Skip to main content
SpringerLink
Log in

Creatine supplementation lowers brain glutamate levels in Huntington’s disease

  • ORIGINAL COMMUNICATION
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

There is evidence from in vitro and animal experiments that oral creatine (Cr) supplementation might prevent or slow down neurodegeneration in Huntington’s disease (HD). However, this neuroprotective effect could not be replicated in clinical trials, possibly owing to treatment periods being too short to impact on clinical endpoints. We used proton magnetic resonance spectroscopy (1H-MRS) as a surrogate marker to evaluate the effect of Cr supplementation on brain metabolite levels in HD.

Twenty patients (age 46±7.3 years, mean duration of symptoms 4.0±2.1 years, number of CAG repeats 44.5±2.7) were included. The primary endpoint was metabolic alteration as measured by 1H-MRS in the parieto-occipital cortex before (t1) and after 8–10 weeks (t2) of Cr administration. Secondary measures comprised the motor section of the Unified Huntington’s Disease Rating Scale and the Mini Mental State Examination.

1H-MRS showed a 15.6% decrease of unresolved glutamate (Glu)+glutamine (Gln; Glu+Gln=Glx; p<0.001) and a 7.8% decrease of Glu (p<0.027) after Cr treatment. N-acetylaspartate trended to fall (p=0.073) whereas total Cr, choline-containing compounds, glucose, and lactate remained unchanged. There was no effect on clinical rating scales.

This cortical Glx and Glu decrease may be explained by Cr enhancing the energy-dependent conversion of Glu to Gln via the Glu-Gln cycle, a pathway known to be impaired in HD. Since Glu-mediated excitotoxicity is presumably pivotal in HD pathogenesis, these results indicate a therapeutic potential of Cr in HD. Thus, longterm clinical trials are warranted.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, Friedlich A, Browne SE, Schilling G, Borchelt DR, Hersch SM, Ross CA, Beal MF (2001) Creatine increases survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis 8:479–491

    Article  Google Scholar 

  2. Andreassen OA, Jenkins BG, Dedeoglu A, Ferrante KL, Bogdanov MB,Kaddurah-Daouk R, Beal MF (2001) Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem 77:383–390

    Google Scholar 

  3. Balsom PD, Soderlund K, Ekblom B (1994) Creatine in humans with special reference to creatine supplementation. Sports Med 18:268–280

    Google Scholar 

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

    Google Scholar 

  5. Beal MF, Ferrante RJ, Swartz KJ, Kowall NW (1991) Chronic quinolinic acid lesions in rats closely resemble Huntington’s disease. J Neurosci 11:1649–1659

    Google Scholar 

  6. Behrens PF, Franz P, Woodman B, Lindenberg KS, Landwehrmeyer GB (2002) Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain 125:1908–1922

    Article  CAS  PubMed  Google Scholar 

  7. Bellocchio EE, Reimer RJ, Fremeau RT Jr, Edwards RH (2000) Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289:957–960

    Google Scholar 

  8. 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 74:1968–1978

    Google Scholar 

  9. 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 41:646–653

    Google Scholar 

  10. Brustovetsky N, Brustovetsky T, Dubinsky JM (2001) On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem 76:425–434

    Google Scholar 

  11. Burke JR, Enghild JJ, Martin ME, Jou YS, Myers RM, Roses AD, Vance JM, Strittmatter WJ (1996) Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat Med 2:347–350

    Google Scholar 

  12. Butterworth J, Yates CM, Reynolds GP (1985) Distribution of phosphate-activated glutaminase, succinic dehydrogenase, pyruvate dehydrogenase and gamma-glutamyl transpeptidase in post-mortem brain from Huntington’s disease and agonal cases. J Neurol Sci 67:161–171

    Google Scholar 

  13. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695

    CAS  PubMed  Google Scholar 

  14. Coyle JT, Schwarcz R (1976) Lesion of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature 263:244–246

    CAS  PubMed  Google Scholar 

  15. Daikhin Y, Yudkoff M (2000) Compartmentation of brain glutamate metabolism in neurons and glia. J Nutr 130:1026S–1031S

    Google Scholar 

  16. Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J (1999) Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol 277:R698–R704

    Google Scholar 

  17. Dedeoglu A, Kubilus JK, Yang L, Ferrante KL,Hersch SM, Beal MF, Ferrante RJ (2003) Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J Neurochem 85:1359–1367

