In 2010, an estimated 2.5 million traumatic brain injury (TBI) cases presented for treatment in the U.S., and it is likely that many more cases were never reported. Penetrating traumatic brain injuries produce the worst outcomes and highest mortality rates.
A new study led by Western University of Health Sciences Graduate College of Biomedical Sciences Dean Michel Baudry, PhD, examines the potential for a targeted calpain inhibitor to reduce the damaging effects of TBI.
The article, “Protection against TBI-induced neuronal death with post-treatment with a selective calpain-2 inhibitor in mice,” by Dr. Yubin Wang, Dr. Yan Liu, Dulce Lopez, Moses Lee, Sujay Dayal, Alexander Hurtado, Dr. Xiaoning Bi, and Dr. Michel Baudry, was published online by the Journal of Neurotrauma in June 2017 ahead of print. Click here to read more: https://doi.org/10.1089/neu.2017.5024.
Calpain, a family of calcium-dependent proteases regulating many cellular functions through the selective truncation of proteins, has been widely shown to be involved in TBI-induced neuronal death.
Research generated out of Baudry’s lab has shown that calpain-1 and calpain-2 play opposite functions in both synaptic plasticity and neuronal survival. Calpain-1 activation is required for the initiation of theta burst stimulation-induced long-term potentiation (LTP) and is neuroprotective. Calpain-2 activation limits the magnitude of LTP and is neurodegenerative.
In this study, the control cortical impact model of TBI in wild-type (WT) and calpain-1 knock-out mice was used to assess the respective roles of calpain-1 and calpain-2 in neuronal death.
“What we did show, which we had not shown before, is that calpain-2 activation is really a very good predictor of the extent of cell death in the brain after this injury,” Baudry said. “We used our selective calpain-2 inhibitor, which we injected after the insult and showed that indeed this inhibitor decreased the extent of cell death and consequently facilitated motor recovery and prevented the loss of cognition after TBI.”
The study also showed more damage in the calpain-1 knock-out mice than in the wild-type mice.
“This strengthens the idea that calpain-1 is neuroprotective and if you don’t have calpain-1 you get more damage,” Baudry said. “That also says that if you use a nonselective calpain inhibitor, which people have tried before, you don’t know what you are going to find in terms of results because you’re going to block both the protective and the neurodegenerative functions of calpains. So you really need to target calpain-2.
“Knowing that calpain-2 is critical to determine the extent of cell death, that if we can indeed bring this compound to the clinic, this might have very significant beneficial effects in patients,” he added.
Concussions are also a big concern, especially among athletes.
“We think this might also provide a potential treatment to prevent the development of pathology following a concussion and repeated concussions,” Baudry said.
Other studies have identified a blood biomarker that serves as a good predictor of long-term consequences of TBI. This blood biomarker is generated by calpain activation in the brain, Baudry said.
“If we can target brain calpain, and show this blood biomarker is indeed prevented, this now becomes a good outcome of potential clinical trials for a selective calpain-2 inhibitor,” he said. “You can do your measurement within hours following the injury and show whether your drug is hitting its target.”