Enzyme worsens traumatic brain injury

MONASH (AUS) — A new study reveals how inhibiting certain enzymes decreases the severity of traumatic brain injury (TBI), and offers a target for future treatments.

Caused by a blow to the head, often suffered during falls or road crashes, severe TBI can result in long-term disability or death. Effects can include impairments to cognitive and motor function, vision, hearing, and emotional regulation.


Additionally, the post-injury disruption to blood flow, oxygen supply, and nerve function around the brain has been linked to debilitating diseases including Alzheimer’s disease and post-traumatic epilepsy. Over 21,000 cases of TBI occur in Australia each year.

Monash University Professor Robert Medcalf and Maithili Sashindranath of the Australian Centre for Blood Diseases (ACBD), led the study and collaborated for five years with scientists at the University of Geneva in Switzerland and the University of Michigan.

As reported in the journal Brain, Medcalf says the researchers identified two enzymes, known as t-PA and MMP-3, that act together to promote injury severity following TBI.

“The enzyme t-PA, well known for its ability to remove blood clots, also has a healthy and very important role in supporting learning and memory functions in everyday life. However, previous research has shown that in TBI cases, its presence makes the injury much worse,” Medcalf says.

Initially, the researchers thought t-PA itself exacerbated the injury. However, a surprising finding of the study was that t-PA is not the culprit – its inhibition triggers the activation of MMP-3, the enzyme which does the damage.

“The activity of naturally occurring enzymes is controlled by specific enzyme inhibitors,” says Medcalf.

“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.

“Now we know that if we block MMP-3 with an inhibitor, we can protect the brain following TBI,” says Medcalf.

Co-author and international expert on TBI, Professor Jeffrey Rosenfeld of Monash’s Department of Surgery says the results were exciting.

“We now have a new and promising therapeutic target for the treatment of human TBI, which has not, so far, been significantly improved by pharmacological intervention,” says Rosenfeld.

Research is continuing with the aim of bringing this finding to a point where clinical trials can evaluate this novel approach in patients with TBI.

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