Anti-neuroinflammatory effect of Sophoraflavanone G from Sophora alopecuroides in LPS-activated BV2 microglia by MAPK, JAK/STAT and Nrf2/HO-1 signaling pathways.
BACKGROUND
Neuroinflammation plays a vital role in Alzheimer's disease (AD) and other neurodegenerative conditions. Sophora alopecuroides is widely used in traditional Uighur's medicine for the treatment of inflammation. Sophoraflavanone G (SG), a major flavonoid found in the S. alopecuroides, has also been reported to exhibit anti-inflammatory activity both in vitro and in vivo. However, the effect of S. alopecuroides and SG on microglia-mediated neuroinflammation has not been investigated.


OBJECTIVE
The present study was designed to evaluate the anti-neuroinflammatory effect of S. alopecuroides and SG against lipopolysaccharide (LPS)-activated BV2 microglial cells and to explore the underlying mechanisms.


METHODS
We measured the production of pro-inflammatory mediators and cytokines, and analyzed relevant mRNA and protein expressions by qRT-PCR and Western Blot.


RESULTS
S. alopecuroides extract (SAE) and SG inhibited the LPS-induced release of nitric oxide (NO), prostaglandin E2(PGE2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). Additionally, SG reduced gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, IL-6 and IL-1β, and further decreased the protein expressions of iNOS and COX-2. Mechanism studies found that SG down-regulated phosphorylated mitogen-activated protein kinases (MAPKs), phosphoinositide-3-kinase (PI3K)/AKT and Janus kinase/signal transducer and activator of transcription (JAK/STAT), and up-regulated heme oxygenase-1 (HO-1) expression via nuclear translocation of nuclear factor E2-related factor 2 (Nrf2). In addition, SG inhibited the cytotoxicity of conditioned medium prepared by LPS-activated BV2 microglia to neuronal PC12 cells and improved cell viability.


CONCLUSIONS
S. alopecuroides and SG displayed anti-neuroinflammatory activity in LPS-activated BV2 microglia. SG was able to inhibit the neuroinflammation by MAPKs, PI3K/AKT, JAK/STAT and Nrf2/HO-1 signaling pathways and might act as a natural therapeutic agent to be further developed for the treatment of various neuroinflammatory conditions.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Chao
C
Guo
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Lei
L
Yang
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Chuan-Xing
CX
Wan
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Yuan-Zheng
YZ
Xia
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Chao
C
Zhang
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Meng-Han
MH
Chen
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Zhen-Dong
ZD
Wang
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Zhong-Rui
ZR
Li
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Xue-Mei
XM
Li
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Ya-Di
YD
Geng
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: cpu_lykong@126.com.
Ling-Yi
LY
Kong
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D029909:Sophora / Q000737:chemistry*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D044950:Flavanones; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D050791:STAT Transcription Factors; D009569:Nitric Oxide; C064849:vexibinol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone
BV2; LPS; Neuroinflammation; Sophoraflavanone G