Amino Acids

, Volume 48, Issue 8, pp 1913–1927 | Cite as

The effects of creatine supplementation on striatal neural progenitor cells depend on developmental stage

  • Robert H. Andres
  • Angelique D. Ducray
  • Lukas Andereggen
  • Tabea Hohl
  • Uwe Schlattner
  • Theo Wallimann
  • Hans R. WidmerEmail author
Original Article
Part of the following topical collections:
  1. Creatine


Transplantation of neural progenitor cells (NPCs) is a promising experimental therapy for Huntington’s disease (HD). The variables responsible for the success of this approach, including selection of the optimal developmental stage of the grafted cells, are however largely unknown. Supporting cellular energy metabolism by creatine (Cr) supplementation is a clinically translatable method for improving cell transplantation strategies. The present study aims at investigating differences between early (E14) and late (E18) developmental stages of rat striatal NPCs in vitro. NPCs were isolated from E14 and E18 embryos and cultured for 7 days with or without Cr [5 mM]. Chronic treatment significantly increased the percentage of GABA-immunoreactive neurons as compared to untreated controls, both in the E14 (170.4 ± 4.7 %) and the E18 groups (129.3 ± 9.3 %). This effect was greater in E14 cultures (p < 0.05). Similarly, short-term treatment for 24 h resulted in increased induction (p < 0.05) of the GABA-ergic phenotype in E14 (163.0 ± 10.4 %), compared to E18 cultures (133.3 ± 9.5 %). Total neuronal cell numbers and general viability were not affected by Cr (p > 0.05). Protective effects of Cr against a metabolic insult were equal in E14 and E18 NPCs (p > 0.05). Cr exposure promoted morphological differentiation of GABA-ergic neurons, including neurite length in both groups (p < 0.05), but the number of branching points was increased only in the E18 group (p < 0.05). Our results demonstrate that the role of Cr as a GABA-ergic differentiation factor depends on the developmental stage of striatal NPCs, while Cr-mediated neuroprotection is not significantly influenced. These findings have potential implications for optimizing future cell replacement strategies in HD.


Creatine Creatine kinase GABA Differentiation Neuroprotection Development 



Adenosine triphosphate


Brain-type cytosolic isoform of CK


Creatine kinase


Central nervous system




Creatine transporter






Day in vitro


Dulbecco’s modified Eagle medium


Fetal calf serum




Embryonic day 14


Embryonic day 18




Guanidinoacetate methyltransferase


Ganglionic eminence


Glial fibrillary acidic protein


Hank’s balanced salt solution


Huntington’s disease


Horse serum






3(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Neural stem cell


Neural progenitor cell






Reactive oxygen species


Reactive nitrogen species


Spinal cord


Sodium dodecyl sulfate


Ubiquitous mitochondrial isoform of CK



We would like to thank Susanne Wälchli, Sandra Krebs, Daniela Olac-Gaona and Tanja Guzman for excellent technical assistance. Professor Roger Harris is kindly acknowledged for careful reading of the manuscript. Highly purified creatine monohydrate (Creapure™) was a gift from AlzChem Trostberg, Germany. The study was supported by the Swiss National Science Foundation (Grants No. 31-064975.01, 31-050824, 31-102075/1, 3100A0-112529, 31003A-135565, PBBEB-117034 and PASMP3-123221/1), by the Department of Clinical Research at the University of Berne, by the Swiss Society for Research on Muscle Diseases and by the German Parents Organization for Muscle Patients, Benni & Co.

Compliance with ethical standards

Ethical statement

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals, as well as human embryonic tissues were approved and in accordance with the ethical standards of the institutions (Department of Neurosurgery, Inselspital, University of Berne, Swiss Federal Institute of Technology, Zurich, and Boston Children’s Hospital, Harvard Medical School) at which the studies were conducted.

Conflicts of interest

The authors declare no conflicts of interest.


