Ammonium-induced impairment of axonal growth is prevented through glial creatine.
Hyperammonemia in neonates and infants affects brain development and causes mental retardation. We report that ammonium impaired cholinergic axonal growth and altered localization and phosphorylation of intermediate neurofilament protein in rat reaggregated brain cell primary cultures. This effect was restricted to the phase of early maturation but did not occur after synaptogenesis. Exposure to NH4Cl decreased intracellular creatine, phosphocreatine, and ADP. We demonstrate that creatine cotreatment protected axons from ammonium toxic effects, although this did not restore high-energy phosphates. The protection by creatine was glial cell-dependent. Our findings suggest that the means to efficiently sustain CNS creatine concentration in hyperammonemic neonates and infants should be assessed to prevent impairment of axonogenesis and irreversible brain damage.
Braissant
Olivier
O
Clinical Chemistry Laboratory, University Hospital, CH-1011 Lausanne, Switzerland. Olivier.Braissant@chuv.hospvd.ch
Henry
Hugues
H
Villard
Anne-Marie
AM
Zurich
Marie-Gabrielle
MG
Loup
Marc
M
Eilers
Barbara
B
Parlascino
Gianni
G
Matter
Edouard
E
Boulat
Olivier
O
Honegger
Paul
P
Bachmann
Claude
C
D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000643:Ammonium Chloride / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis; D018920:Coculture Techniques; D003401:Creatine / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019922:GAP-43 Protein / Q000096:biosynthesis; D005947:Glucose / Q000493:pharmacokinetics; D007150:Immunohistochemistry; D007424:Intracellular Fluid / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D016900:Neurofilament Proteins / Q000096:biosynthesis; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics; D051381:Rats; D013687:Telencephalon / Q000166:cytology / Q000196:embryology
D019922:GAP-43 Protein; D016900:Neurofilament Proteins; D000644:Quaternary Ammonium Compounds; D000643:Ammonium Chloride; D010725:Phosphocreatine; C061195:neurofilament protein M; D019344:Lactic Acid; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002795:Choline O-Acetyltransferase; D005947:Glucose; D003401:Creatine