title: Acute ammonia intoxication induces an NMDA receptor-mediated increase in poly(ADP-ribose) polymerase level and NAD metabolism in nuclei of rat brain cells.
abstract: 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.
authors.affiliation: Institute of Theoretical and Experimental Biophysics RAS, Pushchino, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Kosenko
authors.forename: Carmina
authors.initials: C
authors.lastname: Montoliu
authors.forename: Gennaro
authors.initials: G
authors.lastname: Giordano
authors.forename: Yury
authors.initials: Y
authors.lastname: Kaminsky
authors.forename: Natalia
authors.initials: N
authors.lastname: Venediktova
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Buryanov
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: 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
chemical_list: 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