The integrity and function dysfunction of the blood brain barrier(BBB)is considered to be an early event in the pathogenesis of a variety of neurological diseases in old patients and dysfunction of BBB could be induced bycommon stress that old people often face,such as sepsis during which lipopolysaccharide(LPS)is released into circulation and BBB is damaged.Since decreased melatonin level had been shown in the serum and brain of old people and mice,we aim to investigate whether supplement with melatonin could alleviate LPSinduced BBB damage in old mice.Mice(24-28 months old)received one week melatonin(10 mg·kg-1·d-1,intraperitoneally,ip)or saline before challenge with LPS(1 mg·kg-1,ip).Evan′s blue(EB)and immunoglobulin G(Ig G)leakage were used to assess the BBB permeability.Immunofluoresence and Western blotting were used to detect the protein expression and distribution.Our results showed that LPS significantly increased BBB permeability in old mice accompanied by tight junction protein occludin and claudin-5 degradation,inhibition of AMP-activated protein kinase(AMPK)activation and increase of gp91phox protein expression.Interestingly,one week of melatonin treatment significantly decreased LPS-induced BBB hyperpermeability,activated AMPK and inhibited gp91phox expression upregualtion.Moreover,activation of AMPK by metformin significantly inhibited LPS-induced gp91phox expression upregualtion in endothelial cells.Taken together,our findings demonstrate that melatonin alleviates LPS-impaired integrity of BBB by activation of AMPK and inhibition of gp91phox expression in old mice. The integrity and function dysfunction of the blood brain barrier (BBB) ​​is considered to be an early event in the pathogenesis of a variety of neurological diseases in old patients and dysfunction of BBB could be induced bycommon stress that old people often face, such as sepsis during which lipopolysaccharide (LPS) is released into circulation and BBB is damaged .ince decreased melatonin level had been shown in the serum and brain of old people and mice, we aim to investigate whether supplement with melatonin could couldiate LPSinduced BBB damage in old mice. Mice (24-28 months old) received one week of melatonin (10 mg · kg-1 · d-1, intraperitoneally, ip) or saline before challenge with LPS (1 mg · kg- EB) and immunoglobulin G (Ig G) leakage were used to assess the BBB permeability. Immunofluorescence and Western blotting were used to detect the protein expression and distribution. These results showed that LPS significantly increased BBB permeability in old mice accompanied by tight junction Inhibition of AMP-activated protein kinase (AMPK) activation and increase of gp91phox protein expression. one week of melatonin treatment significantly decreased LPS-induced BBB hyperpermeability, activated AMPK and inhibited gp91phox expression upregion. Moreover , activation of AMPK by metformin significantly inhibited LPS-induced gp91phox expression upregualtion in endothelial cells. Taken together, our findings demonstrate that melatonin alleviates LPS-impaired integrity of BBB by activation of AMPK and inhibition of gp91phox expression in old mice.