Decrease of heart protein kinase C and cyclin‐dependent kinase precedes death in perinatal asphyxia of the rat

Lubec, Barbara; Marx, Manfred; Herrera‐Marschitz, Mario; Labudova, Olga; Hoeger, Harald; Gille, Lars; Nohl, Hans; Mosgoeller, Wilhelm; Lübec, Gert

doi:10.1096/fasebj.11.6.9194529

Cited by 45 publications

(39 citation statements)

References 9 publications

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“…Another possibility is that POL I activity and even nucleolar integrity are affected by dramatic reduction of protein kinases as, for example, protein kinase C (PKC). In brain and in heart, we detected PKC and PKA decreasing with the length of the asphyctic period in the identical animal model used in the present study (15,16). This proposed tentative mechanism is …”

Section: Discussionsupporting

confidence: 66%

Deficient Brain RNA Polymerase and Altered Nucleolar Structure Persists until Day 8 after Perinatal Asphyxia of the Rat

et al. 2003

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[P.S.] RNA polymerases (POL) are integral constituents of the protein synthesis machinery, with POL I and POL III coding for ribosomal RNA and POL II coding for protein. POL I is located in the nucleolus and transcribes class I genes, those that code for large ribosomal RNA. It has been reported that the POL system is seriously affected in perinatal asphyxia (PA) immediately after birth. Because POL I is necessary for protein synthesis and brain protein synthesis was shown to be deranged after hypoxicischemic conditions, we aimed to study whether POL derangement persists in a simple, well-documented animal model of graded global PA at the activity, mRNA, protein, and morphologic level until 8 d after the asphyctic insult. Nuclear POL I activity was determined according to a radiochemical method; mRNA steady state and protein levels of RPA4O-an essential subunit of POL I and III-were evaluated by blotting methods; and the POL I subunit polymerase activating factor-53 was evaluated using immunohistochemistry. Silver staining and transmission electron microscopy were used to examine the nucleolus. At the eighth day after PA, nuclear POL I decreased with the length of the asphyctic period, whereas mRNA and protein levels for RPA4O were unchanged. The subunit polymerase activating factor-53, however, was unambiguously reduced in several brain regions. Dramatic changes of nucleolar morphology were observed, the main finding being nucleolar disintegration at the electron microscopy level. We suggest that severe acidosis and/or deficient protein kinase C in the brain during the asphyctic period may be responsible for disintegration of the nucleolus as well as for decreased POL activity persisting until the eighth day after PA. The biologic effect may be that PA causes impaired RNA and protein synthesis, which has been already observed in hypoxic-ischemic states. In eukaryotes, three different POL transcribe nuclear genes. POL I transcribes class I genes, those that code for large ribosomal RNA (rRNA). It is located in the nucleolus, represents 50 -70% of polymerase activity per cell, and as many as 40,000 copies per cell are present (1). This high number of POL I molecules transcribes as few as about 100 genes, which is appropriate as the rRNA precursor is long (i.e. 6,000 -15,000 nucleotides), and as many as 50 polymerase molecules may transcribe each rRNA gene simultaneously. This intense transcriptional activity reflects the need of the cell for rRNA; 10 million copies of rRNA are required (2) to form the 10 million ribosomes required for a single cell division. rRNA genes, transcribed by POL I, form the primary RNA transcript, the 45S-rRNA. Before release from the nucleus as ribosomal particles, 45S-rRNA is cleaved to a copy of 28S-rRNA, 18S-rRNA, and 5.8S-rRNA each. POL III transcribes class III genes, those that encode a number of small RNA molecules, including 5S-rRNA. It is located in the nucleoplasm, makes up 10% of the polymerase activity of the cell, and about 20,000 copies are present per cell (3). These...

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Section: Discussionsupporting

confidence: 66%

Deficient Brain RNA Polymerase and Altered Nucleolar Structure Persists until Day 8 after Perinatal Asphyxia of the Rat

et al. 2003

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“…We are aware of the inherent problem of comparing rats, humans, and guinea pigs in terms of metabolism, susceptibility to hypoxia, and so forth, but we must point out the importance of the state of maturity or immaturity-although our findings clearly discriminate between consequences of PA in the rat and those in the guinea pig. Rats in our model of PA survive 20 min of hypoxia, whereas the guinea pig only tolerates 4 min of the hypoxic state (25,26). The guinea pig is a developmentally mature animal, able to follow the pack shortly after delivery, whereas rats and humans are less mature or even poorly developed at birth.…”

Section: Discussionmentioning

confidence: 99%

“…Then pups were given to foster mothers and were well accepted. Only litters with pups with a body weight of more than 60 g at the time of delivery were used in the experiments (25,26). Foster mothers and pups were kept in Makrolon type IV cages (1800 cm 2 ) and weaned at the age of 14 d. Animal studies were performed according to the rules of the American Physiology Society and following local ethical law.…”

