Creatine and Guanidinoacetate Transport at Blood-brain and Blood-cerebrospinal Fluid Barriers

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2012 Jan 19

PMID 22252611

Citations 40

Authors

Olivier Braissant

Affiliations

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Abstract

While it was thought that most of cerebral creatine is of peripheral origin, AGAT and GAMT are well expressed in CNS where brain cells synthesize creatine. While the creatine transporter SLC6A8 is expressed by microcapillary endothelial cells (MCEC) at blood-brain barrier (BBB), it is absent from their surrounding astrocytes. This raised the concept that BBB has a limited permeability for peripheral creatine, and that the brain supplies a part of its creatine by endogenous synthesis. This review brings together the latest data on creatine and guanidinoacetate transport through BBB and blood-CSF barrier (BCSFB) with the clinical evidence of AGAT-, GAMT- and SLC6A8-deficient patients, in order to delineate a clearer view on the roles of BBB and BCSFB in the transport of creatine and guanidinoacetate between periphery and CNS, and on brain synthesis and transport of creatine. It shows that in physiological conditions, creatine is taken up by CNS from periphery through SLC6A8 at BBB, but in limited amounts, and that CNS also needs its own creatine synthesis. No uptake of guanidinoacetate from periphery occurs at BBB except under GAMT deficiency, but a net exit of guanidinoacetate seems to occur from CSF to blood at BCSFB, predominantly through the taurine transporter TauT.

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References

Klein A, Ferrante R . The neuroprotective role of creatine. Subcell Biochem. 2008; 46:205-43. DOI: 10.1007/978-1-4020-6486-9_11. View

Ireland Z, Dickinson H, Snow R, Walker D . Maternal creatine: does it reach the fetus and improve survival after an acute hypoxic episode in the spiny mouse (Acomys cahirinus)?. Am J Obstet Gynecol. 2008; 198(4):431.e1-6. DOI: 10.1016/j.ajog.2007.10.790. View

Lunardi G, Parodi A, Perasso L, Pohvozcheva A, Scarrone S, Adriano E . The creatine transporter mediates the uptake of creatine by brain tissue, but not the uptake of two creatine-derived compounds. Neuroscience. 2006; 142(4):991-7. DOI: 10.1016/j.neuroscience.2006.06.058. View

Cagnon L, Braissant O . Hyperammonemia-induced toxicity for the developing central nervous system. Brain Res Rev. 2007; 56(1):183-97. DOI: 10.1016/j.brainresrev.2007.06.026. View

Bender A, Koch W, Elstner M, Schombacher Y, Bender J, Moeschl M . Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial. Neurology. 2006; 67(7):1262-4. DOI: 10.1212/01.wnl.0000238518.34389.12. View

Spector R . Nature and consequences of mammalian brain and CSF efflux transporters: four decades of progress. J Neurochem. 2009; 112(1):13-23. DOI: 10.1111/j.1471-4159.2009.06451.x. View

Hausmann O, Fouad K, Wallimann T, Schwab M . Protective effects of oral creatine supplementation on spinal cord injury in rats. Spinal Cord. 2002; 40(9):449-56. DOI: 10.1038/sj.sc.3101330. View

Sullivan P, Geiger J, Mattson M, Scheff S . Dietary supplement creatine protects against traumatic brain injury. Ann Neurol. 2000; 48(5):723-9. View

Braissant O, Cagnon L, Monnet-Tschudi F, Speer O, Wallimann T, Honegger P . Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency. Eur J Neurosci. 2008; 27(7):1673-85. DOI: 10.1111/j.1460-9568.2008.06126.x. View

10.

Stockler S, Schutz P, Salomons G . Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell Biochem. 2008; 46:149-66. DOI: 10.1007/978-1-4020-6486-9_8. View

11.

Sijens P, Verbruggen K, Oudkerk M, van Spronsen F, Soorani-Lunsing R . 1H MR spectroscopy of the brain in Cr transporter defect. Mol Genet Metab. 2005; 86(3):421-2. DOI: 10.1016/j.ymgme.2005.08.004. View

12.

Beard E, Braissant O . Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochem. 2010; 115(2):297-313. DOI: 10.1111/j.1471-4159.2010.06935.x. View

13.

Bothwell J, Styles P, Bhakoo K . Swelling-activated taurine and creatine effluxes from rat cortical astrocytes are pharmacologically distinct. J Membr Biol. 2002; 185(2):157-64. DOI: 10.1007/s00232-001-0121-2. View

14.

Cecil K, Salomons G, Ball Jr W, Wong B, Chuck G, Verhoeven N . Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect?. Ann Neurol. 2001; 49(3):401-4. DOI: 10.1002/ana.79. View

15.

Schulze A, Bachert P, Schlemmer H, Harting I, Polster T, Salomons G . Lack of creatine in muscle and brain in an adult with GAMT deficiency. Ann Neurol. 2003; 53(2):248-51. DOI: 10.1002/ana.10455. View

16.

Nakashima T, Tomi M, Tachikawa M, Watanabe M, Terasaki T, Hosoya K . Evidence for creatine biosynthesis in Müller glia. Glia. 2005; 52(1):47-52. DOI: 10.1002/glia.20222. View

17.

Perasso L, Adriano E, Ruggeri P, Burov S, Gandolfo C, Balestrino M . In vivo neuroprotection by a creatine-derived compound: phosphocreatine-Mg-complex acetate. Brain Res. 2009; 1285:158-63. DOI: 10.1016/j.brainres.2009.06.009. View

18.

Nakashima T, Tomi M, Katayama K, Tachikawa M, Watanabe M, Terasaki T . Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood-retinal barrier. J Neurochem. 2004; 89(6):1454-61. DOI: 10.1111/j.1471-4159.2004.02437.x. View

19.

Schulze A, Hess T, Wevers R, Mayatepek E, Bachert P, Marescau B . Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J Pediatr. 1997; 131(4):626-31. DOI: 10.1016/s0022-3476(97)70075-1. View

20.

Ohtsuki S, Tachikawa M, Takanaga H, Shimizu H, Watanabe M, Hosoya K . The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J Cereb Blood Flow Metab. 2002; 22(11):1327-35. DOI: 10.1097/01.WCB.0000033966.83623.7D. View