  1. Adcock KH, Nedelcu J, Loenneker T, Martin E, Wallimann T, Wagner BP (2002) Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia. Dev Neurosci 24(5):382–388CrossRefPubMedGoogle Scholar
  2. Andres RH, Ducray AD, Huber AW, Perez-Bouza A, Krebs SH, Schlattner U, Seiler RW, Wallimann T, Widmer HR (2005a) Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue. J Neurochem 95(1):33–45CrossRefPubMedGoogle Scholar
  3. Andres RH, Ducray AD, Perez-Bouza A, Schlattner U, Huber AW, Krebs SH, Seiler RW, Wallimann T, Widmer HR (2005b) Creatine supplementation improves dopaminergic cell survival and protects against MPP+toxicity in an organotypic tissue culture system. Cell Transplant 14(8):537–550CrossRefPubMedGoogle Scholar
  4. Andres RH, Huber AW, Schlattner U, Perez-Bouza A, Krebs SH, Seiler RW, Wallimann T, Widmer HR (2005c) Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience 133(3):701–713CrossRefPubMedGoogle 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(4):329–343. doi: 10.1016/j.brainresbull.2008.02.035 CrossRefPubMedGoogle Scholar
  6. Andres RH, Pendharkar AV, Guzman R, Bliss TM, McMillan E, Svendsen CN, Raabe A, Wallimann T, Widmer HR, Steinberg GK (2010) Creatine improves the metabolic state of murine and human neural stem cells and improves expansion and neuronal induction. Regen Med 3(2):2Google Scholar
  7. Andres RH, Horie N, Slikker W, Keren-Gill H, Zhan K, Sun G, Manley NC, Pereira MP, Sheikh LA, McMillan EL, Schaar BT, Svendsen CN, Bliss TM, Steinberg GK (2011) Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain 134(Pt 6):1777–1789. doi: 10.1093/brain/awr094 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Aronin N, Chase K, Young C, Sapp E, Schwarz C, Matta N, Kornreich R, Landwehrmeyer B, Bird E, Beal MF et al (1995) CAG expansion affects the expression of mutant Huntingtin in the Huntington’s disease brain. Neuron 15(5):1193–1201CrossRefPubMedGoogle Scholar
  9. Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL (2008) Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci USA 105(43):16707–16712. doi: 10.1073/pnas.0808488105 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bachoud-Levi A, Bourdet C, Brugieres P, Nguyen JP, Grandmougin T, Haddad B, Jeny R, Bartolomeo P, Boisse MF, Barba GD, Degos JD, Ergis AM, Lefaucheur JP, Lisovoski F, Pailhous E, Remy P, Palfi S, Defer GL, Cesaro P, Hantraye P, Peschanski M (2000a) Safety and tolerability assessment of intrastriatal neural allografts in five patients with Huntington’s disease. Exp Neurol 161(1):194–202. doi: 10.1006/exnr.1999.7239 CrossRefPubMedGoogle Scholar
  11. Bachoud-Levi AC, Remy P, Nguyen JP, Brugieres P, Lefaucheur JP, Bourdet C, Baudic S, Gaura V, Maison P, Haddad B, Boisse MF, Grandmougin T, Jeny R, Bartolomeo P, Dalla Barba G, Degos JD, Lisovoski F, Ergis AM, Pailhous E, Cesaro P, Hantraye P, Peschanski M (2000b) Motor and cognitive improvements in patients with Huntington’s disease after neural transplantation. Lancet 356(9246):1975–1979CrossRefPubMedGoogle Scholar
  12. Bachoud-Levi AC, Gaura V, Brugieres P, Lefaucheur JP, Boisse MF, Maison P, Baudic S, Ribeiro MJ, Bourdet C, Remy P, Cesaro P, Hantraye P, Peschanski M (2006) Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study. Lancet Neurol 5(4):303–309. doi: 10.1016/S1474-4422(06)70381-7 CrossRefPubMedGoogle Scholar
  13. Bender A, Klopstock T (2016) Creatine for neuroprotection in neurodegenerative disease: end of story? Amino Acids. doi: 10.1007/s00726-015-2165-0
