BETA1ADRENORECEPTOR ACTIVATION PROTECTS NEURONS FROM INFLAMMATION AND HYPOXIA IN MURINE JUVENILE HIPPOCAMPAL SLICES Tina Markus, Sweden    - Biography English - 2007-10-07

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Background and aims: Adrenoreceptor activation has potent immuno-modulatory effects in several immune cell populations. Inflammation and ischemia have a synergistic efect on perinatal brain damage.We evaluated the effect of adreno-receptor activation on neuronal cell death in lipopolysaccharide- induced sensitization to hypoxia in the immature hippocampus.

Methods: Hippocampal slices from BALB/C mice obtained at P6, grown in vitro for 9 days. Slices were exposed to beta1-, beta2-, alpha1- and alpha2 receptor agonists (5 and 50 µM respectively) during 24 h LPS (1 µg/mL) exposure followed by oxygen-glucose deprivation (OGD, 15 min). Cell death was determined with propidium iodide (PI) measured by fluorescent light michroscopy and digital image analysis. Microglial activation and neuronal depletion was determined by immunohistochemistry.

Results: Exposure to LPS + OGD resulted in extensive cell death in neuronal subregions CA1,-2-3 and the dentate gyrus. Co-incubation with beta1agonist (50 µM) during LPS exposure before OGD conferred complete protection from cell death in all neuronal subregions (P < 0.001) whereas beta2agonist (50 µM) had a partially protective effect. Alpha1 and alpha2 agonists had no protective effect. The neuro-protective effect of beta1agonist was associated with decreased levels of secreted TNF-α, IL-6 and MCP-1 and inhibited morphological microglial activation. Co-exposure with beta1- and beta2 antagonists confirmed a specific beta1receptor neuroprotective effect.

Conclusions: Beta1 receptor activation had a pronounced protective effect in an in vitro model of combined inflammation and hypoxia in the immature hippocampus. Enhanced signalling through the beta1adrenoreceptor may enable neuro-protection in the context of perinatal inflammation.