Abstract
Neuroinflammatory microenvironment, regulating neurite regrowth and neuronal survival, plays a critical role in Alzheimer’s disease (AD). During neuroinflammation, microglia are activated, inducing the release of inflammatory or anti-inflammatory factors depending on their polarization into classical M1 microglia or alternative M2 phenotype. Therefore, optimizing brain microenvironment by small molecule-targeted microglia polarization and promoting neurite regeneration might be a potential therapeutic strategy for AD. In this study, we found platycodigenin, a naturally occurring triterpenoid, promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (LPS)-stimulated BV2 and primary microglia. Platycodigenin downregulated pro-inflammatory molecules such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and nitric oxide (NO), while upregulated anti-inflammatory cytokine IL-10. Further investigation confirmed that platycodigenin inhibited cyclooxygenase-2 (Cox2) positive M1 but increased Ym1/2 positive M2 microglial polarization in primary microglia. In addition, platycodigenin significantly decreased LPS-induced the hyperphosphorylation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 subunits. Furthermore, the inactivation of peroxisome proliferators-activated receptor γ (PPARγ) induced by LPS was completely ameliorated by platycodigenin. Platycodigenin also promoted neurite regeneration and neuronal survival after Aβ treatment in primary cortical neurons. Taken together, our study for the first time clarified that platycodigenin effectively ameliorated LPS-induced inflammation and Aβ-induced neurite atrophy and neuronal death.
Highlights
Microglia, the resident brain macrophages, are the main immuno-modulative cells in the central nervous system (CNS) [1,2]
The results indicated that platycodigenin exerts anti-inflammatory effects platycodigenin exerts anti-inflammatory effects via inhibiting M1 microglial polarization andvia inhibiting
We found that LPS treatment significantly suppressed peroxisome proliferators-activated receptor γ (PPARγ) expression (Figure 5B), as previously reported
Summary
The resident brain macrophages, are the main immuno-modulative cells in the central nervous system (CNS) [1,2]. Microglia activation is involved in the pathogenesis of a variety of neurodegenerative diseases including Alzheimer’s disease (AD) [3,4,5]. According to its different roles in immune modulation, microglia can be divided into classically activated M1 and the alternatively activated M2 phenotype [6]. M1 microglia typically release proinflammatory molecules, promote neuroinflammation, and accelerate neuronal death [7]. While activation of M2 microglia increases the secretion of anti-inflammatory factors, resulting in neurogenesis, axonal regeneration, oligodendrogenesis, and anti-neuroinflammation [8].
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