Melatonin Preserves Blood-Brain Barrier Integrity and Permeability via Matrix Metalloproteinase-9 Inhibition. Academic Article uri icon


  • 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-1 (IL-1) 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-1 (10 ng/mL; 2 hours)-induced endothelial monolayer hyperpermeability was significantly attenuated by melatonin (10 g/mL; 1 hour), GM6001 (broad spectrum MMP inhibitor; 10 M; 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-1-induced MMP-9 activity, loss of ZO-1 junctional integrity and f-actin stress fiber formation. IL-1 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.

published proceedings

  • PLoS One

altmetric score

  • 32.2

author list (cited authors)

  • Alluri, H., Wilson, R. L., Anasooya Shaji, C., Wiggins-Dohlvik, K., Patel, S., Liu, Y., ... Tharakan, B.

citation count

  • 87

complete list of authors

  • Alluri, Himakarnika||Wilson, Rickesha L||Anasooya Shaji, Chinchusha||Wiggins-Dohlvik, Katie||Patel, Savan||Liu, Yang||Peng, Xu||Beeram, Madhava R||Davis, Matthew L||Huang, Jason H||Tharakan, Binu

editor list (cited editors)

  • Thomas, B.

publication date

  • May 2016