Modulation of Postnatal Neurogenesis by Perinatal Asphyxia: Effect of D1 and D2 Dopamine Receptor Agonists

Abstract

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 µM, a D agonist), quinpirole (10 µM, a D agonist) or sulpiride (10 μM, a D antagonist) + quinpirole (10 μM) and BrdU (10 μM, 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 receptors.

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

“…We have recently reported that PA induces sustained oxidative stress, reflected by a long-lasting increase of the oxidized glutathione (GSSG) level, and a high GSSG/GSH ratio, together with a decrease in tissue reducing capacity and catalase activity, resulting in apoptotic caspase-3-dependent cell death, mainly in the basal ganglia and hippocampus [ 7 , 19 ]. Endogenous repair mechanisms such as neurogenesis, synaptogenesis, and anti-apoptotic pathways have been suggested to be activated, but these are not always sufficient to resolve the deficit [ 5 , 13 , 20 , 21 ].…”

Could Perinatal Asphyxia Induce a Synaptopathy? New Highlights from an Experimental Model

“…The consumption of extra energy for the reestablishment of homeostasis might compete with the demands required for circuitries and synapsis consolidation [55]. Several studies using the Swedish experimental model have reported distinct alterations induced by PA such as thickening of both pre- [32] and postsynaptic densities [24–29, 50]; protein misfolding, aggregation, and ubiquitination [24–29]; interruption of postnatal neurogenesis [58]; reduction in neurite length and branching [59, 60]; myelination deficits [63]; and modifications in the levels of synapsin [52, 60] and neurotrophic factors [61]. Some researchers have suggested the existence of plastic changes in an attempt to counterbalance neuronal loss [29, 32, 52, 57].…”

“…In other words PA might modulate postnatal neurogenesis. Therefore dopamine agonists might have neuroprotective potential via facilitation of postnatal neurogenesis and restoration of damaged circuitries [58]. Certainly, in vitro studies revealed a selective decrease in the number, neurite length, and branching of dopamine neurons as a consequence of PA [59].…”

Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: a Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia?

“…In humans, PA is a risk factor for several psychiatric disorders, including learning deficits and schizophrenia. Conversely, in rodents, PA is associated with delayed cell death, dopamine and histamine transmission deficits and behavioural impairments assessed at adulthood, affecting learning, spatial, and non-spatial memory and anxiety (Simola et al 2008 ; Morales et al 2010 ; Galeano et al 2011 , 2015 ; Flores-Balter et al 2016 ; Tapia-Bustos et al 2017 ). The idea of progressive dysfunction and “first” and successive hit sequences, triggering and perpetuating pathophysiological conditions and/or diseases, has recently been discussed (Marriott et al 2017 ; Israel et al 2017 ).…”