title: Perinatal asphyxia leads to PARP-1 overactivity, p65 translocation, IL-1β and TNF-α overexpression, and apoptotic-like cell death in mesencephalon of neonatal rats: prevention by systemic neonatal nicotinamide administration.
abstract: Perinatal asphyxia (PA) is a leading cause of neuronal damage in newborns, resulting in long-term neurological and cognitive deficits, in part due to impairment of mesostriatal and mesolimbic neurocircuitries. The insult can be as severe as to menace the integrity of the genome, triggering the overactivation of sentinel proteins, including poly (ADP-ribose) polymerase-1 (PARP-1). PARP-1 overactivation implies increased energy demands, worsening the metabolic failure and depleting further NAD(+) availability. Using a global PA rat model, we report here evidence that hypoxia increases PARP-1 activity, triggering a signalling cascade leading to nuclear translocation of the NF-κB subunit p65, modulating the expression of IL-1β and TNF-α, pro-inflammatory molecules, increasing apoptotic-like cell death in mesencephalon of neonate rats, monitored with Western blots, qPCR, TUNEL and ELISA. PARP-1 activity increased immediately after PA, reaching a maximum 1-8 h after the insult, while activation of the NF-κB signalling pathway was observed 8 h after the insult, with a >twofold increase of p65 nuclear translocation. IL-1β and TNF-α mRNA levels were increased 24 h after the insult, together with a >twofold increase in apoptotic-like cell death. A single dose of the PARP-1 inhibitor nicotinamide (0.8 mmol/kg, i.p.), 1 h post delivery, prevented the effect of PA on PARP-1 activity, p65 translocation, pro-inflammatory cytokine expression and apoptotic-like cell death. The present study demonstrates that PA leads to PARP-1 overactivation, increasing the expression of pro-inflammatory cytokines and cell death in mesencephalon, effects prevented by systemic neonatal nicotinamide administration, supporting the idea that PARP-1 inhibition represents a therapeutic target against the effects of PA.
authors.affiliation: Millenium Institute BNI-Chile, Santiago, Chile, tanyaneira@gmail.com.
authors.forename: T
authors.initials: T
authors.lastname: Neira-Peña
authors.forename: E
authors.initials: E
authors.lastname: Rojas-Mancilla
authors.forename: V
authors.initials: V
authors.lastname: Munoz-Vio
authors.forename: R
authors.initials: R
authors.lastname: Perez
authors.forename: M
authors.initials: M
authors.lastname: Gutierrez-Hernandez
authors.forename: D
authors.initials: D
authors.lastname: Bustamante
authors.forename: P
authors.initials: P
authors.lastname: Morales
authors.forename: M A
authors.initials: MA
authors.lastname: Hermoso
authors.forename: P
authors.initials: P
authors.lastname: Gebicke-Haerter
authors.forename: M
authors.initials: M
authors.lastname: Herrera-Marschitz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001237:Asphyxia / Q000201:enzymology / Q000378:metabolism*; D001238:Asphyxia Neonatorum / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage*; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D009363:Neoplasm Proteins; D029543:Nucleocytoplasmic Transport Proteins; D014409:Tumor Necrosis Factor-alpha; C063447:p65 oncofetal mRNA transport protein, rat; D009536:Niacinamide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
references.citation: Brain Dev. 2006 Apr;28(3):178-82
references.pmid: 16181755
references.citation: Immunology. 2013 Aug;139(4):428-37
references.pmid: 23489378
references.citation: Am J Obstet Gynecol. 1979 Nov 1;135(5):637-46
references.pmid: 507116
references.citation: Stroke. 2007 Feb;38(2 Suppl):632-6
references.pmid: 17261705
