Platycodigenin as Potential Drug Candidate for Alzheimer’s Disease via Modulating Microglial Polarization and Neurite Regeneration

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.

Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

“…As inhibiting M1 microglia alone is not enough, promoting M2 microglia activation simultaneously might also be required for treating neurodegenerative diseases ( Yang et al, 2019 ). Promoting microglia polarization shift from M1 to M2 phenotype may be a more prospective strategy in the therapy of neurodegenerative diseases such as AD, PD, ALS, and MS ( Wen et al, 2017 ; Zhang B. et al, 2018 ).…”

Hederagenin Modulates M1 Microglial Inflammatory Responses and Neurite Outgrowth

“…We previously reported that LPS significantly increased the production of NO at concentrations ranging from 10 to 1000 ng/mL without cell toxicity. 15 We used LPS at a concentration of 100 ng/mL for the following investigations. Different doses of HED (0.01-25 μM) were used for the 24-hour treatment of either BV2 microglia or LPS-treated microglia.…”

ω-3 DPA Protected Neurons from Neuroinflammation by Balancing Microglia M1/M2 Polarizations through Inhibiting NF-κB/MAPK p38 Signaling and Activating Neuron-BDNF-PI3K/AKT Pathways

“…BV2 microglia cells were obtained from the Institute of Biochemistry and Cell Biology (Shanghai, China) and cultured in DMEM/high medium (Hyclone, Logan, Utah, USA) supplemented with 10% fetal bovine serum (FBS, Gibco, Grand Island, New York, USA) and 1% penicillin-streptomycin (Gibco, USA) at 37 °C in a 5% CO2/95% air incubator [54].…”

“…Alexa Fluor 594-conjugated goat antimouse IgG (1:200, ab150116, Abcam, Cambridge, England) was used as secondary antibody. DAPI (Biomol, Hamburg, Germany) was used for counterstaining [54]. Fluorescence images were captured by a fluorescence microscope system (OLYMPUS IX73, Olympus, Japan).…”