Ammonia toxicity to the brain and creatine.
Symptoms of hyperammonemia are age-dependent and some are reversible. Multiple mechanisms are involved. Hyperammonemia increases the uptake of tryptophan into the brain by activation of the L-system carrier while brain glutamine plays a still undefined role. The uptake of tryptophan by the brain is enhanced when the plasma levels of branched-chain amino acids competing with the other large neutral amino acids are low. Hyperammonemia increases the utilization of branched-chain amino acids in muscle when ketoglutarate is low, and this is further enhanced by glutamine depletion (as a result of therapy with ammonia scavengers like phenylbutyrate). Anorexia, most likely a serotoninergic symptom, might further aggravate the deficiency of indispensable amino acids (e.g., branched-chain and arginine). The role of increased glutamine production in astrocytes and the excitotoxic and metabotropic effects of increased extracellular glutamate have been extensively investigated and found to differ between models of acute and chronic hyperammonemia. Using an in vitro model of cultured embryonic rat brain cell aggregates, we studied the role of creatine in ammonia toxicity. Cultures exposed to ammonia before maturation showed impaired cholinergic axonal growth accompanied by a decrease of creatine and phosphocreatine, a finding not observed in mature cultures. By using different antibodies, we have shown that the phosphorylated form of the intermediate neurofilament protein is affected. Adding creatine to the culture medium partially prevents impairment of axonal growth and the presence of glia in the culture is a precondition for this protective effect. Adequate arginine substitution is essential in the treatment of urea cycle defects as creatine is inefficiently transported into the brain.
Bachmann
Claude
C
Laboratoire Central de Chimie Clinique, Centre Hospitalier Universitaire Vaudois, University of Lausanne, LCC, CHUV, Bugnon 46, 1011 Lausanne, Switzerland. Claude.Bachmann@chuv.hospvd.ch
Braissant
Olivier
O
Villard
Anne-Marie
AM
Boulat
Olivier
O
Henry
Hugues
H
D000641:Ammonia / Q000097:blood / Q000633:toxicity*; D000818:Animals; D001923:Brain Chemistry; D003401:Creatine / Q000097:blood / Q000378:metabolism*; D016895:Culture Media, Serum-Free; D018698:Glutamic Acid / Q000378:metabolism; D022124:Hyperammonemia / Q000378:metabolism; D010949:Plasma / Q000378:metabolism; D051381:Rats; D014364:Tryptophan / Q000378:metabolism
D016895:Culture Media, Serum-Free; D018698:Glutamic Acid; D000641:Ammonia; D014364:Tryptophan; D003401:Creatine