Acute ammonia intoxication induces an NMDA receptor-mediated increase in poly(ADP-ribose) polymerase level and NAD metabolism in nuclei of rat brain cells.
Acute ammonia toxicity is mediated by excessive activation of NMDA receptors. Activation of NMDA receptors leads to activation of poly(ADP-ribose) polymerase (PARP) which mediates NMDA excitotoxicity. PARP is activated following DNA damage and may lead to cell death via NAD+ and ATP depletion. The aim of the present work was to assess whether acute ammonia intoxication in vivo leads to increased PARP in brain cells nuclei and to altered NAD+ and superoxide metabolism and the contribution of NMDA receptors to these alterations. Acute ammonia intoxication increases PARP content twofold in brain cells nuclei.NAD+ content decreased by 55% in rats injected with ammonia. This was not due to decreased NAD+ synthetase nor increased NAD+ hydrolase activities and would be due to increased NAD+ consumption by PARP. Superoxide radical formation increased by 75% in nuclei of brains of rats injected with ammonia, that also induced protein nitrotyrosylation and DNA damage. Blocking NMDA receptors prevented ammonia-induced PARP, superoxide and nitrotyrosylation increase, DNA damage and NAD+ decrease. These results show that acute ammonia intoxication in vivo leads to activation of NMDA receptors, leading to increased superoxide formation and PARP content and depletion of NAD+ in brain cells nuclei that contribute to ammonia toxicity.
Kosenko
Elena
E
Institute of Theoretical and Experimental Biophysics RAS, Pushchino, Russia.
Montoliu
Carmina
C
Giordano
Gennaro
G
Kaminsky
Yury
Y
Venediktova
Natalia
N
Buryanov
Yaroslav
Y
Felipo
Vicente
V
D019732:Amide Synthases / Q000378:metabolism; D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009243:NAD / Q000378:metabolism*; D009244:NAD+ Nucleosidase / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D011500:Protein Synthesis Inhibitors; D011506:Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D009243:NAD; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D000641:Ammonia; D011065:Poly(ADP-ribose) Polymerases; D009244:NAD+ Nucleosidase; D019732:Amide Synthases; C038479:NAD+ synthase