Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice.
Blood-brain barrier (BBB) dysfunction is considered to be an early event in the pathogenesis of a variety of neurological diseases in old patients, and this could occur in old people even when facing common stress. However, the mechanism remains to be defined. In this study, we tested the hypothesis that decreased melatonin levels may account for the BBB disruption in old mice challenged with lipopolysaccharide (LPS), which mimicked the common stress of sepsis. Mice (24-28 months of age) received melatonin (10 mg kg-1day-1, intraperitoneally, i.p.) or saline for one week before exposing to LPS (1 mg kg-1, i.p.). Evan's blue dye (EB) and immunoglobulin G (IgG) leakage were used to assess BBB permeability. Immunostaining and Western blot were used to detect protein expression and distribution. Our results showed that LPS significantly increased BBB permeability in old mice accompanied by the degradation of tight junction proteins occludin and claudin-5, suppressed AMP-activated protein kinase (AMPK) activation, and elevated gp91phoxprotein expression. Interestingly, administration of melatonin for one week significantly decreased LPS-induced BBB disruption, AMPK suppression, and gp91phoxupregualtion. Moreover, activation of AMPK with metformin significantly inhibited LPS-induced gp91phoxupregualtion in endothelial cells. Taken together, our findings demonstrate that melatonin alleviates LPS-induced BBB disruption through activating AMPK and inhibiting gp91phoxupregulation in old mice.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Xiaona
X
Wang
Suzhou Municipal Hospital, Suzhou, 215002, China.
Gai-Xiu
GX
Xue
Department of Emergency, Shanxi Provincial People's Hospital, Taiyuan, 030001, China.
Wen-Cao
WC
Liu
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Hui
H
Shu
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Mengwei
M
Wang
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Yanyun
Y
Sun
Translational Center for Stem Cell Research, Tongji Hospital, Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 200065, China.
Xiaojing
X
Liu
Translational Center for Stem Cell Research, Tongji Hospital, Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 200065, China.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Yi Eve
YE
Sun
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.|Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China.
Chun-Feng
CF
Liu
Translational Center for Stem Cell Research, Tongji Hospital, Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 200065, China.
Jie
J
Liu
The Central Laboratory, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China.
Wenlan
W
Liu
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Xinchun
X
Jin
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008550:Melatonin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D062725:Tight Junction Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D008070:Lipopolysaccharides; D062725:Tight Junction Proteins; D019255:NADPH Oxidases; D055372:AMP-Activated Protein Kinases; D008550:Melatonin

AMPK
; Melatonin; blood-brain barrier; lipopolysaccharide; old mice; tight junction protein