Neuropharmacology

Blood-brain barrier (BBB) dysfunction following traumatic brain injury (TBI) often leads to vasogenic brain edema and elevated intracranial pressure. The BBB consists of tight junctions (TJs) between neighboring endothelial cells

that 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 enzyme, matrix metalloproteinase-9 (MMP-9) are mediators of BBB dysfucntions and brain edema. Recent studies demonstrated that the pineal hormone melatonin can inhibit MMP-9 by binding to its catlytic site. We hypothesized that melatonin will protect the BBB agaisnt TBI-induced hyperpermeability via MMP-9 inhibition and conducted in vitro

studies using rat brain microvascular endothelial cell monolayers and using a mouse controlled cortial impact model TBI. Our results show that IL-1β induces TJ disruption and brain endothelial monolayer hyperpermeability that was attenuated by melatonin treatment or MMP-9 inhibition. Melatonin treatment attenuated IL-1β-induced MMP-9 activity, loss of ZO-1 at the TJs and alteration in the actin cytosletal assembly without affecting ZO-1 protein/ mRNA expression or cell viability. Melatonin treatment prior to or after TBI protecetd the BBB in the mouse model of TBI. These studies demonstrate that

melatonin treatment provides protection against BBB hyperpermeability following TBI indicating its potential as a therapeutic agent for brain edema. Also, one of the protective effects of melatonin against BBB hyperpermeability occurs due to enhanced BBB integrity via MMP-9 inhibition.