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- Title
β-Adrenoceptor activation depresses brain inflammation and is neuroprotective in lipopolysaccharide-induced sensitization to oxygen-glucose deprivation in organotypic hippocampal slices.
- Authors
Markus, Tina; Hansson, Stefan R; Cronberg, Tobias; Cilio, Corrado; Wieloch, Tadeusz; Ley, David
- Abstract
<bold>Background: </bold>Inflammation 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 α and β 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).<bold>Method: </bold>Hippocampal 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.<bold>Results: </bold>Exposure 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.<bold>Conclusions: </bold>Our 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.
- Publication
Journal of Neuroinflammation, 2010, Vol 7, p94
- ISSN
1742-2094
- Publication type
journal article
- DOI
10.1186/1742-2094-7-94