The Ohio State University Research Foundation
Philip G. Popovich, Ph.D.
Director - Center for Brain and Spinal Cord Repair;
Ray W. Poppleton Research Chair

Cell loss after spinal cord injury (SCI) occurs in two phases. Primary cell loss occurs through mechanical trauma and damage. At the time of SCI, cells are damaged, destroyed, and lost as consequence of the actual physical events of the injury. Secondary cell loss occurs in a progressive manner for hours, days, and weeks after injury as a host of biological events (chemical, vascular, inflammatory, etc.) are initiated in response to injury. Although primary cell loss is unavoidable, therapeutic interventions that reduce secondary cell death are associated with improved functional recovery. Three general therapeutic strategies for improving the neurological outcomes of SCI are: 1) reducing secondary cell death; 2) replacing lost tissue through transplantation; and 3) stimulating remaining cells to reform connections lost as a result of the injury (regeneration). Transplantation strategies provide a promising area of research, however, various ethical concerns surround the use of some of the more promising transplant sources (e.g., stem cells, fetal tissue). The potential for transplants to form tumors and/or be rejected by the recipient, will also likely hamper any clinical application. Pharmacological interventions have a greater potential for immediate application. One drug, methylprednisolone, is already approved for SCI treatment in humans. Although methylprednisolone application leads to modest functional improvements, greater therapeutic potential may be realized using a combined treatment approach. We propose applying two drugs, clodronate and rolipram, in combination, after experimental SCI. Both drugs have been tested and are acceptable for human use. Clodronate will be applied to reduce secondary damage caused by inflammation after injury. Rolipram will be applied to induce regeneration and establish new connections to replace those that were lost as a consequence of the injury. When individually applied after experimental SCI, both drugs lead to improved functional recovery and tissue sparing. We hypothesize that applying the drugs in combination will lead to greater functional improvements than application of either drug alone. In order for therapies to make the transition from basic science to clinical application, they must be applied in clinically relevant models of injury. We have recently characterized a rat model of cervical SCI. Cervical injury is the common type of SCI in humans and usually results in quadriplegia. Additionally, we have characterized tests that model the function of greatest clinical importance to the quadriplegic patient population, hand and arm use. By applying clodronate and rolipram in this model, we further hypothesize that reducing secondary cell loss and inducing regeneration will result in improved function recovery. Evaluation of a clinically relevant treatment strategy in a clinically relevant model of SCI will help us achieve our goal of reducing the consequences of SCI in humans.