Section: Experimental Designmentioning

confidence: 99%

Neurodegeneration, Neuronal Loss, and Neurotransmitter Changes in the Adult Guinea Pig with Perinatal Asphyxia

et al. 2003

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There is only limited morphologic information on long-term alterations and neurotransmitter changes after perinatal asphyxia, and no long-term study showing neurodegeneration has been reported so far. We used an animal model for perinatal asphyxia well documented in the rat to investigate the guinea pig as a species highly mature at birth. Cesarean section was performed on full-term pregnant guinea pigs, and pups, still in membranes, were placed into a water bath at 37°C for asphyxia periods from 2 to 4 min. Thereafter pups were given to surrogate mothers and examined at 3 mo of age. We studied brain areas reported to be hypoxia-sensitive. Neurodegeneration was evaluated by fluorojade, neuronal loss by Nissl, reactive gliosis by glial fibrillary acidic protein staining, and differentiation by neuroendocrinespecific protein C immunoreactivity. We tested tyrosine hydroxylase, the vesicular monoamine transporter, and dopamine ␤-hydroxylase, representing the monoaminergic system; the vesicular acetylcholine transporter; and the excitatory amino acid carrier 1. Neurodegeneration was evident in cerebellum, hippocampal area CA1, and hypothalamus, and neuronal loss could be observed in cerebellum and hypothalamus; gliosis was observed in cerebellum, hippocampus, hypothalamus, and parietal cortex; dedifferentiation was found in hypothalamus and striatum; and monoaminergic, cholinergic, and amino acidergic deficits were shown in several brain regions. The major finding of the present study was that neurodegeneration and dedifferentiation evolved in the guinea pig, a species highly mature at birth. The relevance of this contribution is that a simple animal model of perinatal asphyxia resembling the clinical situation of intrauterine hypoxia-ischemia and presenting with neurodegeneration was characterized. PA continues to be a major cause of neurologic injury in the newborn, leading to reversible and irreversible brain damage ranging from minimal brain dysfunction to death (1-3). After a hypoxic-ischemic insult certain neuron subpopulations are known to die whereas others survive (4 -6). This phenomenon, referred to as selective vulnerability, occurs in adult and neonatal brain. Neurons in the hippocampus, cerebellum, striatum, thalamus, and neocortex have been identified to be vulnerable to hypoxic-ischemic insults.Apart from acute cell death the question arises whether PA can provoke detrimental effects on the CNS later in life, e.g. as induction of neurodegeneration. There are no long-term studies available reporting on neurodegeneration after PA, and therefore we included a marker for the detection of degenerating cells. Because only subtle morphologic differences between normal and degenerating cells may exist and thus degenerating neurons could be missed easily, we performed FJ staining as the staining pattern of this dye corresponds to the pattern of argyrophilia, staining cell bodies, dendrites, and axon terminals of degenerating neurons but not healthy neurons, myelin, vascular elements, or neuropil (7).In addition...

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“…S100B, 24 NSE, 25 IL-6, urinary uric acid, cardiac troponin-I, creatinine kinase, 26 Glial Fibrillary Acidic Protein (GFAP), 27 Cytochrome C, Caspase 9 have been studied as indicators of diagnostic and prognostic indicators in Hypoxic ischemic encephalopathy. In this study we evaluated the role of cytochrome c and caspase 9 in perinatal asphyxia.…”

Section: Mechanism Of Neuronal Injurymentioning

confidence: 99%

Comparison of cerebrospinal fluid Cytochrome-c and Caspase-9 as biomarkers for newborns with hypoxic ischemic encephalopathy with non-asphyxiated babies and followup of these biomarkers after day 7

Kalyani

Lakshmi

et al. 2015

Int J Res Med Sci

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Decrease of heart protein kinase C and cyclin‐dependent kinase precedes death in perinatal asphyxia of the rat

Cited by 45 publications

References 9 publications

Deficient Brain RNA Polymerase and Altered Nucleolar Structure Persists until Day 8 after Perinatal Asphyxia of the Rat

Deficient Brain RNA Polymerase and Altered Nucleolar Structure Persists until Day 8 after Perinatal Asphyxia of the Rat

Neurodegeneration, Neuronal Loss, and Neurotransmitter Changes in the Adult Guinea Pig with Perinatal Asphyxia

Comparison of cerebrospinal fluid Cytochrome-c and Caspase-9 as biomarkers for newborns with hypoxic ischemic encephalopathy with non-asphyxiated babies and followup of these biomarkers after day 7

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