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

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4443-4454
Number of pages12
JournalJournal of Immunology
Volume186
Issue number7
DOIs
Publication statusPublished - 2011 Apr 1

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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