  14. Berger R, Middelanis J, Vaihinger HM, Mies G, Wilken B, Jensen A (2004) Creatine protects the immature brain from hypoxic-ischemic injury. J Soc Gynecol Investig 11(1):9–15CrossRefPubMedGoogle Scholar
  15. Bessman SP, Geiger PJ (1981) Transport of energy in muscle: the phosphorylcreatine shuttle. Science 211(4481):448–452CrossRefPubMedGoogle Scholar
  16. Bourdelas A, Li HY, Carron C, Shi DL (2009) Dynamic expression pattern of distinct genes in the presomitic and somitic mesoderm during Xenopus development. Int J Dev Biol 53(7):1075–1079. doi: 10.1387/ijdb.072474ab CrossRefPubMedGoogle Scholar
  17. Braissant O, Henry H, Loup M, Eilers B, Bachmann C (2001) Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Brain Res Mol Brain Res 86(1–2):193–201 S0169328X00002692 [pii] CrossRefPubMedGoogle Scholar
  18. Braissant O, Henry H, Villard AM, Zurich MG, Loup M, Eilers B, Parlascino G, Matter E, Boulat O, Honegger P, Bachmann C (2002) Ammonium-induced impairment of axonal growth is prevented through glial creatine. J Neurosci 22(22):9810–9820 22/22/9810 [pii] PubMedGoogle Scholar
  19. Braissant O, Henry H, Villard AM, Speer O, Wallimann T, Bachmann C (2005) Creatine synthesis and transport during rat embryogenesis: spatiotemporal expression of AGAT, GAMT and CT1. BMC Dev Biol 5(1):9CrossRefPubMedPubMedCentralGoogle Scholar
  20. Braissant O, Beard E, Torrent C, Henry H (2010) Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 37(2):423–433. doi: 10.1016/j.nbd.2009.10.022 CrossRefPubMedGoogle Scholar
  21. 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(5):1968–1978CrossRefPubMedGoogle Scholar
  22. Bürklen TS, Schlattner U, Homayouni R, Gough K, Rak M, Szeghalmi A, Wallimann T (2006) The creatine kinase/creatine connection to Alzheimer’s disease: CK-inactivation, APP-CK complexes and focal creatine deposits. J Biomed Biotechnol 2006(3):35936. doi: 10.1155/JBB/2006/35936 PubMedPubMedCentralGoogle Scholar
  23. Calabresi P, Gubellini P, Picconi B, Centonze D, Pisani A, Bonsi P, Greengard P, Hipskind RA, Borrelli E, Bernardi G (2001) Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine. J Neurosci 21(14):5110–5120PubMedGoogle Scholar
  24. Cheng B, Mattson MP (1994) NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res 640(1–2):56–67CrossRefPubMedGoogle Scholar
  25. Chung S, Dzeja PP, Faustino RS, Terzic A (2008) Developmental restructuring of the creatine kinase system integrates mitochondrial energetics with stem cell cardiogenesis. Ann N Y Acad Sci 1147:254–263. doi: 10.1196/annals.1427.004 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Cicchetti F, Soulet D, Freeman TB (2011) Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications. Brain 134(Pt 3):641–652. doi: 10.1093/brain/awq328 CrossRefPubMedGoogle Scholar
  27. Deckel AW, Robinson RG, Coyle JT, Sanberg PR (1983) Reversal of long-term locomotor abnormalities in the kainic acid model of Huntington’s disease by day 18 fetal striatal implants. Eur J Pharmacol 93(3–4):287–288CrossRefPubMedGoogle Scholar
  28. 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(6):1359–1367CrossRefPubMedPubMedCentralGoogle Scholar
  29. Dolder M, Walzel B, Speer O, Schlattner U, Wallimann T (2003) Inhibition of the mitochondrial permeability transition by creatine kinase substrates. Requirement for microcompartmentation. J Biol Chem 278(20):17760–17766CrossRefPubMedGoogle Scholar
  30. Ducray AD, Qualls R, Schlattner U, Andres RH, Dreher E, Seiler RW, Wallimann T, Widmer HR (2007) Creatine promotes the GABAergic phenotype in human fetal spinal cord cultures. Brain Res 1137(1):50–57. doi: 10.1016/j.brainres.2006.12.038 CrossRefPubMedGoogle Scholar
