Cooling Concussed Brain Cells Quickly Post-injury Staves Off Damage

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Despite an immense amount of research, concussions and traumatic brain injuries (TBI) are still poorly understood. We understand the physical reason behind why they occur, but not how to treat them nor the underlying cellular mechanisms at play. Thus, diagnosis of concussions and TBI are difficult and sometimes unreliable.

What we do know is that traumatic impacts to the brain can turn on biochemical pathways that led to neurodegeneration, which can cause long-term health issues for patients—although it’s unclear which patients this applies to and which it does not.

Regardless, researchers at University of Wisconsin-Madison have exploited this minimal knowledge, leading a study that, for the first time, defines critical parameters for therapeutic hypothermia as a possible treatment for TBI. Literature on therapeutic hypothermia has provided conflicting information previously so this study, published in PLOS One, establishes a pivotal foundation to inform future animal, pre-clinical and clinical studies.

Christian Franck, UW-Madison professor of mechanical engineering, and colleagues at Brown University worked with a 3-D, in-vitro neural injury model in which the neural cells were encapsulated in collagen hydrogels. The researchers delivered a mechanical pulse to the model that simulates the injury and cell damage people typically experience with a concussion. Then, they cooled the injured cells to four different temperatures—37, 35, 33. and 31.5 C.

They found that 33 C (91.4 F) provided the most protective benefit for injured cells, while 31 C actually had a detrimental effect.

“Though only 1.5 C lower than the neuroprotective zone, the viability was far lower,” the researchers wrote in their paper. “Indeed, many other studies have shown evidence of deleterious effects when cooling below 32 C, consistent with our findings here.”

Beyond cooling, timing played a huge role in the research results. Through a series of tests, Franck and his team determined cooling should begin no more than four hours post-injury, and should continue for at least 6 to 12 hours, even all the way up to 24 hours. While cooling for even 30 minutes showed some benefits, starting treatment more than four hours after injury showed poor results.

When the researchers adhered to the 33 C, 4-hours post-injury parameters, they were able to keep the cells' biochemical pathways switched off—meaning the cells remained healthy and functioning normally despite suffering a traumatic injury that would normally activate the pathways and, subsequently, neurodegeneration.

The 4-hour post-injury mark is significant due to the upregulation kinetics of two specific enzymes that play an essential role in programmed cell death—caspase 3 and 7.

“There has been some evidence that temperature reduction might lessen the activation of these executioner caspases, which is consistent with our results,” the study reads. “Our data shows significantly reduced levels of both caspase 3 and 7 as long as [therapeutic hypothermia] is administered within the first 4 hours, leading to a clear benefit in maintaining high cell population viability.”

After cooling the concussed brain cells for 6 hours, the researchers brought them back up to normal body temperature to test whether this warming would cause the damaging biochemical pathways to turn on.

“The biggest surprise was that the molecular switches actually stayed off—permanently—through the duration of the lab experiment,” Franck said. “That was huge.”

However, there are practical hurdles to therapeutic hypothermia treatment. For instance, the cooling would need to be isolated to the brain, as it can have a negative effect on a person’s heart and immune system. Also, given the time-sensitive nature of the parameters, clinical trials where participants are tested 4 hours post-injury are much harder to design than usual.

Still, Franck believes further investigation is warranted. He specifically intends to adapt the system for organoids to search for and quantify soluable biomarkers implicated in TBI. Using the parameters laid out in this study, future studies could also examine the effects of repeat or multiple impacts.

Photo: Concussed brain cells imaged at four different temperatures. Credit: UW-Madison


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