Toward Personalized Neuroprotection in Novel Models of Cervical Spinal Cord Injury Mimicking Clinical Injury Mechanisms

People injure their spinal cords in many different ways, with the most common occurring during motor vehicle accidents and falls. During these events, there are common patterns of injury to the spine, but many important features of these injuries are not reflected in animal models that are supposed to mimic the way the human spinal cord gets injured. Thus, it should not be surprising that successful treatments in animal studies have not been met with success in humans. Spinal cord injuries are often incomplete, which means the spinal cord gets bruised but not severed. Unfortunately, in the hours after injury the spinal cord tissue at the injury site undergoes further degeneration that makes the initial injury worse/larger. Recent data in animal models show that some drug treatments that aim to protect the spinal cord and improve animal function do not have the same effectiveness across all injury models. These findings emphasize the importance of evaluating promising therapies in a range of animal models to be able to tailor their application to humans. Our approach in this research project is to combine recent developments from our team in spinal cord drug evaluation with our expertise in injury modeling to pursue a highly novel study. We will use unique models of spinal cord injury in a rat to assess the effectiveness of a novel three-drug combination we discovered to treat acute spinal cord injury in rats. These drugs have limited benefits on their own but are additive in combination. Our experiments will include many of the key elements of human injury - being in the neck region of the spine (i.e., cervical), having a range of injury speeds and displacements, and including the common bruising-type injury (i.e., contusion) with our unique squeezing-type injury (i.e., shear dislocation). The drug combination uses well-known drugs that have been used for other diseases such as diabetes and cancer to protect the spinal cords delicate tissues after the initial impact. If the drug combination is successful in this pre-clinical study, it would need to be tested in a human clinical trial. That trial would ultimately define its efficacy in humans, particularly whether there are certain sub-groups of people who injured their spine in a certain way who would benefit the most. Knowledge generated in this project would provide important information to avoid future failures in clinical trials by focusing on those patients who match the animal injury types in which the drug combination was most beneficial. The proposed research is important for all people who will suffer an acute spinal cord injury in the future, including soldiers in combat. A simple drug combination that could help protect their spinal cord would be a major advance for the field. The ease of application of the combination used here would make is suitable for frontline use. Knowing that the therapy has been evaluated over a robust breadth of pre-clinical models would increase our chances of success in future trials and give the health care provider confidence in its broader administration.