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1.
J Neuroimmunol ; 332: 37-48, 2019 07 15.
Article in English | MEDLINE | ID: mdl-30933849

ABSTRACT

Fundamentally, microglia have two activation states, a pro-inflammatory neurotoxic (M1) and an anti-inflammatory neuroprotective (M2) phenotype, and their conversion from M1-like to M2-like microglia may provide therapeutic benefits to prevent neuronal loss in neurodegenerative diseases such as Parkinson's disease (PD). Previously, we showed that Salmeterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, has neuroprotective effects in PD models in vitro and in vivo through the ß-arrestin2-dependent inhibition of pro-inflammatory M1-type mediator production. In the present study, we explored whether Salmeterol can mediate phenotypic conversion in LPS-activated murine microglial BV2 cells from the neurotoxic M1-like to a neuroprotective M2-like phenotype. Salmeterol inhibited the production of LPS-induced mediators of the pro-inflammatory M1 phenotype such as tumor necrosis factor-α (TNF-α), IL-(interleukin) 18, IL-6, chemokines (CCL2, CCL3, CCL4) and reactive oxygen species from BV2 cells. Conversely, treatment with Salmeterol and other ß2-AR agonists robustly enhances the production of the M2 cytokine IL-10 from LPS-activated microglia. In addition, Salmeterol upregulates the expression of arginase-1 and CXCL14. Furthermore, using siRNA approach we found that silencing of the transcription factor Creb abrogates the Salmeterol-mediated production of IL-10 in LPS-activated BV2 cells, but silencing of ß-arrestin2 with Arrb2 siRNA did not. In addition, our data shows conversion from an M1- to M2-like phenotype in LPS-activated microglia by ß2-AR agonists involves activation of the classical cAMP/PKA/CREB as well as the PI3K and p38 MAPK signaling pathways, and provides a novel therapeutic approach targeting microglial cell activation and inducing their phenotypic conversion in the treatment of neuroinflammatory diseases such as PD.


Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacology , Microglia/drug effects , Salmeterol Xinafoate/pharmacology , Signal Transduction/drug effects , Animals , Biomarkers , Cell Line , Cyclic AMP Response Element-Binding Protein/physiology , Cytokines/biosynthesis , Endotoxins/pharmacology , Gene Expression Regulation/drug effects , Inflammation , Interleukin-10/biosynthesis , Interleukin-10/physiology , MAP Kinase Signaling System/drug effects , Mice , Phenotype , Phosphatidylinositol 3-Kinases/physiology , RNA Interference , Reactive Oxygen Species/metabolism
2.
Front Comput Neurosci ; 9: 116, 2015.
Article in English | MEDLINE | ID: mdl-26441625

ABSTRACT

When quadrupeds stop walking after stepping over a barrier with their forelegs, the memory of barrier height and location is retained for many minutes. This memory is subsequently used to guide hind leg movements over the barrier when walking is resumed. The upslope of the initial trajectory of hind leg paw movements is strongly dependent on the initial location of the paw relative to the barrier. In this study, we have attempted to determine whether mechanical factors contribute significantly in establishing the slope of the paw trajectories by creating a four-link biomechanical model of a cat hind leg and driving this model with a variety of joint-torque profiles, including average torques for a range of initial paw positions relative to the barrier. Torque profiles for individual steps were determined by an inverse dynamic analysis of leg movements in three normal cats. Our study demonstrates that limb mechanics can contribute to establishing the dependency of trajectory slope on the initial position of the paw relative to the barrier. However, an additional contribution of neuronal motor commands was indicated by the fact that the simulated slopes of paw trajectories were significantly less than the observed slopes. A neuronal contribution to the modification of paw trajectories was also revealed by our observations that both the magnitudes of knee flexor muscle EMG bursts and the initial knee flexion torques depended on initial paw position. Previous studies have shown that a shift in paw position prior to stepping over a barrier changes the paw trajectory to be appropriate for the new paw position. Our data indicate that both mechanical and neuronal factors contribute to this updating process, and that any shift in leg position during the delay period modifies the working memory of barrier location.

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