TY - JOUR
T1 - β2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway
AU - Qian, Li
AU - Wu, Hungming
AU - Chen, Shih Heng
AU - Zhang, Dan
AU - Ali, Syed F.
AU - Peterson, Lynda
AU - Wilson, Belinda
AU - Lu, Ru Band
AU - Hong, Jau Shyong
AU - Flood, Patrick M.
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/4/1
Y1 - 2011/4/1
N2 - The role of the β 2 adrenergic receptor (β 2AR) in the regulation of chronic neurodegenerative inflammation within the CNS is poorly understood. The purpose of this study was to determine neuroprotective effects of long-acting β 2AR agonists such as salmeterol in rodent models of Parkinson's disease. Results showed salmeterol exerted potent neuroprotection against both LPS and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4- phenylpyridinium-induced dopaminergic neurotoxicity both in primary neuron-glia cultures (at subnanomolar concentrations) and in mice (1-10 μg/kg/day doses). Further studies demonstrated that salmeterol-mediated neuroprotection is not a direct effect on neurons; instead, it is mediated through the inhibition of LPSinduced microglial activation. Salmeterol significantly inhibited LPS-induced production of microglial proinflammatory neurotoxic mediators, such as TNF-α, superoxide, and NO, as well as the inhibition of TAK1-mediated phosphorylation of MAPK and p65 NF-kB. The anti-inflammatory effects of salmeterol required β 2AR expression in microglia but were not mediated through the conventional G protein-coupled receptor/cAMP pathway. Rather, salmeterol failed to induce microglial cAMP production, could not be reversed by either protein kinase A inhibitors or an exchange protein directly activated by cAMP agonist, and was dependent on β-arrestin2 expression. Taken together, our results demonstrate that administration of extremely low doses of salmeterol exhibit potent neuroprotective effects by inhibiting microglial cell activation through a β2AR/β-arrestin2-dependent but cAMP/protein kinase A-independent pathway.
AB - The role of the β 2 adrenergic receptor (β 2AR) in the regulation of chronic neurodegenerative inflammation within the CNS is poorly understood. The purpose of this study was to determine neuroprotective effects of long-acting β 2AR agonists such as salmeterol in rodent models of Parkinson's disease. Results showed salmeterol exerted potent neuroprotection against both LPS and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4- phenylpyridinium-induced dopaminergic neurotoxicity both in primary neuron-glia cultures (at subnanomolar concentrations) and in mice (1-10 μg/kg/day doses). Further studies demonstrated that salmeterol-mediated neuroprotection is not a direct effect on neurons; instead, it is mediated through the inhibition of LPSinduced microglial activation. Salmeterol significantly inhibited LPS-induced production of microglial proinflammatory neurotoxic mediators, such as TNF-α, superoxide, and NO, as well as the inhibition of TAK1-mediated phosphorylation of MAPK and p65 NF-kB. The anti-inflammatory effects of salmeterol required β 2AR expression in microglia but were not mediated through the conventional G protein-coupled receptor/cAMP pathway. Rather, salmeterol failed to induce microglial cAMP production, could not be reversed by either protein kinase A inhibitors or an exchange protein directly activated by cAMP agonist, and was dependent on β-arrestin2 expression. Taken together, our results demonstrate that administration of extremely low doses of salmeterol exhibit potent neuroprotective effects by inhibiting microglial cell activation through a β2AR/β-arrestin2-dependent but cAMP/protein kinase A-independent pathway.
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U2 - 10.4049/jimmunol.1002449
DO - 10.4049/jimmunol.1002449
M3 - Article
C2 - 21335487
AN - SCOPUS:79955000817
VL - 186
SP - 4443
EP - 4454
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -