Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency.

Details

Serval ID
serval:BIB_6D0B4E54C2D5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency.
Journal
European Journal of Neuroscience
Author(s)
Braissant O., Cagnon L., Monnet-Tschudi F., Speer O., Wallimann T., Honegger P., Henry H.
ISSN
1460-9568 (Electronic)
ISSN-L
0953-816X
Publication state
Published
Issued date
2008
Volume
27
Number
7
Pages
1673-1685
Language
english
Abstract
Hyperammonemic disorders in pediatric patients lead to poorly understood irreversible effects on the developing brain that may be life-threatening. We showed previously that some of these NH4+-induced irreversible effects might be due to impairment of axonal growth that can be protected under ammonium exposure by creatine co-treatment. The aim of the present work was thus to analyse how the genes of arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), allowing creatine synthesis, as well as of the creatine transporter SLC6A8, allowing creatine uptake into cells, are regulated in rat brain cells under NH4+ exposure. Reaggregated brain cell three-dimensional cultures exposed to NH4Cl were used as an experimental model of hyperammonemia in the developing central nervous system (CNS). We show here that NH4+ exposure differentially alters AGAT, GAMT and SLC6A8 regulation, in terms of both gene expression and protein activity, in a cell type-specific manner. In particular, we demonstrate that NH4+ exposure decreases both creatine and its synthesis intermediate, guanidinoacetate, in brain cells, probably through the inhibition of AGAT enzymatic activity. Our work also suggests that oligodendrocytes are major actors in the brain in terms of creatine synthesis, trafficking and uptake, which might be affected by hyperammonemia. Finally, we show that NH4+ exposure induces SLC6A8 in astrocytes. This suggests that hyperammonemia increases blood-brain barrier permeability for creatine. This is normally limited due to the absence of SLC6A8 from the astrocyte feet lining microcapillary endothelial cells, and thus creatine supplementation may protect the developing CNS of hyperammonemic patients.
Keywords
Animals, Biological Transport/drug effects, Biological Transport/physiology, Brain/cytology, Brain/embryology, Cell Culture Techniques/methods, Cells, Cultured, Creatine/biosynthesis, Creatine/deficiency, Female, Membrane Transport Proteins/biosynthesis, Membrane Transport Proteins/genetics, Pregnancy, Quaternary Ammonium Compounds/toxicity, Rats
Pubmed
Web of science
Create date
04/02/2008 10:56
Last modification date
20/08/2019 15:26
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