No abstract

Injury to the peripheral nervous system (PNS) initiates a response controlled by multiple extracellular mediators, many of which contribute to the development of neuropathic pain. Schwann cells in an injured nerve demonstrate increased expression of LDL receptor-related protein-1 (LRP1), an endocytic receptor for diverse ligands and a cell survival factor. Here we report that a fragment of LRP1, in which a soluble or shed form of LRP1 with an intact α-chain (sLRP-α), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-α into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-α and IL-1β locally. sLRP-α also inhibited CCI-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultures of Schwann cells, astrocytes, and microglia, sLRP-α inhibited TNF-α-induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-α did not involve TNF-α binding, but rather glial cell preconditioning, so that the subsequent response to TNF-α was inhibited. Our results show that sLRP-α is biologically active and may attenuate neuropathic pain. In the PNS, the function of LRP1 may reflect the integrated activities of the membrane-anchored and shed forms of LRP1.

Peripheral nerve injury induces endoneural inflammation, controlled by diverse cytokines and extracellular mediators. Although inflammation is coupled to axonal regeneration, fulminant inflammation may increase nerve damage and neuropathic pain. a 2 -Macroglobulin (a2M) is a plasma protease inhibitor, cytokine carrier, and ligand for cell-signaling receptors, which exists in two well-characterized conformations and in less well-characterized intermediate states. Previously, we generated an a2M derivative (a 2 -macroglobulin activated for cytokine binding; MAC) similar in structure to a 2 M conformational intermediates, which binds tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b), and inhibits endotoxin toxicity. In this study, we report that the continuum of cytokines that bind to MAC includes IL-6 and IL-18. MAC inhibited TNF-a-induced p38 mitogen-activated protein kinase activation and cell death in cultured Schwann cells. When administered by i.p. injection to mice with sciatic nerve crush injury, MAC decreased inflammation and preserved axons. Macrophage infiltration and TNF-a expression also are decreased. MAC inhibited TNF-a expression in the chronic constriction injury model of nerve injury. When MAC was prepared using a mutated recombinant a2M, which does not bind to the a2M receptor, low-density lipoprotein receptor-related protein-1, activity in the chronic constriction injury model was blocked. These studies demonstrate that an a2M derivative is capable of regulating the response to peripheral nerve injury by a mechanism that requires low-density lipoprotein receptorrelated protein-1. Keywords: cytokine, low-density lipoprotein receptor-related protein-1, peripheral nerve injury, tumor necrosis factor-a, a 2 -macroglobulin.

The aim of the study was to report the prevalence of spasticity and treatment patterns during first-time admission to inpatient rehabilitation after acute stroke, traumatic brain injury, and spinal cord injury. Design: This is a retrospective cohort study. Methods: A review of 285 adult patients consecutively admitted to inpatient rehabilitation was conducted. Patients with a history of spasticity and inpatient rehabilitation course and those younger than 18 yrs were excluded. Main outcome measures are as follows: admitting diagnosis, length of stay, time from injury to admission, acute transfer rate, prevalence and severity of spasticity using Modified Ashworth Scale at admission and discharge, Functional Independence Measure scores at admission and discharge, Functional Independence Measure efficiency, and treatments for spasticity. Results: Stroke patients had the highest prevalence of spasticity: 68% on admission and 50% at discharge. In traumatic brain injury, spasticity prevalence was 55% on admission and 30% at discharge. In spinal cord injury, spasticity prevalence was 48% on admission and 46% at discharge. Patients with spinal cord injury received the most medications to control spasticity, whereas those with traumatic brain injury and stroke received the most procedural interventions. Conclusions: Spasticity is a common sequela of upper motor neuron injury for patients admitted to inpatient rehabilitation. Early recognition and management are essential to prevent contractures, minimize pain, and maximize functional recovery.