    Article  Google Scholar 

  18. Erecinska M, Silver IA (1990) Metabolism and role of glutamate in mammalian brain. Prog Neurobiol 35:245–296

    Google Scholar 

  19. Erecinska M, Zaleska MM, Nissim I, Nelson D, Dagani F, Yudkoff M (1988) Glucose and synaptosomal glutamate metabolism: studies with [15N]glutamate. J Neurochem 51:892–902

    Google Scholar 

  20. Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF (2000) Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 20:4389–4397

    Google Scholar 

  21. Gramsbergen JB, Veenma-Van der Duin L, Venema K, Korf J (1986) Cerebral cation shifts and amino acids in Huntington’s disease. Arch Neurol 43:1276–1281

    Google Scholar 

  22. Gu M, Gash MT, Mann VM, Javoy-Agid F, Cooper JM, Schapira AH (1996) Mitochondrial defect in Huntington’s disease caudate nucleus. Ann Neurol 39:385–389

    Google Scholar 

  23. Guyot MC, Hantraye P, Dolan R, Palfi S, Maziere M, Brouillet E (1997) Quantifiable bradykinesia, gait abnormalities and Huntington’s disease-like striatal lesions in rats chronically treated with 3-nitropropionic acid. Neuroscience 79:45–56

    Google Scholar 

  24. Harms L, Meierkord H, Timm G, Pfeiffer L, Ludolph AC (1997) Decreased Nacetyl-aspartate/choline ratio and increased lactate in the frontal lobe of patients with Huntington’s disease: a proton magnetic resonance spectroscopy study. J Neurol Neurosurg Psychiatry 62:27–30

    Google Scholar 

  25. Huntington Study Group (1996) Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 11:136–142

    Google Scholar 

  26. Jan GG, Veldink JH, van dT, I, Kalmijn S, Beijer C, de Visser M,Wokke JH, Franssen H, van den Berg LH (2003) A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Ann Neurol 53:437–445

    Google Scholar 

  27. 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 43:2689–2695

    Google Scholar 

  28. Jenkins BG, Rosas HD, Chen YC, Makabe T, Myers R, MacDonald M, Rosen BR, Beal MF, Koroshetz WJ (1998) 1H NMR spectroscopy studies of Huntington’s disease: correlations with CAG repeat numbers. Neurology 50:1357–1365

    CAS  PubMed  Google Scholar 

  29. Juhn MS, Tarnopolsky M (1998) Oral creatine supplementation and athletic performance: a critical review. Clin J Sport Med 8:286–297

    Google Scholar 

  30. Kanner BI, Schuldiner S (1987) Mechanism of transport and storage of neurotransmitters. CRC Crit Rev Biochem 22:1–38

    Google Scholar 

  31. Kay L, Nicolay K, Wieringa B, Saks V, Wallimann T (2000) Direct evidence for the control of mitochondrial respiration by mitochondrial creatine kinase in oxidative muscle cells in situ. J Biol Chem 275:6937–6944

    Google Scholar 

  32. Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, Mueller G, Wermer M, Kaddurah-Daouk R, Beal MF (1999) Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 5:347–350

    Google Scholar 

  33. Lawler JM, Barnes WS, Wu G, Song W, Demaree S (2002) Direct antioxidant properties of creatine. Biochem Biophys Res Commun 290:47–52

    Google Scholar 

  34. Li H, Li SH, Johnston H, Shelbourne PF, Li XJ (2000) Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 25:385–389

    Google Scholar 

  35. Lievens JC, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L, Bates GP (2001) Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 8:807–821

    Article  CAS  PubMed  Google Scholar 

  36. Matthews RT, Ferrante RJ, Klivenyi P, Yang L, Klein AM, Mueller G, Kaddurah-Daouk R, Beal MF (1999) Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol 157:142–149

    Google Scholar 

  37. Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF (1998) Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci 18:156–163

    Google Scholar 

  38. Mazzola JL, Sirover MA (2002) Alteration of nuclear glyceraldehyde-3-phosphate dehydrogenase structure in Huntington’s disease fibroblasts. Brain Res Mol Brain Res 100:95–101

    Google Scholar 

  39. 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 414:253–257

    Google Scholar 

  40. Perry TL, Hansen S (1990) What excitotoxin kills striatal neurons in Huntington’s disease? Clues from neurochemical studies. Neurology 40:20–24

