P75 Neurotrophin Receptor Antagonism to Improve Autonomic, Sensorimotor, and Immune Function after SCI
Abstract
Inflammation is part of the body s way of protecting itself after injury, and in the case of a wound, for example, results in a typical swelling, redness, and pain. This response brings immune cells into the wound to fight infection and start the repair process. When inflammation gets out of control, the attempts to kill bacteria, for example, can cause damage to surrounding tissue. In the acute phase after spinal cord injury (SCI), the injured cord releases signals that activate inflammation in the cord itself and in the whole body. These signals can activate the immune system to produce injury to a host of organ systems, including the urinary bladder, which is a common source of infection and disability in people with SCI. Acute inflammation caused by SCI can resolve into a chronic inflammation that actually reduces the ability of the immune system to fight infections. Therefore, controlling inflammation is a possible way in which to improve outcomes after SCI. This proposal is based on a discovery that we have made using a drug under development that is targeted to protecting the brain and spinal cord after injury by blocking a specific receptor for neurotrophic factors, the so-called "p75 neurotrophin receptor." After SCI or traumatic brain injury (TBI), this receptor can be activated and induce the death of neurons and supporting cells. The drug, called EVT901, blocks this cell death and is surprisingly good at reducing damage and improving function after TBI in rats and mice. In addition, it seems to have potent effects on moderating the immune response to injury and reduces inflammation. The goal of our project is to see whether this protection of the nervous system after injury applies also to SCI in rats and whether the reduction in whole-body inflammation improves outcomes and reduces the incidence of bladder infections. If this is successful, we will have identified a new drug that may be safe and effective for treatment of acute SCI that also reduces some of the long-term consequences of SCI-induced inflammation. We are using a preclinical rat model of SCI that produces almost all of the long-term consequences of thoracic SCI in humans, including paralysis of the lower limbs, changes in blood pressure and heart rate, bladder dysfunction and difficulty in controlling urination, and increased urinary tract infections. There is some recovery of these functions in the model, but there is much room to see improvement with drug treatment should it occur. We will also be analyzing the effects of SCI and the drug on white blood cells (which are involved in inflammation) in an attempt to learn more about their role in producing long-term deficits after SCI. The impact of these studies will be felt in two ways: first, the possible development of an effective therapeutic for acute SCI, and second, by providing a host of new information about the role of injury-produced inflammation in producing long-term problems in cardiovascular function, bladder control, and infections.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610723
Entities
People
- Michael S Beattie
Organizations
- United States Army
- University of California, San Francisco