Tanshinol suppresses inflammatory factors in a rat model of vascular dementia and protects LPS-treated neurons via the MST1-FOXO3 signaling pathway.
Neuroinflammation plays an important role in vascular dementia(VD). Our previous work showed that mammalian Ste20-like kinase 1 (MST1) and the gene for a downstream transcription factor, FOXO3, play major roles in lipopolysaccharide (LPS)-induced apoptosis in hippocampal neurons. The neurotoxic effects of LPS are derived from its ability to cause an inflammatory response. We also previously showed that Tanshinol (TSL) provides neuro-protection in a rat model of VD. The present study further explores the effects of TSL on the neuroinflammatory aspects of VD and investigates whether TSL affects the MST1-FOXO3signaling pathway. VD was induced in rats using transient bilateral coronary artery occlusion. Interleukin(IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels were measured using enzyme-linked immunoabsorbent assay kits. Cell apoptosis was assessed by Hoechst 33342 staining. Protein and mRNA levels were evaluated by western blotting and quantitative polymerase chain reaction, respectively. TSL improved working memory and significantly inhibited plasma and hippocampal protein levels of IL-1β, IL-6, and TNF-α in a rat model of VD. LPS induced apoptosis in hippocampal neurons and increasedMST1 and p-FOXO3 protein expression, whereas MST1 siRNA transfection almost completely reversed LPS-induced neuronal apoptosis, indicating that LPS-induced cytotoxicity in hippocampal neurons is associated with MST1. TSL protected against LPS-induced cell apoptosis and suppressed IL-1β, IL-6, and TNF-α mRNA and protein expression as well as MST1 and p-FOXO3 protein expression in neurons. The present study provided novel mechanisms by which TSL exerts its neuroprotective activity and indicates that TSL may be a potential neuro-protective agent in VD.
Department of Neurology in Medical Healthcare Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Yishu
Y
Yang
National Research Institute of Family Planning, Beijing, China.
Lili
L
Wang
Beijing Institute of Basic Medical Sciences, Beijing, China.
Yan
Y
Wu
National Research Institute of Family Planning, Beijing, China.
Dongmei
D
Su
National Research Institute of Family Planning, Beijing, China.
Ning
N
Wang
National Research Institute of Family Planning, Beijing, China.
Jiedong
J
Wang
National Research Institute of Family Planning, Beijing, China. Electronic address: yushuiyushui@sina.com.
Cuige
C
Shi
Beijing Institute of Transfusion Medicine, Beijing, China. Electronic address: lvlp2007@sina.com.
Liping
L
Lv
National Research Institute of Family Planning, Beijing, China. Electronic address: nrifp@263.net.
Shucheng
S
Zhang
D000818:Animals; D002109:Caffeic Acids / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D015140:Dementia, Vascular / Q000150:complications / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D002109:Caffeic Acids; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C082332:macrophage stimulating protein; C585969:tanshinol; D017228:Hepatocyte Growth Factor
FOXO3; Inflammation; MST1; Tanshinol; Vascular dementia