β2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway

Li Qian, Hungming Wu, Shih Heng Chen, Dan Zhang, Syed F. Ali, Lynda Peterson, Belinda Wilson, Ru Band Lu, Jau Shyong Hong, Patrick M. Flood

研究成果: Article

60 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)4443-4454
頁數12
期刊Journal of Immunology
186
發行號7
DOIs
出版狀態Published - 2011 四月 1

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Qian, L., Wu, H., Chen, S. H., Zhang, D., Ali, S. F., Peterson, L., Wilson, B., Lu, R. B., Hong, J. S., & Flood, P. M. (2011). β2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway. Journal of Immunology, 186(7), 4443-4454. https://doi.org/10.4049/jimmunol.1002449