  31. Dunnett SB, Bjorklund A (1992) Staging and dissection of rat embryos. In: Dunnett SB, Bjorklund A (eds) Neural transplantation: a practical approach. Oxford University, Oxford, pp 1–19Google Scholar
  32. Dunnett SB, Rosser AE (2007) Stem cell transplantation for Huntington’s disease. Exp Neurol 203(2):279–292. doi: 10.1016/j.expneurol.2006.11.007 CrossRefPubMedGoogle Scholar
  33. Dunnett SB, Isacson O, Sirinathsinghji DJ, Clarke DJ, Bjorklund A (1988) Striatal grafts in rats with unilateral neostriatal lesions–III. Recovery from dopamine-dependent motor asymmetry and deficits in skilled paw reaching. Neuroscience 24(3):813–820CrossRefPubMedGoogle Scholar
  34. Dupuis L, Oudart H, Rene F, Gonzalez de Aguilar JL, Loeffler JP (2004) Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci USA 101(30):11159–11164. doi: 10.1073/pnas.0402026101 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Eder M, Schlattner U, Becker A, Wallimann T, Kabsch W, Fritz-Wolf K (1999) Crystal structure of brain-type creatine kinase at 1.41 A resolution. Protein Sci 8(11):2258–2269CrossRefPubMedPubMedCentralGoogle Scholar
  36. Eder M, Fritz-Wolf K, Kabsch W, Wallimann T, Schlattner U (2000) Crystal structure of human ubiquitous mitochondrial creatine kinase. Proteins 39(3):216–225CrossRefPubMedGoogle Scholar
  37. 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(12):4389–4397PubMedGoogle Scholar
  38. Freeman TB, Cicchetti F, Hauser RA, Deacon TW, Li XJ, Hersch SM, Nauert GM, Sanberg PR, Kordower JH, Saporta S, Isacson O (2000) Transplanted fetal striatum in Huntington’s disease: phenotypic development and lack of pathology. Proc Natl Acad Sci USA 97(25):13877–13882. doi: 10.1073/pnas.97.25.13877 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Gallina P, Paganini M, Lombardini L, Mascalchi M, Porfirio B, Gadda D, Marini M, Pinzani P, Salvianti F, Crescioli C, Bucciantini S, Mechi C, Sarchielli E, Romoli AM, Bertini E, Urbani S, Bartolozzi B, De Cristofaro MT, Piacentini S, Saccardi R, Pupi A, Vannelli GB, Di Lorenzo N (2010) Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington’s disease patients after transplantation. Exp Neurol 222(1):30–41. doi: 10.1016/j.expneurol.2009.12.005 CrossRefPubMedGoogle Scholar
  40. Gaura V, Bachoud-Levi AC, Ribeiro MJ, Nguyen JP, Frouin V, Baudic S, Brugieres P, Mangin JF, Boisse MF, Palfi S, Cesaro P, Samson Y, Hantraye P, Peschanski M, Remy P (2004) Striatal neural grafting improves cortical metabolism in Huntington’s disease patients. Brain 127(Pt 1):65–72. doi: 10.1093/brain/awh003 CrossRefPubMedGoogle Scholar
  41. 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(3):385–389. doi: 10.1002/ana.410390317 CrossRefPubMedGoogle Scholar
  42. Hanna-El-Daher L, Braissant O (2016) Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models? Amino Acids. doi: 10.1007/s00726-016-2189-0
  43. Hauser RA, Furtado S, Cimino CR, Delgado H, Eichler S, Schwartz S, Scott D, Nauert GM, Soety E, Sossi V, Holt DA, Sanberg PR, Stoessl AJ, Freeman TB (2002) Bilateral human fetal striatal transplantation in Huntington’s disease. Neurology 58(5):687–695CrossRefPubMedGoogle Scholar
  44. Hefter H, Homberg V, Lange HW, Freund HJ (1987) Impairment of rapid movement in Huntington’s disease. Brain 110(Pt 3):585–612CrossRefPubMedGoogle Scholar
  45. Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD (2006) Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG. Neurology 66(2):250–252. doi: 10.1212/01.wnl.0000194318.74946.b6 CrossRefPubMedGoogle Scholar
