In vivo evaluation of quantitative percussion diagnostics for determining implant stability.

Purpose: To test in a rat model whether quantitative percussion diagnostics provide reliable, reproducible indications of osseointegration.

Materials And Methods: Titanium implants were placed in femurs of 36 Sprague-Dawley rats. Each animal was assigned to one of six groups defined by one of three time points (2, 4, or 8 weeks postplacement) and one of two treatments (matrix metalloproteinase [MMP] inhibitor GM6001 or control).

The ology of neuropathy: an integrative review of the role of neuroinflammation and TNF-α axonal transport in neuropathic pain.

This 2011 Peripheral Nerve Society plenary lecture reviews the role of axonal transport in neuroimmune communication following peripheral nerve injury, linking focal changes in Schwann cell activation and release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) with subsequent activation and sensitization of ascending sensory neurons and glia which culminate in the neuropathic pain state. New data demonstrate that axonally transported (biotinylated) TNF-α activates and localizes with dorsal horn astrocytes within 96 h after injection into sciatic nerve, and that glial fibrillary acidic protein (GFAP) activation in these glial cells is diminished in TNF receptor 1 knockout mice. The pathophysiology, neuropathology and molecular biology of Wallerian degeneration are also reviewed from a perspective that links it to upregulation of proinflammatory cytokines and the development of neuropathic pain states.

Immediate anti-tumor necrosis factor-alpha (etanercept) therapy enhances axonal regeneration after sciatic nerve crush.

Peripheral nerve regeneration begins immediately after injury. Understanding the mechanisms by which early modulators of axonal degeneration regulate neurite outgrowth may affect the development of new strategies to promote nerve repair. Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the initiation of degenerative cascades after peripheral nerve injury.

MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage.

Matrix metalloproteinases (MMPs) emerge as modulators of neuropathic pain. Because myelin protects Abeta afferents from ectopic hyperexcitability and nociception from innocuous mechanical stimuli (or mechanical allodynia), we analyzed the role of MMPs in the development of mechanical allodynia through myelin protein degradation after rat and MMP-9-/- mouse L5 spinal nerve crush (L5 SNC). MMPs were shown to promote selective degradation of myelin basic protein (MBP), with MMP-9 regulating initial Schwann cell-mediated MBP processing after L5 SNC.

A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents.

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 alpha-chain (sLRP-alpha), was shed by Schwann cells in vitro and in the PNS after injury.

A derivative of the plasma protease inhibitor alpha(2)-macroglobulin regulates the response to peripheral nerve injury.

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. alpha(2)-Macroglobulin (alpha2M) 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.

Cytokine regulation of MMP-9 in peripheral glia: implications for pathological processes and pain in injured nerve.

Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is induced in Schwann cells hours after peripheral nerve injury and controls axonal degeneration and macrophage recruitment to the lesion. Here, we report a robust (90-fold) increase in MMP-9 mRNA within 24 h after rat sciatic nerve crush (1 to 60 days time-course). Using direct injection into a normal sciatic nerve, we identify the proinflammatory cytokines TNF-alpha and IL-1beta as potent regulators of MMP-9 expression (Taqman qPCR, zymography).

Mitigation of direct neurotoxic effects of lidocaine and amitriptyline by inhibition of p38 mitogen-activated protein kinase in vitro and in vivo.

Background: Local anesthetic-induced direct neurotoxicity (paresthesia, failure to regain normal sensory and motor function) is a potentially devastating complication of regional anesthesia. Local anesthetics activate the p38 mitogen-activated protein kinase (MAPK) system, which is involved in apoptotic cell death. The authors therefore investigated in vitro (cultured primary sensory neurons) and in vivo (sciatic nerve block model) the potential neuroprotective effect of the p38 MAPK inhibitor SB203580 administered together with a clinical (lidocaine) or investigational (amitriptyline) local anesthetic.

TNF-alpha and phosphorylation of ERK in DRG and spinal cord: insights into mechanisms of sciatica.

Study Design: Characterize extracellular signal-regulated kinase (ERK) and its phosphorylation (pERK) in neural tissues after topical application of tumor necrosis factor-alpha (TNF-alpha) to L5 nerve root.

Objective: Identify time-course, localization, and expression of pERK.

Summary Of Background Data: TNF-alpha has a key role in disc herniation and sciatica as an inflammatory component of the nucleus pulposus.

Erythropoietin reduces Schwann cell TNF-alpha, Wallerian degeneration and pain-related behaviors after peripheral nerve injury.

Chronic sciatic nerve constriction injury (CCI) induces Wallerian degeneration and exaggerated pain-like behaviors. These effects are mediated in large part by pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha). In this study, we demonstrate that systemically administered recombinant human erythropoietin (rhEpo) facilitates recovery from chronic neuropathic pain associated with CCI in rats.

