Abstract
Guanidino compounds (GCs), such as creatine, phosphocreatine, guanidinoacetic acid, creatinine, methylguanidine, guanidinosuccinic acid, γ-guanidinobutyric acid, β-guanidinopropionic acid, guanidinoethane sulfonic acid and α-guanidinoglutaric acid, are present in the mammalian brain. Although creatine and phosphocreatine play important roles in energy homeostasis in the brain, accumulation of GCs may induce epileptic discharges and convulsions. This review focuses on how physiologically important and/or neurotoxic GCs are distributed in the brain under physiological and pathological conditions. Transporters for GCs at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) have emerged as substantial contributors to GCs distribution in the brain. Creatine transporter (CRT/solute carrier (SLC) 6A8) expressed at the BBB regulates creatine concentration in the brain, and represents a major pathway for supply of creatine from the circulating blood to the brain. CRT may be a key factor facilitating blood-to-brain guanidinoacetate transport in patients deficient in S-adenosylmethionine:guanidinoacetate N-methyltransferase, the creatine biosynthetic enzyme, resulting in cerebral accumulation of guanidinoacetate. CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF. Interestingly, BBB efflux transport of GCs, including guanidinoacetate and creatinine, is negligible, though the BBB has a variety of efflux transport systems for synthetic precursors of GCs, such as amino acids and neurotransmitters. Instead, the BCSFB functions as a major cerebral clearance system for GCs. In conclusion, transport of GCs at the BBB and BCSFB appears to be the key determinant of the cerebral levels of GCs, and changes in the transport characteristics may cause the abnormal distribution of GCs in the brain seen in patients with certain neurological disorders.
Highlights
Guanidino compounds (GCs), such as creatine (CT), phosphocreatine (PCT), guanidinoacetic acid (GAA), creatinine (CTN), methylguanidine (MG), guanidinosuccinic acid (GSA), g-guanidinobutyric acid (GBA), b-guanidinopropionic acid (GPA), guanidinoethane sulfonic acid (GES) and a-guanidinoglutaric acid (GGA), are present in the mammalian brain at individual concentrations in the nanomolar to millimolar range [1,2,3]
We present an overview of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) transport of GCs and related amino acids and neurotransmitters
creatine transporter (CRT) expressed at the BBB regulates the CT concentration in the brain at millimolar levels as a major pathway for supplying CT from the circulating blood to the brain
Summary
Guanidino compounds (GCs), such as creatine (CT), phosphocreatine (PCT), guanidinoacetic acid (GAA), creatinine (CTN), methylguanidine (MG), guanidinosuccinic acid (GSA), g-guanidinobutyric acid (GBA), b-guanidinopropionic acid (GPA), guanidinoethane sulfonic acid (GES) and a-guanidinoglutaric acid (GGA), are present in the mammalian brain at individual concentrations in the nanomolar to millimolar range [1,2,3]. The influx and efflux transport of GAA across the brain barriers are well balanced, at least under normal conditions [56], the degree of CRT saturation by endogenous CT in the circulating blood of the patients would be smaller, contributing to the significant increase of the blood-to-brain GAA transport This mechanism could explain the fact that treatment with CT supplementation resulted in partial normalization of cerebral levels of CT and GAA in patients [77]. The key factors facilitating GAA accumulation in the brains of patients with GAMT deficiency could be (i) the lack of efflux transport across the BBB, (ii) the increase of CRT-mediated blood-to-brain GAA transport at the BBB, and (iii) the Na+-dependent concentrative GAA transport by brain parenchymal cells. It will be clinically beneficial, as far as the cerebral accumulation of CTN is concerned, to block the BBB influx transport of CTN in patients with renal insufficiency
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