Expression and possible role of creatine transporter in the brain and at the blood‐cerebrospinal fluid barrier as a transporting protein of guanidinoacetate, an endogenous convulsant

Abstract

Little is known about the cerebral distribution and clearance of guanidinoacetate (GAA), the accumulation of which induces convulsions. The purpose of the present study was to identify creatine transporter (CRT)‐mediated GAA transport and to clarify its cerebral expression and role in GAA efflux transport at the blood‐cerebrospinal fluid barrier (BCSFB). CRT mediated GAA transport with a Km value of 269 μM/412 μM which was approximately 10‐fold greater than that of CRT for creatine. There was wide and distinct cerebral expression of CRT and localization of CRT on the brush‐border membrane of choroid plexus epithelial cells. The in vivo elimination clearance of GAA from the CSF was 13‐fold greater than that of d‐mannitol reflecting bulk flow of the CSF. This process was partially inhibited by creatine. The characteristics of GAA uptake by isolated choroid plexus and an immortalized rat choroid plexus epithelial cell line (TR‐CSFB cells) used as an in vitro model of BCSFB are partially consistent with those of CRT. These results suggest that CRT plays a role in the cerebral distribution of GAA and GAA uptake by the choroid plexus. However, in the presence of endogenous creatine in the CSF, CRT may make only a limited contribution to the GAA efflux transport at the BCSFB.

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

“…These observations may explain the absence of Cr in CNS of SLC6A8-deficient patient, despite normal expression of AGAT and GAMT in their brain , as well as the lack of effect of treatment of SLC6A8-deficient patients with arginine as a precursor of Cr (Fons et al 2008). Recent studies also demonstrated the potential role of SLC6A8 (and taurine transporter) for GAA transport across BBB and in brain parenchymal cells (Tachikawa et al 2008(Tachikawa et al , 2009). …”

“…As described above, GAA may appear as a key intermediate player for endogenous Cr synthesis in CNS, as it must most probably be transported from AGAT-to GAMT-expressing cells for Cr synthesis to occur (Braissant et al 2010), just as it does in periphery between AGAT in kidney and GAMT in liver (Edison et al 2007;da Silva et al 2009). It was recently demonstrated that both BBB endothelial cells (Tachikawa et al 2009) and CNS parenchymal cells (Tachikawa et al 2008;Braissant et al 2010) are able to take up GAA by SLC6A8. The Km value of SLC6A8 for GAA appears ten times lower than that for Cr (Tachikawa et al 2008).…”

“…In vivo, mouse and rat CNS can take up Cr from the blood against its concentration gradient (Ohtsuki et al 2002;Perasso et al 2003). SLC6A8 is expressed throughout the main regions of adult mammalian brain (Schloss et al 1994;Happe and Murrin 1995;Braissant et al 2001b;Tachikawa et al 2008;Mak et al 2009). In the first detailed analyses of Cr transporter expression in CNS, it was demonstrated that SLC6A8 is found in neurons and oligodendrocytes but, in contrast to AGAT and GAMT, cannot be detected in astrocytes ( Fig.…”

Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

“…Conversely, the decrease in total Cr levels observed in our group of athletes with concussive head injury may well be explained by the experimentally documented general depression of brain metabolism after mTBI and corresponding to the window of metabolic brain vulnerability. Since Cr homeostasis in the brain is regulated by exogenous Cr source as well as de novo intracellular synthesis, imbalance in cerebral Cr levels might be caused either by a decreased activity of the Cr transporter 40,42 or by an inhibition of the Cr synthesis. 40,[42][43][44] A further consideration about this intricate matter of the Cr levels following mTBI [26][27][28][29] is given by the preliminary evidence that dietary supplementation of Cr can facilitate recovery of function in TBI.…”

“…Since Cr homeostasis in the brain is regulated by exogenous Cr source as well as de novo intracellular synthesis, imbalance in cerebral Cr levels might be caused either by a decreased activity of the Cr transporter 40,42 or by an inhibition of the Cr synthesis. 40,[42][43][44] A further consideration about this intricate matter of the Cr levels following mTBI [26][27][28][29] is given by the preliminary evidence that dietary supplementation of Cr can facilitate recovery of function in TBI. [45][46][47] If cerebral Cr levels were induced to increase following mTBI, it is not clear why exogenously administered Cr would enhance recovery after TBI.…”