Guangda Yao1, Zijun Bai1, Jianguo Niu1, Rui Zhang1, Youyuan Lu1, Tiantian Gao1, Hanqing Wang2,3,4. 1. College of Pharmacy, Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Ningxia, Yinchuan, 750004, China. 2. College of Pharmacy, Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Ningxia, Yinchuan, 750004, China. hqwangnx@tom.com. 3. Ningxia Engineering and Technology Research Center for Modernization of Regional Characteristic Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, 750004, China. hqwangnx@tom.com. 4. Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China. hqwangnx@tom.com.
Abstract
RATIONALE: Neuroinflammation can be alleviated via M2 microglia polarization, which could promote the recovery of perimenopausal depression. Astragalin (AST) possesses anti-neuroinflammatory activity. However, the effects of AST on perimenopausal depression and the molecular mechanism in regulating microglia polarization remained unknown. OBJECTIVES: The purpose was to investigate the effects of AST on mice with simulated perimenopausal depression through regulating microglia polarization. It was aimed to clarify the molecular mechanism related to the interleukin-4 receptor (IL-4R)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 6 signaling pathway. METHODS: The ovariectomy (OVX)/chronic unpredictable mild stress (CUMS)-induced murine model of perimenopausal depression was established and treated with AST. Then the depression-like behaviors and cognitive ability of mice were examined. After that, we detected the markers of microglia polarization and its regulatory signals. In addition, lipopolysaccharides (LPS)/adenosine triphosphate (ATP)-induced inflammatory BV2 model were used to verify the potential molecular mechanism. RESULTS: AST alleviated perimenopausal depression-like behaviors and memory deficits. AST alleviated microglia activation and increased Ki67-positive cells in dentate gyrus (DG). The viability of BV2 decreased by LPS/ATP was raised by AST. Moreover, both in vivo and in vitro, AST switched microglia from M1 phenotype caused by OVX/CUMS or LPS/ATP to M2 phenotype. The IL-4R/JAK1/STAT6 signaling was restored, and the levels of inducible nitric oxide synthase (iNOS), nuclear NF-KappaB-p65 were reduced by AST. Importantly, AST showed prevention against the ubiquitination modification and degradation of STAT6. CONCLUSIONS: Our results revealed new insights into molecular mechanism associated with microglia polarization in the effect of AST on the mouse model of perimenopausal depression.
RATIONALE: Neuroinflammation can be alleviated via M2 microglia polarization, which could promote the recovery of perimenopausal depression. Astragalin (AST) possesses anti-neuroinflammatory activity. However, the effects of AST on perimenopausal depression and the molecular mechanism in regulating microglia polarization remained unknown. OBJECTIVES: The purpose was to investigate the effects of AST on mice with simulated perimenopausal depression through regulating microglia polarization. It was aimed to clarify the molecular mechanism related to the interleukin-4 receptor (IL-4R)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 6 signaling pathway. METHODS: The ovariectomy (OVX)/chronic unpredictable mild stress (CUMS)-induced murine model of perimenopausal depression was established and treated with AST. Then the depression-like behaviors and cognitive ability of mice were examined. After that, we detected the markers of microglia polarization and its regulatory signals. In addition, lipopolysaccharides (LPS)/adenosine triphosphate (ATP)-induced inflammatory BV2 model were used to verify the potential molecular mechanism. RESULTS: AST alleviated perimenopausal depression-like behaviors and memory deficits. AST alleviated microglia activation and increased Ki67-positive cells in dentate gyrus (DG). The viability of BV2 decreased by LPS/ATP was raised by AST. Moreover, both in vivo and in vitro, AST switched microglia from M1 phenotype caused by OVX/CUMS or LPS/ATP to M2 phenotype. The IL-4R/JAK1/STAT6 signaling was restored, and the levels of inducible nitric oxide synthase (iNOS), nuclear NF-KappaB-p65 were reduced by AST. Importantly, AST showed prevention against the ubiquitination modification and degradation of STAT6. CONCLUSIONS: Our results revealed new insights into molecular mechanism associated with microglia polarization in the effect of AST on the mouse model of perimenopausal depression.
Authors: Garnet L Anderson; Marian Limacher; Annlouise R Assaf; Tamsen Bassford; Shirley A A Beresford; Henry Black; Denise Bonds; Robert Brunner; Robert Brzyski; Bette Caan; Rowan Chlebowski; David Curb; Margery Gass; Jennifer Hays; Gerardo Heiss; Susan Hendrix; Barbara V Howard; Judith Hsia; Allan Hubbell; Rebecca Jackson; Karen C Johnson; Howard Judd; Jane Morley Kotchen; Lewis Kuller; Andrea Z LaCroix; Dorothy Lane; Robert D Langer; Norman Lasser; Cora E Lewis; JoAnn Manson; Karen Margolis; Judith Ockene; Mary Jo O'Sullivan; Lawrence Phillips; Ross L Prentice; Cheryl Ritenbaugh; John Robbins; Jacques E Rossouw; Gloria Sarto; Marcia L Stefanick; Linda Van Horn; Jean Wactawski-Wende; Robert Wallace; Sylvia Wassertheil-Smoller Journal: JAMA Date: 2004-04-14 Impact factor: 56.272
Authors: Christoph Anacker; Victor M Luna; Gregory S Stevens; Amira Millette; Ryan Shores; Jessica C Jimenez; Briana Chen; René Hen Journal: Nature Date: 2018-06-27 Impact factor: 49.962