  46. Holtzman D, Tsuji M, Wallimann T, Hemmer W (1993) Functional maturation of creatine kinase in rat brain. Dev Neurosci 15(3–5):261–270PubMedGoogle Scholar
  47. Isacson O, Dunnett SB, Bjorklund A (1986) Graft-induced behavioral recovery in an animal model of Huntington disease. Proc Natl Acad Sci USA 83(8):2728–2732CrossRefPubMedPubMedCentralGoogle Scholar
  48. Keene CD, Sonnen JA, Swanson PD, Kopyov O, Leverenz JB, Bird TD, Montine TJ (2007) Neural transplantation in Huntington disease: long-term grafts in two patients. Neurology 68(24):2093–2098. doi: 10.1212/01.wnl.0000264504.14301.f5 CrossRefPubMedGoogle Scholar
  49. 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(3):347–350CrossRefPubMedGoogle Scholar
  50. Klivenyi P, Kiaei M, Gardian G, Calingasan NY, Beal MF (2004) Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 88(3):576–582CrossRefPubMedGoogle Scholar
  51. Kordower JH, Chen EY, Winkler C, Fricker R, Charles V, Messing A, Mufson EJ, Wong SC, Rosenstein JM, Bjorklund A, Emerich DF, Hammang J, Carpenter MK (1997) Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington’s disease. J Comp Neurol 387(1):96–113CrossRefPubMedGoogle Scholar
  52. Kutorasinska J, Setkowicz Z, Janeczko K, Sandt C, Dumas P, Chwiej J (2013) Differences in the hippocampal frequency of creatine inclusions between the acute and latent phases of pilocarpine model defined using synchrotron radiation-based FTIR microspectroscopy. Anal Bioanal Chem 405(23):7337–7345. doi: 10.1007/s00216-013-7191-8 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Kuzyk A, Kastyak M, Agrawal V, Gallant M, Sivakumar G, Rak M, Del Bigio MR, Westaway D, Julian R, Gough KM (2010) Association among amyloid plaque, lipid, and creatine in hippocampus of TgCRND8 mouse model for Alzheimer disease. J Biol Chem 285(41):31202–31207. doi: 10.1074/jbc.M110.142174 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Lensman M, Korzhevskii DE, Mourovets VO, Kostkin VB, Izvarina N, Perasso L, Gandolfo C, Otellin VA, Polenov SA, Balestrino M (2006) Intracerebroventricular administration of creatine protects against damage by global cerebral ischemia in rat. Brain Res 1114(1):187–194. doi: 10.1016/j.brainres.2006.06.103 CrossRefPubMedGoogle Scholar
  55. Li X, Bürklen T, Yuan X, Schlattner U, Desiderio DM, Wallimann T, Homayouni R (2006) Stabilization of ubiquitous mitochondrial creatine kinase preprotein by APP family proteins. Mol Cell Neurosci 31(2):263–272CrossRefPubMedGoogle Scholar
  56. Lin YS, Chen CM, Soong BW, Wu YR, Chen HM, Yeh WY, Wu DR, Lin YJ, Poon PW, Cheng ML, Wang CH, Chern Y (2011) Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease. J Clin Invest 121(4):1519–1523. doi: 10.1172/JCI43220 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Lin YS, Cheng TH, Chang CP, Chen HM, Chern Y (2013) Enhancement of brain-type creatine kinase activity ameliorates neuronal deficits in Huntington’s disease. Biochim Biophys Acta 1832(6):742–753. doi: 10.1016/j.bbadis.2013.02.006 CrossRefPubMedGoogle Scholar
  58. 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(1):156–163PubMedGoogle Scholar
  59. McBride JL, Behrstock SP, Chen EY, Jakel RJ, Siegel I, Svendsen CN, Kordower JH (2004) Human neural stem cell transplants improve motor function in a rat model of Huntington’s disease. J Comp Neurol 475(2):211–219. doi: 10.1002/cne.20176 CrossRefPubMedGoogle Scholar
  60. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63CrossRefPubMedGoogle Scholar
  61. 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(2):253–257CrossRefPubMedGoogle Scholar
