β-Adrenoceptor activation depresses brain inflammation and is neuroprotective in lipopolysaccharide-induced sensitization to oxygen-glucose deprivation in organotypic hippocampal slices

Background: 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).method: 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.results: 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.conclusions: 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. © 2010 markus et al; licensee biomed central ltd.