beta-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-alpha through TNF receptor (TNFR) 1. Adrenoceptor (AR) activation is known to modulate the immune response and synaptic transmission. The possible protective effect of (alpha) over tilde and (beta) over tilde 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 beta 1(dobutamine)-, beta 2(terbutaline)-, alpha 1(phenylephrine)- and alpha 2(clonidine)-AR agonists (5 and 50 mu M, respectively) during LPS (1 mu g/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 beta 1-agonist (50 mu M) during LPS exposure before OGD conferred complete protection from cell death (P < 0.001) whereas the beta 2-agonist (50 mu M) was partially protective (p < 0.01). Phenylephrine was weakly protective while no protection was attained by clonidine. Exposure to both beta 1-and beta 2-agonist during LPS exposure decreased the levels of secreted TNF-alpha, 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 beta 1-and beta 2-receptors is neuroprotective and may offer mechanistic insights valuable for development of neuro-protective strategies in neonates.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Publication and Content Type

art (subject category)

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