Abstract
BackgroundInflammation acting in synergy with brain ischemia aggravates perinatal ischemic brain damage. The sensitizing effect of pro-inflammatory exposure prior to hypoxia is dependent on signaling by TNF-α through TNF receptor (TNFR) 1. Adrenoceptor (AR) activation is known to modulate the immune response and synaptic transmission. The possible protective effect of and AR activation against neuronal damage caused by tissue ischemia and inflammation, acting in concert, was evaluated in murine hippocampal organotypic slices treated with lipopolysaccharide (LPS) and subsequently subjected to oxygen-glucose deprivation (OGD).MethodHippocampal slices from mice were obtained at P6, and were grown in vitro for 9 days on nitrocellulose membranes. Slices were treated with β1(dobutamine)-, β2(terbutaline)-, α1(phenylephrine)- and α2(clonidine)-AR agonists (5 and 50 μM, respectively) during LPS (1 μg/mL, 24 h) -exposure followed by exposure to OGD (15 min) in a hypoxic chamber. Cell death in the slice CA1 region was assessed by propidium iodide staining of dead cells.ResultsExposure to LPS + OGD caused extensive cell death from 4 up to 48 h after reoxygenation. Co-incubation with β1-agonist (50 μM) during LPS exposure before OGD conferred complete protection from cell death (P < 0.001) whereas the β2-agonist (50 μM) was partially protective (p < 0.01). Phenylephrine was weakly protective while no protection was attained by clonidine. Exposure to both β1- and β2-agonist during LPS exposure decreased the levels of secreted TNF-α, IL-6 and monocyte chemoattractant protein-1 and prevented microglia activation in the slices. Dobutamine remained neuroprotective in slices exposed to pure OGD as well as in TNFR1-/- and TNFR2-/- slices exposed to LPS followed by OGD.ConclusionsOur data demonstrate that activation of both β1- and β2-receptors is neuroprotective and may offer mechanistic insights valuable for development of neuro-protective strategies in neonates.
Highlights
Inflammation acting in synergy with brain ischemia aggravates perinatal ischemic brain damage
Phenylephrine was weakly protective while no protection was attained by clonidine. Exposure to both b1- and b2-agonist during LPS exposure decreased the levels of secreted tumor necrosis factor (TNF)-a, IL-6 and monocyte chemoattractant protein-1 and prevented microglia activation in the slices
Dobutamine remained neuroprotective in slices exposed to pure oxygen-glucose deprivation (OGD) as well as in TNF receptor 1 (TNFR1)-/and TNFR2-/- slices exposed to LPS followed by OGD
Summary
Inflammation acting in synergy with brain ischemia aggravates perinatal ischemic brain damage. The possible protective effect of and AR activation against neuronal damage caused by tissue ischemia and inflammation, acting in concert, was evaluated in murine hippocampal organotypic slices treated with lipopolysaccharide (LPS) and subsequently subjected to oxygen-glucose deprivation (OGD). Perinatal hypoxia-ischemia remains an important cause of brain damage which may result in long-term impairment including cerebral palsy and mental retardation. We speculated that CA release at very preterm birth may be causal in generating a circulating anti-inflammatory response. This is supported by in vitro studies showing that exposure of both peripheral immune cells and microglia to adrenergic agonists causes a suppression of stimulated release of the proinflammatory cytokine TNF-a with an increase in IL-10 [3,4]
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