Brain RNA Polymerase and Nucleolar Structure in Perinatal Asphyxia of the Rat

Mosgoeller, Wilhelm; Kastner, Philomena; Fang-Kircher, S; Kitzmueller, Erwin; Hoeger, Harald; Seither, Peter; Labudova, Olga; Lübec, Gert; Lubec, Barbara

doi:10.1006/exnr.1999.7232

Cited by 14 publications

(4 citation statements)

References 43 publications

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“…Suppression and/or over-activation of gene expression occurs immediately or during the re-oxygenation period following perinatal asphyxia (Labudova et al 1999; Seidl et al 2000; Mosgoeller et al 2000; Lubec et al 2002). When the DNA integrity is compromised, a number of sentinel proteins are activated, including (i) poly(ADP-ribose) polymerases (PARPs) (Amé et al 2004); (ii) X-ray Cross-Complementing Factor 1 (XRCC1) (Green et al 1992); (iii) DNA ligase IIIα (Leppard et al 2003); (iv) DNA polymerase β (Wilson 1998; Mishra et al 2003); (v) Excision Repair Cross-Complementing Rodent Repair Group 2 (ERCC2) (Sung et al 1993; Chiappe-Gutierrez et al 1998; Lubec et al 2002) and (vi) DNA-dependent protein kinases (de Murcia and Menissier de Murcia 1994).…”

Section: Sentinel Proteinsmentioning

confidence: 99%

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

et al. 2010

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Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care.

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Section: Sentinel Proteinsmentioning

confidence: 99%

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

et al. 2010

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“…In a mouse model of accelerated aging caused by the loss of the klotho gene transcript, oxidative neuronal DNA damage, reduced RNAPol1 activity and neurodegeneration were also reported (Nagai et al 2003; Anamizu et al 2005). Finally, hypoxia/ischemia induces nucleolar disruption in brain neurons (Mosgoeller et al 2000; Kastner et al 2003; Kerr et al 2007). As AD , aging and hypoxia are associated with the accumulation of DNA damage, these results provide further, albeit indirect, support for the concept that nucleolar transcription senses neuronal DNA damage.…”

Section: Nucleolar Stress As a Neurotoxic Consequence Of Dna Damagementioning

confidence: 99%

Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition

Hetman

Vashishta

Rempała

2010

Journal of Neurochemistry

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J. Neurochem. (2010) 114, 1537–1549. Abstract Although DNA damage‐induced neurotoxicity is implicated in various pathologies of the nervous system, its underlying mechanisms are not completely understood. Transcription is a DNA transaction that is highly active in the nervous system. In addition to its direct role in expression of the genetic information, transcription contributes to DNA damage detection and repair as well as chromatin organization including biogenesis of the nucleolus. Transcription is inhibited by DNA single‐strand breaks and DNA adducts. Hence, transcription inhibition may be an important contributor to the neurotoxic consequences of such types of DNA damage. This review discusses the existing evidence in support of the latter hypothesis. The presented literature suggests that neuronal DNA damage interferes with the RNA‐Polymerase‐2‐dependent transcription of genes encoding proteins with critical functions in neurotransmission and intracellular signaling. The latter category includes extracellular signal‐regulated kinase‐1/2 mitogen‐activated protein kinase phosphatases whose lowered expression results in chronic activation of extracellular signal‐regulated kinase‐1/2 and its reduced responsiveness to physiological stimuli. Conversely, DNA damage‐induced inhibition of RNA‐Polymerase‐1 and the subsequent disruption of the nucleolus induce p53‐mediated apoptosis of developing neurons. Finally, decreasing nucleolar transcription may link DNA damage to chronic neurodegeneration in adults.

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“…Suppression and/or overactivation of gene expression occur immediately or during the re-oxygenation period following perinatal asphyxia (Labudova et al, 1999; Mosgoeller et al, 2000; Seidl et al, 2000; Lubec et al, 2002). When DNA integrity is compromised, a number of sentinel proteins is activated, including poly(ADP-ribose) polymerases (PARPs) (Amé et al, 2004); X-Ray Cross Complementing Factor 1 (XRCC1) (Green et al, 1992); DNA ligase IIIα (Leppard et al, 2003); DNA polymerase β (Wilson, 1998; Mishra et al, 2003); Excision Repair Cross-Complementing Rodent Repair Group 2 (ERCC2) (Sung et al, 1993; Chiappe-Gutierrez et al, 1998; Lubec et al, 2002), and DNA-dependent protein kinases (De Murcia and Menissier de Murcia, 1994).…”

Section: Sentinel Proteinsmentioning

confidence: 99%

Perinatal asphyxia: CNS development and deficits with delayed onset

et al. 2014

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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.

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Brain RNA Polymerase and Nucleolar Structure in Perinatal Asphyxia of the Rat

Cited by 14 publications

References 43 publications

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition

Perinatal asphyxia: CNS development and deficits with delayed onset

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