Ronald Perez - Academia.edu (original) (raw)

Papers by Ronald Perez

Neurotoxicity research, Jan 29, 2018

The present report evaluates the effect of global perinatal asphyxia on several parameters of oxi... more The present report evaluates the effect of global perinatal asphyxia on several parameters of oxidative stress and cell viability in rat brain tissue sampled at an extended neonatal period up to 14 days, a period characterised by intensive neuritogenesis, synaptogenesis, synaptic consolidation, pruning and delayed cell death. Perinatal asphyxia was induced by immersing foetus-containing uterine horns removed by a caesarean section from on term rat dams into a water bath at 37 °C for 21 min. Asphyxia-exposed and sibling caesarean-delivered foetuses were manually resucitated and nurtured by surrogate dams for 1 to 14 postnatal (P) days. Brain samples (mesencephalon, telencephalon and hippocampus) were assayed for glutathione (reduced and oxidated levels; spectrophotometry), tissue reducing capacity (potassium ferricyanide reducing assay, FRAP), catalase (the key enzyme protecting against oxidative stress and reactive oxygen species, Western blots and ELISA) and cleaved caspase-3 (the ...

Neurotoxicity Research, 2016

Perinatal asphyxia (PA) is associated to delayed cell death, affecting neurocircuitries of basal ... more Perinatal asphyxia (PA) is associated to delayed cell death, affecting neurocircuitries of basal ganglia and hippocampus, and long-term neuropsychiatric disabilities. Several compensatory mechanisms have been suggested to take place, including cell proliferation and neurogenesis. There is evidence that PA can increase postnatal neurogenesis in hippocampus and subventricular zone (SVZ), modulated by dopamine, by still unclear mechanisms. We have studied here the effect of selective dopamine receptor agonists on cell death, cell proliferation and neurogenesis in organotypic cultures from control and asphyxia-exposed rats. Hippocampus and SVZ sampled at 1-3 postnatal days were cultured for 20-21 days. At day in vitro (DIV) 19, cultures were treated either with SKF38393 (10 and 100 lM, a D 1 agonist), quinpirole (10 lM, a D 2 agonist) or sulpiride (10 lM, a D 2 antagonist) ? quinpirole (10 lM) and BrdU (10 lM, a mitosis marker) for 24 h. At DIV 20-21, cultures were processed for immunocytochemistry for microtubule-associated protein-2 (MAP-2, a neuronal marker), and BrdU, evaluated by confocal microscopy. Some cultures were analysed for cell viability at DIV 20-21 (LIVE/DEAD kit). PA increased cell death, cell proliferation and neurogenesis in hippocampus and SVZ cultures. The increase in cell death, but not in cell proliferation, was inhibited by both SKF38393 and quinpirole treatment. Neurogenesis was increased by quinpirole, but only in hippocampus, in cultures from both asphyxia-exposed and control-animals, effect that was antagonised by sulpiride, leading to the conclusion that dopamine modulates neurogenesis in hippocampus, mainly via D 2 receptors.

Handbook of Neurotoxicity, 2014

ABSTRACT Perinatal asphyxia implies oxygen interruption at birth, leading to death whenever reoxy... more ABSTRACT Perinatal asphyxia implies oxygen interruption at birth, leading to death whenever reoxygenation is not promptly reestablished. Reoxygenation triggers a cascade of biochemical events for restoring function at the cost of improper homeostasis. 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 reoxygenation, leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy. Asphyxia also induces transcriptional activation of proinflammatory factors, including NFκB, and its subunit p65, whose translocation to the nucleus was found here, is significantly increased in brain tissue from asphyxia-exposed animals, in tandem with PARP-1 overactivation, suggesting that PARP-1 inhibition downregulates the expression of proinflammatory cytokines. Indeed, TNF-α and IL-1β were found to be increased 8 and 24 h after perinatal asphyxia in mesencephalon and hippocampus of rat neonates. The possible neuroprotection effect of nicotinamide has been studied in an experimental model of global perinatal asphyxia in rats, inducing the insult by immersing rat fetuses into a water bath for various periods of time. Following asphyxia, the pups are delivered, immediately treated, or given to surrogate dams for nursing, pending further experiments. Systemic administration of nicotinamide was found to rapidly distribute into the brain reaching a steady-state concentration sufficient to inhibit PARP-1 activity for several hours. Nicotinamide prevented several of the long-term consequences elicited by perinatal asphyxia, supporting the idea that it constitutes a lead for exploring compounds with similar or better pharmacological profiles.

Neurotoxicity Research, 2017

Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is ... more Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short-and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult. PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1α (HIF-1α) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in

Perinatal asphyxia: CNS development and deficits with

International Journal of Molecular Sciences, 2021

The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viabil... more 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, ...