  62. Ohtsuki S, Tachikawa M, Takanaga H, Shimizu H, Watanabe M, Hosoya K, Terasaki T (2002) The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J Cereb Blood Flow Metab 22(11):1327–1335. doi: 10.1097/00004647-200211000-00006 CrossRefPubMedGoogle Scholar
  63. Prass K, Royl G, Lindauer U, Freyer D, Megow D, Dirnagl U, Stockler-Ipsiroglu G, Wallimann T, Priller J (2006) Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. J Cereb Blood Flow Metab 27(3):452–459. doi: 10.1038/sj.jcbfm.9600351 CrossRefPubMedGoogle Scholar
  64. Raha S, Robinson BH (2000) Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25(10):502–508CrossRefPubMedGoogle Scholar
  65. Reuter I, Tai YF, Pavese N, Chaudhuri KR, Mason S, Polkey CE, Clough C, Brooks DJ, Barker RA, Piccini P (2008) Long-term clinical and positron emission tomography outcome of fetal striatal transplantation in Huntington’s disease. J Neurol Neurosurg Psychiatry 79(8):948–951. doi: 10.1136/jnnp.2007.142380 CrossRefPubMedGoogle Scholar
  66. Roberts TJ, Price J, Williams SC, Modo M (2006) Preservation of striatal tissue and behavioral function after neural stem cell transplantation in a rat model of Huntington’s disease. Neuroscience 139(4):1187–1199. doi: 10.1016/j.neuroscience.2006.01.025 CrossRefPubMedGoogle Scholar
  67. Rosas HD, Doros G, Gevorkian S, Malarick K, Reuter M, Coutu JP, Triggs TD, Wilkens PJ, Matson W, Salat DH, Hersch SM (2014) PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology 82(10):850–857. doi: 10.1212/WNL.0000000000000187 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Rubinstein LV, Shoemaker RH, Paull KD, Simon RM, Tosini S, Skehan P, Scudiero DA, Monks A, Boyd MR (1990) Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines. J Natl Cancer Inst 82(13):1113–1118CrossRefPubMedGoogle Scholar
  69. Sanberg PR, Coyle JT (1984) Scientific approaches to Huntington’s disease. CRC Crit Rev Clin Neurobiol 1(1):1–44PubMedGoogle Scholar
  70. Schlattner U, Mockli N, Speer O, Werner S, Wallimann T (2002a) Creatine kinase and creatine transporter in normal, wounded, and diseased skin. J Invest Dermatol 118(3):416–423CrossRefPubMedGoogle Scholar
  71. Schlattner U, Reinhart C, Hornemann T, Tokarska-Schlattner M, Wallimann T (2002b) Isoenzyme-directed selection and characterization of anti-creatine kinase single chain Fv antibodies from a human phage display library. Biochim Biophys Acta 1579(2–3):124–132CrossRefPubMedGoogle Scholar
  72. Schlattner U, Tokarska-Schlattner M, Wallimann T (2006) Mitochondrial creatine kinase in human health and disease. Biochim Biophys Acta 1762(2):164–180CrossRefPubMedGoogle Scholar
  73. Schulze A (2003) Creatine deficiency syndromes. Mol Cell Biochem 244(1–2):143–150CrossRefPubMedGoogle Scholar
  74. Shao A, Hathcock JN (2006) Risk assessment for creatine monohydrate. Regul Toxicol Pharmacol 45(3):242–251. doi: 10.1016/j.yrtph.2006.05.005 CrossRefPubMedGoogle Scholar
  75. Shear DA, Haik KL, Dunbar GL (2000) Creatine reduces 3-nitropropionic-acid-induced cognitive and motor abnormalities in rats. Neuroreport 11(9):1833–1837CrossRefPubMedGoogle Scholar
  76. Sistermans EA, de Kok YJ, Peters W, Ginsel LA, Jap PH, Wieringa B (1995) Tissue- and cell-specific distribution of creatine kinase B: a new and highly specific monoclonal antibody for use in immunohistochemistry. Cell Tissue Res 280(2):435–446CrossRefPubMedGoogle Scholar
