A new study reveals how inhibiting certain enzymes decreased the severity of Traumatic Brain Injury (TBI), providing a target for future treatments.

Researchers at the Australian Center for Blood Diseases (ACBD; Melbourne, Australia), the University of Geneva (Switzerland), and the University of Michigan (Ann Arbor, USA) identified two enzymes, tissue plasminogen activator (t-PA) and matrix metalloproteinase-3 (MMP-3), that act together to promote injury severity following TBI. Initially, the researchers speculated that t-PA itself exacerbated the injury; however, a surprising finding of the study was that t-PA is not the culprit, but rather its inhibition by plasminogen activator inhibitor-1 (PAI-1), neuroserpin, and protease-nexin 1 that does the damage, by activating MMP-3.

The research was based on previous studies involving models of acute ischemic stroke that indicated that t-PA--a protease that facilitates the breakdown of blood clots in the circulation via the conversion of plasminogen into plasmin--can exacerbate blood brain barrier (BBB) damage in a process that involves it binding to a cell surface receptor known as low-density lipoprotein receptor related protein (LRP); t-PA can also promote activation of other members of the MMP family of enzymes, which have the capacity directly break down the structural support of the BBB. The study was published on July 19, 2012, in the journal Brain.

“The activity of naturally occurring enzymes is controlled by specific enzyme inhibitors; unexpectedly, we found that the process of t-PA inactivation by one of its natural inhibitors actually contributed to brain injury, because it leads to the activation of MMP-3,” said study lead author Prof. Robert Medcalf, PhD, of the ABCD. “Now we know that if we block MMP-3 with an inhibitor, we can protect the brain following TBI.”

TBI is the leading cause of death and disability in individuals under the age of 45. Following trauma, a complex series of neurochemical and signaling changes are initiated that cause severe damage to the BBB, a structure that protects the brain from the entrance of potentially harmful substances present in the blood and maintains the homeostasis of the central nervous system. Breakdown of the BBB causes bleeding as well as a build-up of the fluid in the brain.


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