Abstract
BackgroundLabor subjects the fetus to an hypoxic episode and concomitant adrenomodullary catecholamine surge that may provide protection against the hypoxic insult. The beta1-adrenergic agonist dobutamine protects against hypoxia/aglycemia induced neuronal damage. We aimed to identify the associated protective biological processes involved.ResultsHippocampal slices from 6 days old mice showed significant changes of gene expression comparing slices with or without dobutamine (50 mM) in the following two experimental paradigms: (1) control conditions versus lipopolysacharide (LPS) stimulation and (2) oxygen–glucose deprivation (OGD), versus combined LPS/OGD. Dobutamine depressed the inflammatory response by modifying the toll-like receptor-4 signalling pathways, including interferon regulatory factors and nuclear factor κ B activation in experimental paradigm 1. The anti-oxidant defense genes superoxide dismutase 3 showed an upregulation in the OGD paradigm while thioredoxin reductase was upregulated in LPS paradigm. The survival genes Bag-3, Tinf2, and TMBIM-1, were up-regulated in paradigm 1. Moreover, increased levels of SOD3 were verified on the protein level 24 h after OGD and control stimulation in cultures with or without preconditioning with LPS and dobutamine, respectively.ConclusionsNeuroprotective treatment with dobutamine depresses expression of inflammatory mediators and promotes the defense against oxidative stress and depresses apoptotic genes in a model of neonatal brain hypoxia/ischemia interpreted as pharmacological preconditioning. We conclude that beta1-adrenoceptor activation might be an efficient strategy for identifying novel pharmacological targets for protection of the neonatal brain.
Highlights
Labor subjects the fetus to an hypoxic episode and concomitant adrenomodullary catecholamine surge that may provide protection against the hypoxic insult
Neuroprotective treatment with dobutamine depresses expression of inflammatory mediators and promotes the defense against oxidative stress and depresses apoptotic genes in a model of neonatal brain hypoxia/ ischemia interpreted as pharmacological preconditioning
Beta1-adrenoceptor activation was neuroprotective against oxygen–glucose deprivation (OGD) without pre-exposure to LPS as well as in hippocampal slices lacking tumor necrosis factor receptor 1 (TNFR1), indicating that beta1-adrenoceptors may activate a broad panel of neuroprotective mechanisms
Summary
Labor subjects the fetus to an hypoxic episode and concomitant adrenomodullary catecholamine surge that may provide protection against the hypoxic insult. The beta1-adrenergic agonist dobutamine protects against hypoxia/aglycemia induced neuronal damage. During the neonatal period, inflammation and infections may sensitize the immature brain and, subsequent to an Markus et al BMC Neurosci (2018) 19:9 lesions in the locus coeruleus caused a decreased noradrenergic input which is associated with aggravated cortical and hippocampal damage following global cerebral ischemia [5]. We have earlier shown that beta1-adrenoceptor activation provides a robust neuroprotection in the setting of LPS-induced inflammation and oxygen–glucose deprivation (OGD) in a neonatal murine organtypic hippocampal slice culture system [8]. The neuroprotective effect was associated with decreased levels of secreted pro-inflammatory cytokines, including tumor necrosis factor a (TNFα), supporting the notion of an antiinflammatory action of beta1-adrenoceptor activation. Astrocytes treated with adrenergic agonists secrete brainderived neurotrophic factor which could mitigate apoptosis [10]
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