Cervical spinal injury and demyelination in aged rats

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The demographic of spinal cord injury (SCI) is changing, with more and more aged individuals showing up at emergency rooms with spinal cord injuries, especially cervical SCIs related to falls (Ho et al, 2007). In addition, aging is associated with spondylosis and narrowing of the cervical spinal canal. The resultant chronic compression is thought to be associated with slow neurodegenerative changes including demyelination, resulting in loss of function even without a precipitating acute injury. Spondylosis and stenosis also increase the probability of contusion injury associated with falls. Aging also affects myelination and the capacity for remyelination (e.g. Peters and Sethares, 2003) and there is evidence that the CNS itself may be more vulnerable to injury with aging and may have a less plastic response to injury. Both factors could lead to less recovery. Here we propose that that increased vulnerability may be due in part to changes in the reparative response to injury mounted by endogenous adult glial progenitor cells of the oligodendrocyte lineage, which are characterized by the expression of the PDGFR1 and the proteoglycan NG2 (see Horner et al, 2002; Polito and Reynolds, 2006; Rhodes et al, 2006). In Aim 1. we will establish a model of chronic cervical compression that produces progressive neurological deficits and demyelination in young, adult Fischer 344xBN hybrid rats. Rats will be followed with a panel of neurological outcome measures, including forelimb motor function tests and tests for the development of altered sensation (e.g. allodynia and pain). Histological characterization of cord damage, demyelination and remyelination will be made post-mortem. In Aims 2 and 3, we will use the model developed in aim 1 to test the hypothesis that aging results in a greater susceptibility to chronic cervical compression, and ask if the effects of aging are due to increased susceptibility to oligodendrocyte and axonal death, and reduced progenitor cell repair and remyelination, or a combination. We also hypothesize that differences in the inflammatory response in young vs. old rats may play a role. We will compare the responses of young (3 months), middle aged (9 months) and old (15 months) rats to chronic compression injury using both behavioral and histological outcome measures. If the repair response is found to be deficient or reduced in aging, in future studies we will test treatments to reinvigorate or replace the progenitor cell population to ameliorate the deficits. PUBLIC HEALTH RELEVANCE Spinal cord injury (SCI) is now occurring more and more in the aged population, and can be due to acute injury, or the kinds of chronic cervical spinal cord myelopathy that occurs due to age-related arthritis and cord compression. The work proposed here will examine the role of a population of adult stem cells, oligodendrocyte progenitor cells (OPCs) in the development of myelopathy, and in recovery after SCI in aging using rat models of injury. It is expected that the results will contribute to the development of therapies that will improve neurological function in aging humans.