau B, De Deyn PP, Trijbels JM, Hanefeld F (1997) Guanidino compounds in guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis. Metabolism 46:1189–1193PubMedCrossRefGoogle Scholar
  68. Tarnopolsky MA, Beal MF (2001) Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol 49:561–574PubMedCrossRefGoogle Scholar
  69. Tarnopolsky MA, Safdar A (2008) The potential benefits of creatine and conjugated linoleic acid as adjuncts to resistance training in older adults. Appl Physiol Nutr Metab 33:213–227. doi:10.1139/H07-142 PubMedCrossRefGoogle Scholar
  70. Thomas B, Beal MF (2007) Parkinson’s disease. Hum Mol Genet 16(2):R183–R194PubMedCrossRefGoogle Scholar
  71. Van der Knaap MS, Verhoeven NM, Maaswinkel-Mooij P, Pouwels PJ, Onkenhout W, Peeters EA et al (2000) Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect. Ann Neurol 47:540–543PubMedCrossRefGoogle Scholar
  72. Wallimann T, Hemmer W (1994) Creatine kinase in non-muscle tissues and cells. Mol Cell Biochem 133–134:193–220. doi:101007/BF01267955 PubMedCrossRefGoogle Scholar
  73. Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands. The ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281(Pt 1):21–40PubMedGoogle Scholar
  74. Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER et al (2006) Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metabolism 4:349–362PubMedCrossRefGoogle Scholar
  75. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA et al (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105–1116PubMedCrossRefGoogle Scholar
  76. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ et al (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA 99:15983–15987PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Neurology and NeuroscienceWeill Cornell Medical CollegeNew YorkUSA

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