Helping the Traumatized Brain Help Itself: A Novel Approach to the Restoration of Post-TBI Brain Energy Metabolism

The Critical Problem: The human brain has very high energy demands, and brain cells need to be constantly provided with fuel that allows them to perform their many functions, and, importantly, to stay alive. This fuel is called adenosine triphosphate, or ATP. ATP is generated inside cells by a process that requires a constant supply of oxygen and glucose from the bloodstream. The last step in the process is the conversion of adenosine diphosphate (ADP) to ATP. Under normal circumstances in the healthy brain, the blood supply to the brain ensures continual conversion of ADP to ATP so that our brains function normally. However, when the brain is injured, for example as might occur in combat from a blast, gunshot wound or shrapnel, the process of ATP synthesis is interrupted, and cellular levels of ATP rapidly fall. This has immediate effects, especially on brain nerve cells (neurons), which have the highest energy demands. Neurons rapidly (within seconds) lose their ability to control their electrical activity. This leads to seizure-like events that damage both them and their immediate neighbors, leading to the spread of brain damage from the initial focus into adjacent vulnerable tissue, resulting in its recruitment into the pathological cascade and continuation of the spread of injury. This loss of ATP is made more profound and prolonged by the breakdown of ATP beyond ADP to further breakdown products that are lost from the brain into the bloodstream. Thus, the normal process of conversion of ADP to ATP cannot take place, even when blood supply is restored as the components have been lost from the brain. This likely explains why there is a prolonged impairment in brain energy use for days or even weeks after an initial brain injury.

Our Innovative Idea: We have shown that providing injured brain tissue with the molecules necessary for early steps of ATP synthesis (ribose and adenine) restores ATP levels to normal values. We have also shown that this approach: (i) increases the release of the 'A' in ATP – adenosine, which is an important naturally occurring brain-protective and anti-epileptic agent, which would help protect the brain after injury, and (ii) that a combination of ribose, adenine and another drug, allopurinol ('RibAdeAll') protected brain tissue and improved recovery in a rat model of stroke. Of great importance is the fact that these compounds are already in use in humans: ribose as a nutritional supplement, adenine in blood transfusion products, and allopurinol as a common treatment for gout. We now wish to test this innovative approach in clinically relevant models of TBI by delivering our treatment (RibAdeAll) in a manner that is consistent with current combat casualty care, i.e., at regular temperature, rapidly (30 minutes after injury), and conveniently (intravenously).

Applicability, Impact, and Beneficiaries: The compounds we propose to use, ribose, adenine and allopurinol, are all in use in humans, and thus have undergone previous safety testing. Their combination should pose no complications, and did not do so in our previous rat studies. Their delivery is simple and could be done via an intravenous infusion solution as part of field fluid resuscitation, and therefore could be done promptly (within minutes) of injury. The proposed solution has therefore strong applicability for the rapid treatment of combat TBI casualties in supporting energy metabolism in vulnerable brain tissue before medevac to advanced treatment centers. Accordingly, if successful, our innovative treatment would have huge impact, not just for injured Service personnel in lessening the impact of TBI and improving outcome, but also for their families and Veteran care services. Moreover, such a simple procedure could equally be transferred to first responders in civilian settings, and of benefit to all who suffer a TBI, be it from a fall, assault, or road traffic collision. Given that similar energy metabolism principles apply in the spinal cord, a potential extension could be into spinal cord injury. As such, we expect there to be a wide variety of beneficiaries among both the American military and public. We believe that our innovative idea has the potential to deliver great benefits in the context of acute TBI, and thus fits firmly within the remit of the Traumatic Brain Injury and Psychological Health Research Program Idea Development Award.