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; Terasaki, Tetsuya

doi:10.1097/01.wcb.0000033966.83623.7d

Cited by 139 publications

(110 citation statements)

References 27 publications

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“…In brain parenchyma, SLC6A8 is expressed by neurons and oligodendrocytes. However, while SLC6A8 is also expressed by MCEC at BBB, allowing CNS to import Cr from periphery, it is absent from astrocytes, particularly from their feet lining (Braissant et al 2001b;Ohtsuki et al 2002;Tachikawa et al 2004). This raised the concept that BBB has a limited permeability for peripheral Cr, and that the brain supplies a part of its Cr by endogenous synthesis (Braissant et al 2001b;Braissant et al 2011;Braissant and Henry 2008).…”

Section: Introductionmentioning

confidence: 97%

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Braissant

2012

J of Inher Metab Disea

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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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Section: Introductionmentioning

confidence: 97%

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Braissant

2012

J of Inher Metab Disea

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“…10,47,73,74) Nevertheless, the retina is especially differentiated for vision. This prompts the hypothesis that the inner BRB expresses different molecules than the BBB.…”

Section: Cell-to-cell Interactions and Differencesmentioning

confidence: 99%

Advances in the Cell Biology of Transport via the Inner Blood-Retinal Barrier: Establishment of Cell Lines and Transport Functions

Hosoya

Tomi

2005

Biological & Pharmaceutical Bulletin

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The retina, which is a highly differentiated tissue playing a key role in vision, has a blood-retinal barrier (BRB) to maintain a constant milieu and shield the neural retina from the circulating blood. The BRB forms complex tight junctions of retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (RPE; outer BRB).1,2) The inner two thirds of the human retina is nourished by retinal capillaries and the remainder is covered by choriocapillaris via the outer BRB.3) In addition to the BRB, the blood-aqueous barrier, which is formed by epithelial barriers of the cilliary body and by the iridial endothelial cells, is present in the anterior segment of the eye to maintain aqueous humor conditions. Both barriers form the so-called blood-ocular barrier (Fig. 1). 4)The concept of the BRB was first proposed by Schnaudigel in 1913 5) following the classical work of Ehrlich and Goldman who discovered the blood-brain barrier (BBB). 6,7)The inner BRB is structurally similar to the BBB and the retinal capillary endothelial cells are covered with pericytes and glial cells.2) Glial Müller cells predominantly support retinal endothelial cells, although glial astrocytes play a major role in supporting endothelial functions at the BBB and also, partly, at the inner BRB (Fig. 1). 8) Many groups have carried out detailed investigations of the transport functions at the BBB and Cornford postulated that the BBB acts as a dynamic regulatory interface. [9][10][11] Since then, many influx and efflux transporters have been identified and characterized at the BBB.12,13) It was believed that the transport functions at the inner BRB are the same as those at the BBB. Nevertheless, information about transport functions and transporters at the inner BRB is very limited. Until 1999, only three transporters, i.e. facilitative D-glucose transporter (GLUT)1, 14) monocarboxylate transporter (MCT)1, 15) and Pglycoprotein (P-gp), 16) had been identified immunohistochemically at the inner BRB. This lack of interest in this aspect of vision research is somewhat surprising, given that the inner BRB plays important roles in supplying nutrients to the neural retina and is responsible for the efflux of neurotransmitter metabolites from the retina to maintain neural functions. In vivo transport studies using the Retinal Uptake Index (RUI) method have been performed to investigate solute transport into the retina. [17][18][19] Although these have the advantage of being able to estimate the ability to transport solutes from the circulating blood to the retina under physiological conditions, it is difficult to distinguish between substrates that are taken up by the inner BRB and the outer BRB. In order to successfully identify the transporters and transport mechanisms at the inner BRB, we need to develop a good in vitro system, which accurately reflects in vivo transport functions. The techniques of isolation 20) and primary culture of bovine retinal capillaries 21) have been applied to studies of the inner BRB. However, it is no...

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“…12,13) The CRT cDNA fragment was amplified by RT-PCR from TM-BBB cells possibly due to the similarity in the nucleotide sequence between CRT and neurotransmitter transporters. 5) Furthermore, TM-BBB cells exhibited creatine uptake which is significantly inhibited by CRT inhibitors, such as b-guanidinopropionate and guanidinoacetate. Our immunohistochemical analysis revealed that there is intense expression of CRT in mouse BCECs (Fig.…”

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confidence: 99%

“…1). 5) Creatine plays a key role in this energy-storing process. The phosphate-bound energy of ATP is transferred to creatine and stored as phosphocreatine to regenerate ATP from ADP ( Fig.…”

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New Aspects of the Blood-Brain Barrier Transporters; Its Physiological Roles in the Central Nervous System

Ohtsuki

2004

Biological & Pharmaceutical Bulletin

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The blood-brain barrier (BBB) is formed by complex tight-junctions of the brain capillary endothelial cells (BCECs) and expresses various transport systems. These characteristics of the BBB make it possible to control selective transport across the BBB and to limit the non-selective brain distribution of drugs. Since understanding the mechanism of BBB transport is important for improving the BBB permeability of CNS-acting drugs, the molecular mechanism of the BBB transport has been analyzed mainly with respect to drug transport. At first, blood-to-brain influx transport was regarded as a system for transporting drugs and nutrients to the brain. This resulted in the discovery of transport systems for glucose and amino acids. 1) Subsequently, the importance of efflux transport at the BBB has been recognized after finding that P-glycoprotein (P-gp) is involved in the efflux transport of xenobiotics.2,3) Due to these studies, the BBB is now accepted as a complex transport system which is an important determinant of drug distribution to the brain.In addition to the drug permeability aspects, the physiological function of the BBB is important in the central nervous system (CNS). To date, the BBB transport system has been shown to supply nutrients, such as glucose, lactate, amino acids and nucleotides, to the brain. However, it is conceivable that the BBB have many other physiological functions involving regulation of the CNS milieu. For instance, the brain is a highly energy-consuming tissue and produces various metabolites. In particular, metabolism is essential for the inactivation of neurotransmitters after their secretion from the pre-synapses, as well as re-uptake. The metabolites produced in the brain must be removed in order to maintaine proper neural function. Therefore, the BBB can be thought to act as a clearance system to remove various metabolites from the CNS.Clarifying the physiological role of the BBB is also necessary to understand the role of the BBB in CNS disorders. This is because an alteration in BBB functions may result in a change in CNS conditions leading to CNS disorders. Furthermore, analyzing the BBB functions from a different point of view could result in the discovery of a new transport system that is involved in drug permeability. In this review, I shall introduce the recent advances in research into the molecular basis of BBB transport, focusing on its physiological functions.The BBB Supplies Creation to the Brain The brain consumes 18% of total body energy, while its weight is only 2% of the total body weight. The brain cannot store glucose for energy synthesis, and the BBB plays a crucial role in glucose supply to the brain by expressing glucose transporter 1 (GLUT1) (Fig. 1). 4) Besides energy synthesis, an energystoring system is necessary for maintain energy homeostasis in high energy-consuming tissues. We have shown that the BBB also plays an important role in the energy storing process (Fig. 1). 5)Creatine plays a key role in this energy-storing process. The phosphate-bound energy...

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The Blood–Brain Barrier Creatine Transporter is a Major Pathway for Supplying Creatine to the Brain

Cited by 139 publications

References 27 publications

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Advances in the Cell Biology of Transport via the Inner Blood-Retinal Barrier: Establishment of Cell Lines and Transport Functions

New Aspects of the Blood-Brain Barrier Transporters; Its Physiological Roles in the Central Nervous System

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