Signaling proteins in spinal parenchyma and dorsal root ganglion in rat with spinal injury-induced spasticity

Abstract

Development of progressive muscle spasticity resulting from spinal traumatic injury can be mediated by loss of local segmental inhibition and/or by an increased sensory afferent drive with resulting exacerbated α-motoneuron activity. To identify potential contributions of neuroactive substances in the development of such spasticity state, we employed a well-defined spinal injury-evoked spasticity rat model. Signaling molecules were analyzed in the spinal parenchyma below the level of spinal injury and in the corresponding dorsal root ganglion cells using Kinex™ antibody microarrays. The results uncovered the involvement of angiogenesis and neurodegeneration pathways together with direct cross-talk mediated by several hub proteins with SH-2 domains. At 2 and 5weeks after transection, up-regulation of several proteins including CaMKIV, RONα and PKCδ as well as MAPK3/ERK1 phosphorylation was observed in the spinal ventral horns. Our results indicate that these signaling molecules and their neuronal effector systems cannot only play an important role in the initiation but also in the maintenance of spasticity states after spinal trauma. The exclusivity of specific protein changes observed in lumbar spinal parenchyma but not in dorsal root ganglia indicates that new treatment strategies should primarily target specific spinal segments to prevent or attenuate spasticity states. Development of progressive muscle spasticity and rigidity represents a serious complication associated with spinal ischemic or traumatic injury. Signaling proteins, including their phosphorylation status, were analyzed in the spinal parenchyma below the level of spinal injury and in the corresponding dorsal root ganglion cells in a rat model of spinal injury using Kinex™ antibody microarrays. The results uncovered direct protein interaction mediated cross-talk between angiogenesis and neurodegeneration pathways, which may significantly contribute to the healing process in the damaged region. Importantly, we identified several target proteins exclusively observed in the spinal lumbar ventral horns, where such proteins may not only play an important role in the initiation but also in the maintenance of spasticity states after spinal trauma. Hence, potential new treatment strategies such as gene silencing or drug treatment should primarily target spinal parenchymal sites at and around the injury epicenter and most likely employ intrathecal or targeted spinal segment-specific vector or drug delivery. We believe that this work will stimulate future translational research, ultimately leading to the improvement of quality of life of patients with spinal traumatic injury.