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Neurosci Lett. 2016 Apr 21;619:34-42. doi: 10.1016/j.neulet.2016.02.021. Epub 2016 Feb 12.

Z-guggulsterone negatively controls microglia-mediated neuroinflammation via blocking IκB-α-NF-κB signals.

Author information

1
Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
2
Department of Anesthesiology, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong, Jiangsu Province 226001, China. Electronic address: charliechao888888@163.com.
3
Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China. Electronic address: asicampa@aliyun.com.

Abstract

Induction of pro-inflammatory factors is one of the characteristics of microglial activation and can be regulated by numerous active agents extracted from plants. Suppression of pro-inflammatory factors is beneficial to alleviate neuroinflammation. Z-guggulsterone, a compound extracted from the gum resin of the tree commiphora mukul, exhibits numerous anti-inflammatory effects. However, the role and mechanism of Z-guggulsterone in pro-inflammatory responses in microglia remains unclear. This study addressed this issue in in vitro murine microglia and in vivo neuroinflammation models. Results showed that Z-guggulsterone reduced inducible nitric oxide (iNOS) protein expression as well as nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production in LPS-stimulated BV-2 cells. Z-guggulsterone also reduced the mRNA level of iNOS, TNF-α, and IL-6. Mechanistic studies revealed that Z-guggulsterone attenuated the LPS-induced degradation of inhibitor κ B-α (IκB-α) as well as the LPS-induced nuclear translocation of nuclear factor-κB (NF-κB). Z-guggulsterone, however, failed to reduce the LPS-induced increase in NF-κB phosphorylation level. These major findings were ascertained in primary microglia where the LPS-induced increases in iNOS expression, NO content, and IκB-α degradation were diminished by Z-guggulsterone treatment. In a mouse model of neuroinflammation, Z-guggulsterone exhibited significant anti-inflammatory effects, which were exemplified by the attenuation of microglial activation and neuroinflammation-induced behavioral abnormalities in Z-guggulsterone-treated mice. Taken together, these studies demonstrate that Z-guggulsterone attenuates the LPS-mediated induction of pro-inflammatory factors in microglia via inhibition of IκB-α-NF-κB signals, providing evidence to uncover the potential role of Z-guggulsterone in neuroinflammation-associated disorder therapies.

KEYWORDS:

Inhibitor of κB-α; Lipopolysaccharide; Neuroinflammation; Nuclear factor-κB; Z-guggulsterone

PMID:
26879835
DOI:
10.1016/j.neulet.2016.02.021
[Indexed for MEDLINE]

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