ß-Adrenoceptor activation depresses brain inflammation and is neuroprotective in lipopolysaccharide-induced sensitization to oxygen-glucose deprivation in organotypic hippocampal slices.
J Neuroinflammation
; 7: 94, 2010 Dec 20.
Article
em En
| MEDLINE
| ID: mdl-21172031
ABSTRACT
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 ß 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 ß1(dobutamine)-, ß2(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 ß1-agonist (50 µM) during LPS exposure before OGD conferred complete protection from cell death (P < 0.001) whereas the ß2-agonist (50 µM) was partially protective (p < 0.01). Phenylephrine was weakly protective while no protection was attained by clonidine. Exposure to both ß1- and ß2-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 ß1- and ß2-receptors is neuroprotective and may offer mechanistic insights valuable for development of neuro-protective strategies in neonates.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxigênio
/
Isquemia Encefálica
/
Lipopolissacarídeos
/
Receptores Adrenérgicos beta
/
Encefalite
/
Glucose
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Hipocampo
Limite:
Animals
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article