Synergistically Enhanced Neuroprotection via Dexmedetomidine-Induced Early Hypothermia and ERK Activation After Spinal Cord Injury
Abstract
Objectives and Rationale: Spinal cord injury (SCI) results in many devastating physical problems that have long-lasting impact on an individual’s life and the quality of their life. These include changes/dysfunction in movement, feelings and sensations, and urine discharge. SCI is initially caused by the impact of an external force. Changes within the spinal cord following this impact such as swelling and reduced blood supply in the injured site (called secondary injury) increases the severity of the injury. It is, therefore, very important to find an effective treatment that can delay the progression of these changes, protect further tissue damage and limit the functional impairment. Treatment that lowers the body temperature can protect the spinal cord tissue and limit the secondary injury. This treatment is most effective if done as soon as possible after injury. Unfortunately, the beneficial effect of this cooling therapy remains significantly limited in clinical practice because of the time needed to transport and medically stabilize the patient and determine potential other injuries. Our goal is to provide patients with SCI access to low body temperature treatment as soon as possible, within the golden time window (less than 4 hours after injury) that maximizes the protective effects. In our pilot study, mice who sustained SCI received a one-time injection of dexmedetomidine (Dex), an Food and Drug Administration (FDA)-approved drug, within 1 hour of injury, which cooled the whole body for up to 16 hours without the need for any special cooling equipment. This early onset and long-lasting effect of lowering body temperature greatly improved physical movement and urinary function after SCI. Moreover, Dex has been shown to activate a molecule that leads to a series of chemical changes in cells that also protects the spinal cord. This further protection may lessen some of the secondary injuries following SCI and subsequent disability from the injury. Our idea is that Dex can provide a unique and powerful protective effect after SCI by rapidly inducing low body temperature and reducing secondary injuries. Furthermore, refining the procedure of using this drug will extend the time for the patients to access low temperature therapy. It may also reduce the time needed to maintain low body temperature, and allow this therapy to be more accessible to a larger number of patients who may avoid or reduce the secondary injuries that lead to substantial disability. Relevance to Military Health: SCIs account for nearly 11% of Service Member deaths and affects thousands of military Service Members serving overseas, with significant disability for the remainder of their life. The poor medical conditions and delayed transportation from the battlefield, make it very difficult for injured soldiers to have access to effective neuroprotective treatment, such as low body temperature, within the golden therapeutic time window. Our proposal will explore a new treatment approach using Dex that conveniently, rapidly, and effectively induces lower body temperature without the need for auxiliary cooling equipment and can provide a powerful new treatment option for use on the battlefield. Impact in the Field of SCI Research: There is urgent need within the area of SCI research to develop effective therapies that can initiate strong neuroprotection as early as possible after injury. To the best of our knowledge, this study will be the first to confirm the novel great protection of the FDA-approved drug Dex and determine how it protects spinal cord cells following SCI. Our study will evaluate the effect of Dex-induced low body temperature therapy on urinary function and explore if there are gender differences in recovery following treatment with low body temperature. Taken together, these findings will refine the protocol for using Dex-induced hypothermia in order to maximize the therapeutic effects and improve patien
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310700
Entities
People
- Lingxiao Deng
Organizations
- Indiana University
- United States Army