Molecular, Cellular, and Behavioural Effects Produced by Perinatal Asphyxia: Protection by Poly (ADP-Ribose) Polymerase 1 (PARP-1) Inhibition

Neira-Peña, T.; Espina-Marchant, Pablo; Rojas-Mancilla, Edgardo; Esmar, D.; Kraus, Christina N.; Munoz, Valentina; Perez, Ronald S.; Rivera, Benjamin; Bustamante, Diego; Valdés, José Luís; Hermoso, Marcela A.; Gebicke‐Haerter, Peter J.; Morales, Paola; Herrera‐Marschitz, Mario

doi:10.1007/978-1-4614-5836-4_115

Cited by 5 publications

(6 citation statements)

References 97 publications

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“…We suggest, therefore, that IL-6 mRNA expression using RT-qPCR to total RNA from telencephalic brain samples is more sensitive than directly measuring protein levels. Similar effect was observed by Neira-Pena et al, who showed that PA increased several pro-inflammatory cytokines, but not necessarily increased protein levels [ 94 , 95 ]. Changes in pro-inflammatory cytokines were observed in the hippocampus 8 h after PA [ 94 ], but in mesencephalon, up to 24 h after the insult [ 95 ], which could be explained by temporally and regionally selective mechanisms.…”

Section: Discussionsupporting

confidence: 83%

Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats

Tapia-Bustos

Lespay-Rebolledo

Vio

et al. 2021

IJMS

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The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 μL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.

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Section: Discussionsupporting

confidence: 83%

Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats

Tapia-Bustos

Lespay-Rebolledo

Vio

et al. 2021

IJMS

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“…Increased TUNEL-positive cell death and cleaved-caspase-3 have been described in hippocampus at P1, P3, and P7 in PA rats [ 5 , 7 , 25 ], even at P30 [ 6 ]. In this report, we found that treatment with either DFX-MSC-S or TNFα−IFNγ-MSC-S decreased PA-induced hippocampus cell death evaluated at P7, monitored by cleaved-caspase-3, suggesting decreased apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Neuroinflammation generated by oxidative stress is another key player of PA pathology. ROS lead to nuclear translocation of the transcription factor nuclear factor-kappa B (NF-κB) subunit p65, overexpressing the pro-inflammatory cytokines IL-1β and TNF-α, leading to glial reactivity and cell death [ 25 ]. Microglia and astrocytes are the cells firstly activated by PA, as evidenced by morphological changes, migration to damaged regions, and release of: (i) pro-inflammatory cytokines, TNF-α, IL1-β, and IL-6; (ii) glutamate; (iii) nitric oxide, and (iv) additional free radicals [ 26 , 27 , 28 ], contributing to a harmful cellular environment, causing neuronal and glial death [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

“…Microglial infiltration, astrogliosis and upregulation of TNF-α and IL-1β have been observed 24 h and up to 2 months after birth in white and grey matter of post-mortem brains of infants suffering from hypoxic-ischemic encephalopathy [ 31 , 32 ]. Moreover, NF-κB /p65 translocation, IL-1β and TNF-α overexpression, and apoptotic-like cell death were found 8 and 24 h after PA in the mesencephalon and hippocampus of rat neonates [ 10 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

Farfan

Carril

Redel

et al. 2020

IJMS

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Perinatal Asphyxia (PA) is a leading cause of motor and neuropsychiatric disability associated with sustained oxidative stress, neuroinflammation, and cell death, affecting brain development. Based on a rat model of global PA, we investigated the neuroprotective effect of intranasally administered secretome, derived from human adipose mesenchymal stem cells (MSC-S), preconditioned with either deferoxamine (an hypoxia-mimetic) or TNF-α+IFN-γ (pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 °C for 21 min. Thereafter, 16 μL of MSC-S (containing 6 μg of protein derived from 2 × 105 preconditioned-MSC), or vehicle, were intranasally administered 2 h after birth to asphyxia-exposed and control rats, evaluated at postnatal day (P) 7. Alternatively, pups received a dose of either preconditioned MSC-S or vehicle, both at 2 h and P7, and were evaluated at P14, P30, and P60. The preconditioned MSC-S treatment (i) reversed asphyxia-induced oxidative stress in the hippocampus (oxidized/reduced glutathione); (ii) increased antioxidative Nuclear Erythroid 2-Related Factor 2 (NRF2) translocation; (iii) increased NQO1 antioxidant protein; (iv) reduced neuroinflammation (decreasing nuclearNF-κB/p65 levels and microglial reactivity); (v) decreased cleaved-caspase-3 cell-death; (vi) improved righting reflex, negative geotaxis, cliff aversion, locomotor activity, anxiety, motor coordination, and recognition memory. Overall, the study demonstrates that intranasal administration of preconditioned MSC-S is a novel therapeutic strategy that prevents the long-term effects of perinatal asphyxia.

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“…Consequently, signs of apoptosis have been found in normal and asphyxia-exposed animals, independently upon the severity of the insult. However, in neocortex, neostriatum and mesencephalon a significant increase of apoptotic cells is only observed in asphyxia-exposed animals, which documents regional vulnerability (Dell'Anna et al, 1997 ; Neira-Peña et al, 2014 ).…”

Section: Cell Death and Regional Vulnerability: Endpoints For The Outmentioning

confidence: 90%

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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Molecular, Cellular, and Behavioural Effects Produced by Perinatal Asphyxia: Protection by Poly (ADP-Ribose) Polymerase 1 (PARP-1) Inhibition

Cited by 5 publications

References 97 publications

Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats

Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats

Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

Perinatal asphyxia: CNS development and deficits with delayed onset

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