Abstract
Microvascular hyperpermeability that occurs at the level of the blood-brain barrier (BBB) often leads to vasogenic brain edema and elevated intracranial pressure following traumatic brain injury (TBI). At a cellular level, tight junction proteins (TJPs) between neighboring endothelial cells maintain the integrity of the BBB via TJ associated proteins particularly, zonula occludens-1 (ZO-1) that binds to the transmembrane TJPs and actin cytoskeleton intracellularly. The pro-inflammatory cytokine, interleukin-1β (IL-1β) as well as the proteolytic enzymes, matrix metalloproteinase-9 (MMP-9) are key mediators of trauma-associated brain edema. Recent studies indicate that melatonin a pineal hormone directly binds to MMP-9 and also might act as its endogenous inhibitor. We hypothesized that melatonin treatment will provide protection against TBI-induced BBB hyperpermeability via MMP-9 inhibition. Rat brain microvascular endothelial cells grown as monolayers were used as an in vitro model of the BBB and a mouse model of TBI using a controlled cortical impactor was used for all in vivo studies. IL-1β (10 ng/mL; 2 hours)-induced endothelial monolayer hyperpermeability was significantly attenuated by melatonin (10 μg/mL; 1 hour), GM6001 (broad spectrum MMP inhibitor; 10 μM; 1 hour), MMP-9 inhibitor-1 (MMP-9 specific inhibitor; 5 nM; 1 hour) or MMP-9 siRNA transfection (48 hours) in vitro. Melatonin and MMP-9 inhibitor-1 pretreatment attenuated IL-1β-induced MMP-9 activity, loss of ZO-1 junctional integrity and f-actin stress fiber formation. IL-1β treatment neither affected ZO-1 protein or mRNA expression or cell viability. Acute melatonin treatment attenuated BBB hyperpermeability in a mouse controlled cortical impact model of TBI in vivo. In conclusion, one of the protective effects of melatonin against BBB hyperpermeability occurs due to enhanced BBB integrity via MMP-9 inhibition. In addition, acute melatonin treatment provides protection against BBB hyperpermeability in a mouse model of TBI indicating its potential as a therapeutic agent for brain edema when established in humans.
Highlights
Microvascular hyperpermeability is the abnormal extravasation of plasma proteins and fluid into extravascular space and often results in vasogenic edema
The results from this study demonstrate that melatonin has protective effects against IL-1βinduced blood-brain barrier (BBB) dysfunction and hyperpermeability in vitro via matrix metalloproteinase-9 (MMP-9) inhibition and by maintaining tight junctional and cytoskeletal integrity
The results show that IL-1β-induced acute barrier dysfunctions are not due to alterations in endothelial cell viability or a decrease in the content or expression of the key tight junction associated protein zonula occludens-1 (ZO-1)
Summary
Microvascular hyperpermeability is the abnormal extravasation of plasma proteins and fluid into extravascular space and often results in vasogenic edema. Hyperpermeability in the brain occurs at the level of the blood-brain barrier (BBB). The key structural and functional elements that maintain the integrity of the BBB are the tight junctions between the neighboring endothelial cells [1]. Zonula occludens-1 (ZO-1) acts as a scaffolding molecule mediating the link between the transmembrane tight junctions and the actin cytoskeleton [1]. It plays an important role in maintaining the important properties of the BBB including resistance and permeability [1]. Alterations in BBB integrity leading to hyperpermeability and vasogenic edema often occur following inflammation [2,3]
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