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Abstract
Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted. The primary insult relates to the duration of the period lacking oxygenation, leading to death if not re-established. Re-oxygenation leads to a secondary insult, related to a cascade of biochemical events required for restoring proper function. Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated to mental and neurological diseases with delayed clinical onset, by mechanisms not yet clarified. In the experimental scenario, the effects observed long after perinatal asphyxia have been explained by overexpression of sentinel proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1), competing for NAD+ during re-oxygenation, leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy. Asphyxia induces transcriptional activation of pro-inflammatory factors, in tandem with PARP-1 overactivation, and pharmacologically induced PARP-1 inhibition also down-regulates the expression of proinflammatory cytokines. Nicotinamide has been proposed as a suitable PARP-1 inhibitor. Its effect has been studied in an experimental model of global hypoxia in rats. In that model, the insult is induced by immersing rat fetus into a water bath for various periods of time. Following asphyxia, the pups are delivered, treated, and nursed by surrogate dams, pending further experiments. Nicotinamide rapidly distributes into the brain following systemic administration, reaching steady state concentrations sufficient to inhibit PARP-1 activity for several hours, preventing several of the long-term consequences of perinatal asphyxia, supporting the idea that nicotinamide constitutes a lead for exploring compounds with similar or better pharmacological profiles.
Highlights
It has been proposed that metabolic and environmental insults occurring during early development stages (i.e., pre- and perinatal) lead to psychiatric manifestations with an onset at Abbreviations: ADP, adenosine diphosphate; Apoptosis-Inducing Factor (AIF), apoptosis-inducing factor; ATP, adenosine triphosphate; ATPase, ATP polymerase; Bcl-2 associated death (BAD), Bcl-2-associated death factor; BAX, Bcl-2-associated X protein; BBB, blood-brain barrier; bFGF, basic fibroblast growth factor; Bcl-2, B-cell lymphoma-2; CA, cornus Ammonis (CA1, C2, C3); CAM, cell adhesion molecule; CNS, central nervous system; COX-2, cyclooxygenase-2; CS, caesarean-delivered saline treated animal; CSF, cerebral spinal fluid; DAMPs, damage-associated molecular pattern molecules; DG, dentate gyrus of the hippocampus; DNA, deoxyribonucleic acid; EAAC1, excitatory amino acid carrier 1; Elk1, ETS domain-containing protein 1; Excision Repair CrossComplementing Rodent Repair Group 2 (ERCC2), excision repair cross-complementing rodent repair group 2; ERK, extracellular signal-regulated kinases; FGFR, bFGF receptors; FLRT3, leucine-rich repeat transmembrane protein; GPx, glutathione peroxidase; HIF, hypoxia inducible factor; IκB, inhibitor of kappa B protein; inducible nitric oxide synthase (iNOS), inducible NOS; IL-1β/-6, interleukin-1β/-6; ICAM-1, TNFα adhesion molecule-1; L1, L1 CAM; LPS, lipopolysaccharide; MAP-2, microtubule-associated protein-2; MAPK, mitogen-activated protein kinase; MNNG, N-methyl-N-nitro-N-nitrosoguanidine; NACHT, LRR and PYD domains-containing protein 3 (cryopyrin); NAD+, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NALP3, NACHT, LRR, and PYD domain-containing protein 3 (cryopyrin); NAMPT, nicotinamide phosphoribosyltransferase; NF-κB, nuclear factor κB; NMDA, Nmethyl-D-aspartate; NO, nitric oxide; NOS, nitric oxide synthase; nNOS, neuronal NOS; p65/p50, protein subunits of 65/50 k Dalton MW; P1, postnatal day 1; PARP1, poly(ADP-ribose) polymerase-1; PIP2, phosphatidylinositol-4,5-bisphosphate; PJ34, [N-(6-Oxo-5, 6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl]; PKC, protein kinase C; poly polymers (pADPr), poly (ADP-ribose) polymers; PSD95, postsynaptic density protein 95; RhoA, ras homolog gene family, member A, small GTPase protein; ROS, reactive oxygen species; Sef, similar expression fgf gene; SEM, standard error of the means; SIN, 1, 3-morpholinosydonimine; SIRT, sirtuin; SOD, superoxide dismutase; Spry, sprouty; SRY, sex determining region Y; SVZ, subventricular zone; TH, tyrosine hydroxylase; Thy1, thymocyte differentiation antigen 1; TNF-α, tumor necrosis factor-alpha cytokine; TUNEL, TdT-mediated dUTP nick-end labeling; VTA, ventral tegmental area; X-Ray Cross Complementing Factor 1 (XRCC1), X-ray cross complementing F factor 1.www.frontiersin.orgHerrera-Marschitz et al.Neuroprotective strategies following perinatal asphyxia adolescence and/or young adulthood stages (Basovich, 2010)