references.citation: J Obstet Gynaecol Res. 2004 Aug;30(4):276-86
references.pmid: 15238103
references.citation: Lancet. 2003 Mar 1;361(9359):736-42
references.pmid: 12620738
references.citation: Neurotox Res. 2011 May;19(4):603-27
references.pmid: 20645042
references.citation: J Pediatr. 2005 Apr;146(4):453-60
references.pmid: 15812446
references.citation: Pediatr Res. 2007 Nov;62(5):559-63
references.pmid: 18049371
references.citation: J Neurosci Res. 2008 Sep;86(12):2650-62
references.pmid: 18512760
references.citation: Neurotox Res. 2012 Jul;22(1):79-90
references.pmid: 22311271
references.citation: J Neurochem. 2003 Apr;85(2):306-17
references.pmid: 12675907
references.citation: Exp Brain Res. 2010 Apr;202(1):1-14
references.pmid: 20012537
references.citation: Biosci Trends. 2010 Dec;4(6):288-96
references.pmid: 21248426
references.citation: Front Neurosci. 2014 Mar 26;8:47
references.pmid: 24723845
references.citation: Biol Neonate. 2002;81(3):146-57
references.pmid: 11937719
references.citation: Biol Chem. 1999 Jul-Aug;380(7-8):953-9
references.pmid: 10494847
references.citation: Bioessays. 2004 Aug;26(8):882-93
references.pmid: 15273990
references.citation: Nat Rev Drug Discov. 2003 Sep;2(9):736-46
references.pmid: 12951580
references.citation: Radiat Res. 1985 Jan;101(1):4-15
references.pmid: 3155867
references.citation: Trends Pharmacol Sci. 2004 May;25(5):259-64
references.pmid: 15120492
references.citation: Nat Cell Biol. 2001 Dec;3(12):1035-42
references.pmid: 11781564
references.citation: Cell. 2010 Mar 19;140(6):821-32
references.pmid: 20303873
references.citation: Dev Neurosci. 2001;23(3):213-8
references.pmid: 11598323
references.citation: Neuroscience. 2005;135(2):421-31
references.pmid: 16112481
references.citation: J Biol Chem. 1996 Jul 26;271(30):17771-8
references.pmid: 8663540
references.citation: Science. 2002 Jul 12;297(5579):259-63
references.pmid: 12114629
references.citation: Int J Environ Res Public Health. 2011 Jul;8(7):2980-3018
references.pmid: 21845170
references.citation: Neurobiol Dis. 2001 Apr;8(2):207-19
references.pmid: 11300718
references.citation: Exp Brain Res. 2001 Jun;138(3):375-83
references.pmid: 11460776
references.citation: J Investig Med. 1997 Jun;45(5):284-94
references.pmid: 9250002
references.citation: J Dev Physiol. 1991 Oct;16(4):181-207
references.pmid: 1812154
references.citation: J Neurochem. 2010 Mar;112(5):1099-114
references.pmid: 20002526
references.citation: J Perinat Med. 2000;28(4):261-85
references.pmid: 11031697
references.citation: Exp Brain Res. 1997 Jun;115(1):105-15
references.pmid: 9224838
references.citation: Int J Dev Neurosci. 2005 Dec;23(8):673-86
references.pmid: 16209916
references.citation: Eur J Pediatr. 1985 Sep;144(3):225-7
references.pmid: 2996903
references.citation: Neuroscience. 2003;119(4):1023-32
references.pmid: 12831861
references.citation: Pediatr Neurol. 1991 Mar-Apr;7(2):147-9
references.pmid: 2059257
references.citation: Mol Neurobiol. 2010 Jun;41(2-3):187-96
references.pmid: 20411356
references.citation: Neuroscience. 2007 Apr 14;145(4):1267-72
references.pmid: 17084037
references.citation: Biochem Med Metab Biol. 1994 Feb;51(1):1-15
references.pmid: 8192912
references.citation: J Pediatr. 2013 Oct;163(4):949-54
references.pmid: 23759422
references.citation: Lancet. 2004 Oct 9-15;364(9442):1329-33
references.pmid: 15474135
references.citation: Pharmacol Rev. 2002 Sep;54(3):375-429
references.pmid: 12223530
references.citation: J Pediatr. 2011 Jun;158(6):904-11
references.pmid: 21232764
references.citation: J Immunol. 2010 Aug 1;185(3):1894-902
references.pmid: 20610652
references.citation: Amino Acids. 2006 Nov;31(4):377-84
references.pmid: 16871361