More than just mascots: Hibernating mammals could reveal treatments for traumatic brain injury

I’ve been a football fan for most of my life. Growing up in the 1990s, I found my love for the sport by attending University of Southern California football games with my grandfather, who had begun attending when he was a child in the 1930s. Since this time, a lot has changed in medical knowledge about the lasting effects of traumatic brain injuries suffered while on the field. While aspects of the sport undoubtedly need to change to better protect players, on this Super Bowl Sunday, I’d like to reflect on the potential treatments on the horizon for those suffering from these devastating injuries. 

Chronic Traumatic Encephalopathy or CTE is a neurodegenerative disorder associated with the repetitive head trauma that can occur in football and other sports. The symptoms of CTE which include cognitive decline, depression, aggression, and dementia often do not present until several years after the injuries occur and increase in severity over time. Unfortunately, there currently are no  effective treatments for this disorder [1].

Therapeutic hypothermia for patients with traumatic brain injury initially showed promising results in preclinical studies, and has neuroprotective effects. The approach involves cooling the patient as soon as possible after an injury, often to temperatures below 35°C using sedatives and paralytics to prevent shivering [2]. However, this approach ultimately failed clinical trials due to lack of efficacy, and researchers are currently searching for new methods and ways to refine the approach [3].

Hibernating mammals are an interesting model for neuroprotection that may provide insight into the development of better therapies for human brain injury. These animals experience long-term suspended animation in torpor and receive cerebral blood flow at only 10% of the normal rate, yet they are able to protect their brains from this ischemia and subsequent reperfusion upon arousal [4]. Because ischemia and traumatic brain injury share common pathologies including inflammation, oxidative stress, excitotoxicity and perturbation of calcium homeostasis, it was hypothesized that adaptations in hibernators may also be useful in protection against traumatic brain injury. Indeed, a study comparing hibernating to non-hibernating Arctic ground squirrels with a penetrating brain injury revealed that the hibernating animals had enhanced protection from damage, with dramatically reduced cell death. The neuroprotection gained during hibernation likely comes from a variety of sources including hypothermia, leukocytopenia (decreased numbers of white blood cells), and increased antioxidant defenses [5].

Encouragingly, development of a therapy for trauma and blood loss modeled after hibernators’ enhanced antioxidant protection has already begun. Matthew Andrews’ lab, (a Fauna Bio advisor) showed increased survivability in rats after hemorrhagic shock who received an antioxidant solution based on hibernation physiology composed of beta-hydroxybutyrate (BHB) and melatonin [6].  These results have since been reproduced in pigs [7] and Phase I Clinical Trials are currently being planned. There is also potential for this therapy to be adapted for the treatment of head injuries. "The protective properties of melatonin, combined with the ability of D-beta hydroxybutyrate (BHB) to cross the blood-brain barrier and provide a non-lactate generating fuel source for the brain, suggests that BHB-Melatonin could be a potential treatment for traumatic brain injury in addition to its originally designed function as a therapy for hemorrhagic shock" says University of Nebraska Professor Matthew Andrews.

Despite these exciting research findings, much remains to be discovered about how best to treat traumatic brain injury, which can lead to CTE. As a lifelong football fan I still intensely enjoy watching the sport, but clearly, much more needs to be done to prevent potential long-term health consequences to the athletes. Protecting players needs to start on the field, but it’s encouraging to think that we can develop future treatments using our understanding of the protective mechanisms of mammalian hibernation.

References:

1. Stern RA, Riley DO, Daneshvar DH, Nowinski CJ, Cantu RC, McKee AC: Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy. (2011) Phys Med Rehabil Clin N Am. 3: 460-467.

2. Song SS, Lyden PD. Overview of therapeutic hypothermia. Curr Treat Options Neurol. (2012) Dec;14(6):541-8.

3. Dietrich, W.D.; Bramlett, H.M. Therapeutic hypothermia and targeted temperature management for traumatic brain injury: Experimental and clinical experience. (2017) Brain Circ.  3, 186–198.

4. Dave KR, Christian SL, Perez-Pinzon MA, Drew KL (2012) Neuroprotection: lessons from hibernators. Comp Biochem Physiol B Biochem Mol Biol 162:1–9.

5. Zhou, F., Zhu, X., Castellani, R. J., Stimmelmayr, R., Perry, G., Smith, M. A. and Drew, K. L. (2001b). Hibernation, a model of neuroprotection. Am. J. Pathol. 158, 2145-2151.

6. Perez de Lara Rodriguez, C. E., Drewes, L. R. and Andrews, M. T. (2017). Hibernation-based blood loss therapy increases survivability of lethal hemorrhagic shock in rats. J. Comp. Physiol. B 187, 769-778.

7. Wolf, A., Mulier, K.E., Muratore, S.L., Beilman, G.J., D-β-Hydroxybutyrate and melatonin for treatment of porcine hemorrhagic shock and injury: a melatonin dose-ranging study. (2017) BMC Res Notes. Nov 29;10(1):649.