    Google Scholar 

  41. Reynolds GP, Pearson SJ (1987) Decreased glutamic acid and increased 5-hydroxytryptamine in Huntington’s disease brain. Neurosci Lett 78:233–238

    Google Scholar 

  42. Rothman DL, Sibson NR, Hyder F, Shen J, Behar KL, Shulman RG (1999) In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philos Trans R Soc Lond B Biol Sci 354:1165–1177

    Google Scholar 

  43. Schiefer J, Landwehrmeyer GB, Luesse HG, Sprunken A, Puls C, Milkereit A, Milkereit E, Kosinski CM (2002) Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington’s disease. Mov Disord 17:748–757

    Article  Google Scholar 

  44. Shear DA, Haik KL, Dunbar GL (2000) Creatine reduces 3-nitropropionicacid-induced cognitive and motor abnormalities in rats. Neuroreport 11:1833–1837

    Google Scholar 

  45. Shoulson I (1981) Huntington disease: functional capacities in patients treated with neuroleptic and antidepressant drugs. Neurology 31:1333–1335

    Google Scholar 

  46. Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT (2003) Creatine therapy for Huntington’s disease: Clinical and MRS findings in a 1-year pilot study. Neurology 61:141–142

    Google Scholar 

  47. Tabrizi SJ, Cleeter MW, Xuereb J, Taanman JW, Cooper JM, Schapira AH (1999) Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann Neurol 45:25–32

    Article  CAS  PubMed  Google Scholar 

  48. Tarnopolsky MA, Beal MF (2001) Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol 49:561–574

    Google Scholar 

  49. Taylor-Robinson SD, Weeks RA, Bryant DJ, Sargentoni J, Marcus CD, Harding AE, Brooks DJ (1996) Proton magnetic resonance spectroscopy in Huntington’s disease: evidence in favour of the glutamate excitotoxic theory. Mov Disord 11:167–173

    Google Scholar 

  50. Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Van Leemputte M, Hespel P, Dom R (2003) Creatine supplementation in Huntington’s disease: A placebo-controlled pilot trial. Neurology 61:925–930

    Google Scholar 

  51. Vielhaber S, Kaufmann J, Kanowski M, Sailer M, Feistner H, Tempelmann C, Elger CE, Heinze HJ, Kunz WS (2001) Effect of creatine supplementation on metabolite levels in ALS motor cortices. Exp Neurol 172:377–382

    Google Scholar 

  52. Xu CJ, Klunk WE, Kanfer JN, Xiong Q, Miller G, Pettegrew JW (1996) Phosphocreatine-dependent glutamate uptake by synaptic vesicles.A comparison with atp-dependent glutamate uptake. J Biol Chem 271:13435–13440

    Google Scholar 

  53. Yudkoff M, Nissim I, Daikhin Y, Lin ZP, Nelson D, Pleasure D, Erecinska M (1993) Brain glutamate metabolism: neuronal-astroglial relationships. Dev Neurosci 15:343–350

    Google Scholar 

  54. Zeron MM, Chen N, Moshaver A, Lee AT, Wellington CL, Hayden MR, Raymond LA (2001) Mutant huntingtin enhances excitotoxic cell death. Mol Cell Neurosci 17:41–53

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Klinikum Grosshadern, University of Munich, Marchioninistr. 15, 81377, Munich, Germany

    Andreas Bender*, Julia Bender, Thomas Gasser &  Thomas Klopstock

  2. Max-Planck-Institute of Psychiatry, Munich, Germany

    Dorothee P. Auer*, Thomas Merl, Phillip Saemann & Alexander Yassouridis

  3. Department of Neurology, University of Muenster, Germany

    Ralf Reilmann

  4. Department of Neurology, Technical University, Munich, Germany

    Adolf Weindl

  5. Department of Neurology, Bezirkskrankenhaus, Taufkirchen, Germany

    Matthias Dose

Authors
  1. Andreas Bender*
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dorothee P. Auer*
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Merl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ralf Reilmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Phillip Saemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alexander Yassouridis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julia Bender
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Adolf Weindl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Matthias Dose
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas Gasser
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas Klopstock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Klopstock.

Additional information

* Drs Bender and Auer both contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bender*, A., Auer*, D.P., Merl, T. et al. Creatine supplementation lowers brain glutamate levels in Huntington’s disease. J Neurol 252, 36–41 (2005). https://doi.org/10.1007/s00415-005-0595-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-005-0595-4

Key words

Search

Navigation