The blood-brain barrier transport and cerebral distribution of guanidinoacetate in rats: involvement of creatine and taurine transporters.
Although the cerebral accumulation of guanidinoacetate (GAA) contributes to neurological complications in S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT) deficiency, how GAA is abnormally distributed in the brain remains unknown. The purpose of this study was to investigate the transport of GAA across the blood-brain barrier (BBB) and in brain parenchymal cells in rats. [(14)C]GAA microinjected into the rat cerebrum was not eliminated from the brain, implying the negligible contribution of GAA efflux transport across the BBB. In contrast, in vivo analysis and an uptake study by TR-BBB cells, a rat in vitro BBB model, revealed that GAA was transported from the circulating blood across the BBB most likely via a creatine transporter (CRT). Although CRT at the BBB is almost saturated by endogenous creatine under physiological conditions, the creatine level in the blood significantly decreases in GAMT deficiency. This might lead to the increase of CRT-mediated blood-to-brain transport of GAA at the BBB. Furthermore, [(14)C]GAA was taken up by brain parenchymal cells in a concentrative manner most likely via taurine transporter and CRT. These characteristics of GAA transport across the BBB and in the brain parenchymal cells could be the key factors that facilitate GAA accumulation in the brains of patients with GAMT deficiency.
Tachikawa
Masanori
M
Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Kasai
Yasuyuki
Y
Yokoyama
Reiji
R
Fujinawa
Jun
J
Ganapathy
Vadivel
V
Terasaki
Tetsuya
T
Hosoya
Ken-ichi
K
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003401:Creatine / Q000493:pharmacokinetics; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008845:Microinjections; D008954:Models, Biological; D009865:Oocytes / Q000502:physiology; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000493:pharmacokinetics; D014982:Xenopus laevis; D000099247:Taurine Transporters
D002250:Carbon Radioisotopes; D003401:Creatine; D005998:Glycine; D050937:Guanidinoacetate N-Methyltransferase; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D013654:Taurine; D000099247:Taurine Transporters; C080679:creatine transporter; C494508:Gamt protein, rat; C004946:glycocyamine