Protecting Our Brains from Ongoing Trauma After Injury

Principal Investigators: Juan M. Saavedra, MD, Mark Burns, PhD

Traumatic Brain Injury (TBI) results from an external force injuring the brain. Common in civilian and military life, TBI carries with it high fatality and disability rates and immense cost to society.

While the primary injury from the event that causes a TBI is usually over very quickly, many patients continue to deteriorate in the following weeks and months because of the activation of multiple detrimental biochemical cascades in the brain – a process known as “secondary injury.” Secondary injury cascades can include brain inflammation, neuronal cell death (apoptosis) and reduced blood flow to the brain.

All past clinical trials for TBI therapies have failed, often because they have only targeted a single secondary injury pathway and have not addressed the complexity of the disease. For these reasons there is a need to consider novel neuroprotective agents to target the main coexisting pathological mechanisms of TBI.

Our focus is on a group of FDA-approved compounds called sartans that are widely used for the treatment of patients suffering from hypertension, heart failure, diabetes and renal disease. Recently, we have discovered that some of these sartans are also powerful neuroprotective agents. Sartans can reduce brain inflammation, neuronal death, brain hemorrhage (bleeding), brain edema (swelling), and increase blood supply and improve cognitive function in animal models of stroke.

We believe that because the sartans can target multiple secondary injury pathways, they have strong potential as therapeutic drugs for the treatment of TBI. We hypothesize that a specific sartan, telmisartan, is the strongest candidate for testing in a clinical setting as we believe it will reduce not only the short term but also the long term pathological effects of TBI.

We propose to:

  • Clarify the mechanisms of telmisartan neuroprotection in a rodent model of TBI.
  • Test on cultured brain cells to elucidate the principal mechanisms of neuroprotection.
  • Compare telmisartan with other sartans to establish if the unique PPARϒ activation caused by telmisartan leads to greater neuroprotection.

Identification of the most neuroprotective sartan will have immediate translational significance: if telmisartan is confirmed as the most effective sartan in an animal model of TBI, clinical studies could be fast-tracked since this would be repurposing an FDA-approved drug for a new indication.