poly(ADP-ribose) polymerase-1 (PARP-1) has been involved in the long-term effects produced by perinatal asphyxia (Martin et al, 2005), interacting with X-Ray Cross Complementing Factor 1 (XRCC1), deoxyribonucleic acid (DNA) ligase IIIα, and DNA polymerase-β, working in tandem to repair single-strand breaks
DNA damage elicited by perinatal asphyxia implies poly(ADP-ribose) polymerases (PARPs)-1 overactivation, promoting nuclear factor κB (NF-κB) translocation and expression of proinflammatory cytokines (Ullrich et al, 2001), a phenomenon associated with microglial migration toward the site of neuronal injury
Summary
It has been proposed that metabolic and environmental insults occurring during early development stages (i.e., pre- and perinatal) lead to psychiatric manifestations with an onset at Abbreviations: ADP, adenosine diphosphate; AIF, apoptosis-inducing factor; ATP, adenosine triphosphate; ATPase, ATP polymerase; BAD, Bcl-2-associated death factor; BAX, Bcl-2-associated X protein; BBB, blood-brain barrier; bFGF, basic fibroblast growth factor; Bcl-2, B-cell lymphoma-2; CA, cornus Ammonis (CA1, C2, C3); CAM, cell adhesion molecule; CNS, central nervous system; COX-2, cyclooxygenase-2; CS, caesarean-delivered saline treated animal; CSF, cerebral spinal fluid; DAMPs, damage-associated molecular pattern molecules; DG, dentate gyrus of the hippocampus; DNA, deoxyribonucleic acid; EAAC1, excitatory amino acid carrier 1; Elk1, ETS domain-containing protein 1; ERCC2, excision repair cross-complementing rodent repair group 2; ERK, extracellular signal-regulated kinases; FGFR, bFGF receptors; FLRT3, leucine-rich repeat transmembrane protein; GPx, glutathione peroxidase; HIF, hypoxia inducible factor; IκB, inhibitor of kappa B protein; iNOS, inducible NOS; IL-1β/-6, interleukin-1β/-6; ICAM-1, TNFα adhesion molecule-1; L1, L1 CAM; LPS, lipopolysaccharide; MAP-2, microtubule-associated protein-2; MAPK, mitogen-activated protein kinase; MNNG, N-methyl-N-nitro-N-nitrosoguanidine; NACHT, LRR and PYD domains-containing protein 3 (cryopyrin); NAD+, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NALP3, NACHT, LRR, and PYD domain-containing protein 3 (cryopyrin); NAMPT, nicotinamide phosphoribosyltransferase; NF-κB, nuclear factor κB; NMDA, Nmethyl-D-aspartate; NO, nitric oxide; NOS, nitric oxide synthase; nNOS, neuronal NOS; p65/p50, protein subunits of 65/50 k Dalton MW; P1, postnatal day 1; PARP1, poly(ADP-ribose) polymerase-1; PIP2, phosphatidylinositol-4,5-bisphosphate; PJ34, [N-(6-Oxo-5, 6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl]; PKC, protein kinase C; pADPr, poly (ADP-ribose) polymers; PSD95, postsynaptic density protein 95; RhoA, ras homolog gene family, member A, small GTPase protein; ROS, reactive oxygen species; Sef, similar expression fgf gene; SEM, standard error of the means; SIN, 1, 3-morpholinosydonimine; SIRT, sirtuin; SOD, superoxide dismutase; Spry, sprouty; SRY, sex determining region Y; SVZ, subventricular zone; TH, tyrosine hydroxylase; Thy1, thymocyte differentiation antigen 1; TNF-α, tumor necrosis factor-alpha cytokine; TUNEL, TdT-mediated dUTP nick-end labeling; VTA, ventral tegmental area; XRCC1, X-ray cross complementing F factor 1.www.frontiersin.orgHerrera-Marschitz et al.Neuroprotective strategies following perinatal asphyxia adolescence and/or young adulthood stages (Basovich, 2010). Hypothermia has been proposed as a therapeutic intervention, targeting functional hyperoxemia and oxidative stress, decreasing the metabolic demands, attenuating the disturbances of metabolism elicited by re-oxygenation, preventing the short- and long-term consequences of perinatal asphyxia (Gunn et al, 1998; Engidawork et al, 2001).
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