Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice

Abstract

SummaryBlood–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−1 day−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 gp91phox protein expression. Interestingly, administration of melatonin for one week significantly decreased LPS‐induced BBB disruption, AMPK suppression, and gp91phox upregualtion. Moreover, activation of AMPK with metformin significantly inhibited LPS‐induced gp91phox upregualtion in endothelial cells. Taken together, our findings demonstrate that melatonin alleviates LPS‐induced BBB disruption through activating AMPK and inhibiting gp91phox upregulation in old mice.

Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

“…Moreover, melatonin alleviates lipopolysaccharide-mediated blood-brain barrier damage via AMPK signaling pathway activation. 64 Consistent with the previous studies, our study also reported that AMPK, signaled by melatonin, and contributed to the OPA1 stabilization and mitochondrial fusion/mitophagy activation, ultimately sending pro-survival signals for the reperfused heart and mitochondria.…”

“…In the model of doxorubicin cardiotoxicity and cardiac microvascular I/R injury, melatonin activates the AMPK signaling pathway to improve cardiomyocyte and endothelial cell survival via the modulation of mitochondrial oxidative stress and mitochondrial dynamics. Moreover, melatonin alleviates lipopolysaccharide‐mediated blood‐brain barrier damage via AMPK signaling pathway activation . Consistent with the previous studies, our study also reported that AMPK, signaled by melatonin, and contributed to the OPA1 stabilization and mitochondrial fusion/mitophagy activation, ultimately sending pro‐survival signals for the reperfused heart and mitochondria.…”

Melatonin Supplementation, a Strategy to Prevent Neurological Diseases through Maintaining Integrity of Blood Brain Barrier in Old People

“…Worth of note, LPS has been shown to increase BBB permeability in vitro (Nonaka et al, 2004) and compromise BBB integrity in young (Ruiz-Valdepeñas et al, 2011; Zhou T. et al, 2014) and old mice (Wang et al, 2017). More interesting, LPS has been shown to induce BBB dysfunction via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS (Liu et al, 2012; Zhao et al, 2014).…”

“…Interestingly, AMPK activation has been shown to alleviate LPS-induced BBB disruption in both in vitro cell model (Zhao et al, 2014) and in vivo mice model (Zhou X. et al, 2014; Wang et al, 2017). Activation of AMPK also demonstrated protective effect against diabetes-induced BBB damage by inhibiting NADPH oxidase expression upregulation in brain capillary endothelial cells (Liu et al, 2012).…”

AMP-activated protein kinase activation: therapeutic potential in human diseases

“…AMPK activity declines with advancing age in various murine tissues, particularly the aorta and cerebral arteries [6]. Endothelial dysfunction induced by lipopolysaccharide was ameliorated in ageing mice after treatment with the AMPK activator metformin [7]. Moreover, loss of sirtuin 2 (SIRT2), a cytosolic member of the sirtuin family, aggravated age-related cardiac hypertrophy by reducing AMPK activation [8].…”