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Theses and Dissertations

Characterizing the mode of action of super long-acting beta2-adrenergic receptor agonists: A more effective therapeutic for Parkinson's disease. Open Access


Other title
Parkinson's disease
Anti-inflammatory conversion
kinetics of action
Type of item
Degree grantor
University of Alberta
Author or creator
Arbabzada, Naik Bakht
Supervisor and department
Dr. Patrick Flood (Centre for Neuroscience)
Dr. Maria Febbraio (Dentistry)
Dr. Thomas Simmen (Cell Biology)
Examining committee member and department
Dr. Patrick Flood (Centre for Neuroscience)
Dr. Thomas Simmen (Cell Biology)
Dr. Maria Febbraio (Dentistry)
Dr. Simonetta Sipione (Centre for Neuroscience)
Centre for Neuroscience

Date accepted
Graduation date
2016-06:Fall 2016
Master of Science
Degree level
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons in the Substantia nigra (SN) resulting in hypokinetic motor movements. The long-acting beta2-adrenergic receptor (β2-AR) agonist salmeterol has been shown to be neuroprotective in animal models of PD. Salmeterol was found to work by inhibiting the inflammatory response of microglial cells (Qian et al., 2011), a key cell in the pathogenesis of PD. Recently, super long-acting β2-AR agonists vilanterol and indacaterol have been described; the objective of this study was to examine the effects of these super long-acting agonists on the inflammatory response of the microglial cell line BV-2, and compare their mode of action to that of the long-acting agonist salmeterol. We report that the super long-acting agonists were more effective in inhibiting TNF-alpha then the long-acting agonists, and that all three agonists enhanced IL-10 cytokine release from stimulated BV-2 cells. Furthermore, like salmeterol, indacaterol and vilanterol also exerted their inhibitory effect on TNF-α through the inhibition of NF-kappaB in a TAK-1 and beta-arrestin2-dependent but PKA-independent manner. In contrast, the IL-10 effect was NF-kappaB, TAK1, and PKA-dependent but beta-arrestin2-independent. Furthermore, inhibition of all three MAPKs (ERK1/2, JNK, and p38) consistently synergized with the long-acting agonist salmeterol to further inhibit TNF-alpha but not with the super long-acting agonists. As well, JNK activity is needed to reverse IL-10 enhancement by all three 2-AR agonists. Combined, our data suggests that beta2-AR agonists mediate an anti-inflammatory conversion in the cytokine phenotype of activated microglial cells. These findings provide insight into how β2-AR agonists’ work to reverse the Central Nervous System (CNS) inflammation that occurs in PD. Characterization and validation of the reported data in in vivo models of PD will assist in selecting the more effective beta2-AR agonist as an adjunct therapy for PD.
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