Protecting spinal cord tissue from the effects of contusive injury in white matter and gray matter.

摘要

Secondary losses of white matter (WM) and gray matter (GM) contribute significantly to morbidity and mortality of spinal cord injury (SCI). A remaining challenge is to understand and to mitigate secondary injury processes. While in vitro WM injury models implicate abnormal Na+ influx as a key mechanism both neuronal necrosis and apoptosis occur in GM, largely due to glutamate/aspartate toxicity. I hypothesized that local blockade of Na+ channels with tetrodotoxin (TTX) could rescue WM after SCI in vivo. Further, I postulated that basic fibroblast growth factor (FGF2, an endogenous neurotrophic factor) could protect neurons. To test the first hypothesis, TTX (0.15 nmol) or vehicle was microinjected into the injury epicenter at 15 minutes after a standardized contusive SCI at T8 in the rat. TTX treatment tripled the spared WM area at the epicenter at 8 weeks post injury (p.i.). Serotonin immunoreactivity caudal to the epicenter, a marker for descending motor axons, was nearly threefold that of controls. The increase of WM was significantly correlated with reduction of functional deficits. To test the second hypothesis, I focally applied FGF2 at 5 minutes after SCL. FGF2 treatment spared cholinergic neurons of ventral horn (VH) and intermediolateral column (IML), but not WK, at 24-hours and 5-weeks p.i. Since thoracic VH neurons mainly innervate respiratory muscles, respiration was evaluated by a plethysmograph system in conscious rats. SCI significantly reduced tidal volume, and increased respiratory rate at 24 hours and 7 days p.i. FGF2 treatment dose-dependently eliminated respiratory deficits, and restored respiratory sensitivity to CO2, which was correlated with numbers of VH neurons. Therefore, FGF2 treatment not only protected VH-neurons morphologically, but also preserved their function. Moreover, Fluoro-Gold retrograde labeling from the adrenal medulla showed higher numbers of IML neurons in the FGF2-treated animals, evidencing that these neurons still innervated their target. Thus, blockade of Na+ channels protects WM after SCI, and FGF2 treatment preferentially rescues neurons. The results may form bases for new strategies to treat SCI.