The Blood???Brain Barrier Creatine Transporter Is a Major Pathway for Supplying Creatine to the Brain

Ohtsuki, Sumio; Tachikawa, Masanori; Takanaga, Hitomi; Shimizu, Hidemi; Watanabe, Masahiko; Hosoya, Ken‐ichi; Terasaki, Toshio

doi:10.1097/00004647-200211000-00006

Cited by 82 publications

(90 citation statements)

References 25 publications

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“…Hence, D-glucose and Lphenylalanine might be preferentially transported from circulating blood into the peripheral nervous parenchyma via GLUT1 and system L in BNB. Recently, creatine has been determined as a major energy-storing source of neuron in the brain and CRT has been reported to play an important role in the uptake of creatine from blood (Ohtsuki et al, 2002). Although there is no direct evidence that peripheral nerves use creatine as an energy-storing source, our results suggest that peripheral nerves also use creatine incorporated via CRT.…”

Section: Discussionmentioning

confidence: 52%

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Endothelial Cells Constituting Blood-nerve Barrier Have Highly Specialized Characteristics as Barrier-forming Cells

Sano

Shimizu

Nakayama

et al. 2007

Cell Struct. Funct.

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ABSTRACT. In autoimmune disorders of the peripheral nervous system (PNS) such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, breakdown of the blood-nerve barrier (BNB) has been considered as a key step in the disease process. Hence, it is important to know the cellular property of peripheral nerve microvascular endothelial cells (PnMECs) constituting the bulk of BNB. Although many in vitro models of the blood-brain barrier (BBB) have been established, very few in vitro BNB models have been reported so far. We isolated PnMECs from transgenic rats harboring the temperature-sensitive SV40 large T-antigen gene (tsA58 rat) and investigated the properties of these "barrier-forming cells". Isolated PnMECs (TR-BNBs) showed high transendothelial electrical resistance and expressed tight junction components and various types of influx as well as efflux transporters that have been reported to function at BBB. Furthermore, we confirmed the in vivo expression of various BBB-forming endothelial cell markers in the endoneurium of a rat sciatic nerve. These results suggest that PnMECs constituting the bulk of BNB have a highly specialized characteristic resembling the endothelial cells forming BBB.

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Section: Discussionmentioning

confidence: 52%

“…Creatine plays a pivotal role in the storage of phosphatebound energy in the brain, and creatine transporter (CRT) supplies creatine to the brain via BBB. (Ohtsuki et al, 2002). CRT was also expressed in TR-BNBs (Fig.…”

Section: Expression Of Influx Transporters In Tr-bnbsmentioning

confidence: 89%

Endothelial Cells Constituting Blood-nerve Barrier Have Highly Specialized Characteristics as Barrier-forming Cells

Sano

Shimizu

Nakayama

et al. 2007

Cell Struct. Funct.

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“…In the CNS, the creatine/phosphocreatine/CK system plays an important role in neurotransmitter release, membrane potential maintenance, Ca 2+ homeostasis, and/or ion gradient restoration (1)(2)(3). SLC6A8, a member of the solute carrier 6 family, is expressed in many tissues, such as CNS, heart, and skeletal muscle (4), and is highly specific for creatine (5)(6)(7). Interestingly, the CNS is the main organ affected by creatine deficiency syndromes, including CRT deficiency.…”

Section: Introductionmentioning

confidence: 99%

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

Kurosawa¹,

deGrauw²,

Lindquist³

et al. 2012

J. Clin. Invest.

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“…In contrast, while SLC6A8 is expressed by microcapillary endothelial cells (MCEC) at blood-brain barrier (BBB), allowing CNS to import Cr from periphery, it is absent from astrocytes, at least in physiological conditions, and particularly from their feet lining MCEC ( Fig. 1; Braissant et al 2001b;Ohtsuki et al 2002;Tachikawa et al 2004). This made us suggest that BBB has a limited permeability for peripheral Cr and that CNS must supply an important part of its Cr needs by endogenous synthesis rather than on an exclusive supply from the blood (Braissant et al 2001b;.…”

Section: Introductionmentioning

confidence: 99%

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

et al. 2011

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Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT-and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not coexpressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT-to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

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The Blood???Brain Barrier Creatine Transporter Is a Major Pathway for Supplying Creatine to the Brain

Cited by 82 publications

References 25 publications

Endothelial Cells Constituting Blood-nerve Barrier Have Highly Specialized Characteristics as Barrier-forming Cells

Endothelial Cells Constituting Blood-nerve Barrier Have Highly Specialized Characteristics as Barrier-forming Cells

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

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