  77. Slosman DO, Ludwig C, Zerarka S, Pellerin L, Chicherio C, de Ribaupierre A, Annoni JM, Bouras C, Herrmann F, Michel JP, Giacobini E, Magistretti PJ (2001) Brain energy metabolism in Alzheimer’s disease: 99mTc-HMPAO SPECT imaging during verbal fluency and role of astrocytes in the cellular mechanism of 99mTc-HMPAO retention. Brain Res Brain Res Rev 36(2–3):230–240CrossRefPubMedGoogle Scholar
  78. Tachikawa M, Fukaya M, Terasaki T, Ohtsuki S, Watanabe M (2004) Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis. Eur J Neurosci 20(1):144–160CrossRefPubMedGoogle Scholar
  79. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72(6):971–983CrossRefGoogle Scholar
  80. 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(7):925–930CrossRefPubMedGoogle Scholar
  81. Wallimann T, Schnyder T, Schlegel J, Wyss M, Wegmann G, Rossi AM, Hemmer W, Eppenberger HM, Quest AF (1989) Subcellular compartmentation of creatine kinase isoenzymes, regulation of CK and octameric structure of mitochondrial CK: important aspects of the phosphoryl-creatine circuit. Prog Clin Biol Res 315:159–176PubMedGoogle Scholar
  82. Wallimann T, Dolder M, Schlattner U, Eder M, Hornemann T, Kraft T, Stolz M (1998a) Creatine kinase: an enzyme with a central role in cellular energy metabolism. MAGMA 6(2–3):116–119CrossRefPubMedGoogle Scholar
  83. Wallimann T, Dolder M, Schlattner U, Eder M, Hornemann T, O’Gorman E, Ruck A, Brdiczka D (1998b) Some new aspects of creatine kinase (CK): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. BioFactors 8(3–4):229–234CrossRefPubMedGoogle Scholar
  84. Wallimann T, Tokarska-Schlattner M, Neumann D, Epand RM, Epand RF, Hornemann T, Saks V, Schlattner U (2007) The Phosphocreatine Circuit: Molceular and Cellular Physiology of Creatine Kinases, Sensitivity to Free Radicals, and Enhancement by Creatine Supplementation. In: Saks V (ed) Molecular System Bioenergetics: Energy for Life. WILEY-VCH Verlag GmbH & Co., Weinheim, pp 195–264CrossRefGoogle Scholar
  85. Watts C, Dunnett SB, Rosser AE (1997) Effect of embryonic donor age and dissection on the DARPP-32 content of cell suspensions used for intrastriatal transplantation. Exp Neurol 148(1):271–280. doi: 10.1006/exnr.1997.6646 CrossRefPubMedGoogle Scholar
  86. Watts C, Brasted PJ, Dunnett SB (2000) Embryonic donor age and dissection influences striatal graft development and functional integration in a rodent model of Huntington’s disease. Exp Neurol 163(1):85–97. doi: 10.1006/exnr.1999.7341 CrossRefPubMedGoogle Scholar
  87. Woznicki DT, Walker JB (1979) Formation of a supplemental long time-constant reservoir of high energy phosphate by brain in vivo and in vitro and its reversible depletion by potassium depolarization. J Neurochem 33(1):75–80CrossRefPubMedGoogle Scholar
  88. Zhang W, Narayanan M, Friedlander RM (2003) Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol 53(2):267–270. doi: 10.1002/ana.10476 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Robert H. Andres
    • 1
  • Angelique D. Ducray
    • 1
  • Lukas Andereggen
    • 1
    • 2
  • Tabea Hohl
    • 1
  • Uwe Schlattner
    • 3
    • 4
  • Theo Wallimann
    • 5
  • Hans R. Widmer
    • 1
    Email author
  1. 1.Department of NeurosurgeryUniversity of Berne, InselspitalBerneSwitzerland
  2. 2.Department of Neurosurgery and F.M. Kirby Neurobiology Center, Boston Children’s HospitalHarvard Medical SchoolBostonUSA
  3. 3.Laboratory of Fundamental and Applied BioenergeticsUniversité Grenoble Alpes, BP53Grenoble CedexFrance
  4. 4.Inserm, U1055, BP53Grenoble CedexFrance
  5. 5.Professor emeritus, formerly at Institute of Cell BiologySwiss Federal Institute of Technology (ETH)ZurichSwitzerland

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