The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets.

Neuroinflammation is a proinflammatory cytokine-mediated process that can be provoked by systemic tissue injury but it is most often associated with direct injury to the nervous system. It involves neural-immune interactions that activate immune cells, glial cells and neurons and can lead to the debilitating pain state known as neuropathic pain. It occurs most commonly with injury to peripheral nerves and involves axonal injury with Wallerian degeneration mediated by hematogenous macrophages.

Ephedrine blocks rat sciatic nerve in vivo and sodium channels in vitro.

Background: The sympathomimetic drug ephedrine has been used intrathecally as the sole local anesthetic for labor and delivery. Because ephedrine may be a useful adjuvant to local anesthetics, the authors investigated the local anesthetic properties of ephedrine in a rat sciatic nerve block model and the underlying mechanism in cultured cells stably expressing Na channels.

Methods: After approval of the animal protocol, the sciatic nerves of anesthetized rats were exposed by lateral incision of the thighs, 0.

TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve.

Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is induced hours after injury to peripheral nerve. This study shows that MMP-9 gene deletion and neutralization with MMP-9 antibody reduce macrophage content in injured wild-type nerves. In mice with delayed Wallerian degeneration (WldS), MMP-9 and tumor necrosis factor alpha (TNFalpha) decline in association with the reduced macrophage recruitment to injured nerve that characterizes this strain of mice.

Differential block of N-propyl derivatives of amitriptyline and doxepin for sciatic nerve block in rats.

Background And Objectives: The propyl group of ropivacaine ( N -propyl-2',6'-pipecoloxylidide hydrochloride) could be responsible for conferring some sensory selectivity to this drug. Thus, adding a propyl group to experimental local anesthetics (LAs) (e.g.

The histologic effects of pulsed and continuous radiofrequency lesions at 42 degrees C to rat dorsal root ganglion and sciatic nerve.

Study Design: Experimental histologic study of the effects of radiofrequency (RF) or convective heating of the rat dorsal root ganglion or sciatic nerve to 42 degrees C.

Objective: To determine whether treatment causes neuropathologic changes in an effort to explore the mechanisms and safety of pulsed RF pain therapy.

Summary Of Background Data: Clinical data suggest that low temperature pulsed RF energy delivered to the DRG is a safe and effective form of therapy for low back pain.

Effect of acute nerve root compression on endoneurial fluid pressure and blood flow in rat dorsal root ganglia.

The objective of the current study was to test the hypothesis that crush injury to nerve root increases endoneurial fluid pressure (EFP) and decreases blood flow in the associated dorsal root ganglion (DRG). A total of 21 adult, female Sprague-Dawley rats had their left L5 nerve root and DRG exposed. The L5 nerve root was clamped for 2 s with a vascular suture clip just proximal to the DRG (compression group).

Titanium implants induce expression of matrix metalloproteinases in bone during osseointegration.

Implanted pure titanium fixtures are able to completely integrate with bone, in part because of the formation of a strong extracellular matrix (ECM) bond at the titanium-bone interface. In this study, we used a rodent femur model of intramedullary osseointegration to analyze the changes in immunoreactivity of ECM-controlling matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase-3 (TIMP-3), and tumor necrosis factor alpha (TNF-alpha) during osseointegration. We observed dramatic increases in MMP-2, MMP-9, MMP-7, TIMP-3, and TNF-alpha in osteocytes, osteoclasts, haversian canals, and the interface matrix in bone ipsilateral to the titanium implant.

Exacerbated synucleinopathy in mice expressing A53T SNCA on a Snca null background.

Alpha-Synuclein is a major component of Lewy bodies, neuronal inclusions diagnostic for Parkinson's disease (PD). While an Ala53Thr mutation in alpha-synuclein can cause PD in humans, in mice the wildtype residue at position 53 is threonine, indicating that mice are either too short-lived to develop PD, or are protected by the six other amino acid differences between the proteins in these two species. Mice carrying an Ala53Thr human SNCA transgene driven by the mouse prion promoter show a mild movement disorder and only rarely develop severe pathology by 2 years of age.

Matrix metalloproteinase-9 promotes nerve growth factor-induced neurite elongation but not new sprout formation in vitro.

Matrix metalloproteinase-9 (MMP-9) is a basal-lamina-degrading protease that we have recently shown to be localized in regenerating sciatic nerve. We now demonstrate that MMP-9 colocalizes with growth-associated protein GAP-43 in regenerating nerves in vivo and is involved in vitro in axonal sprouting. By using a PC12 cell model for neuronal sprouting, we analyzed the effects of recombinant MMP-9, MMP-9-neutralizing antibody, and a broad-spectrum MMP inhibitor (Ro 31-9790) on sprout formation, elongation, and branching.

Amitriptyline neurotoxicity: dose-related pathology after topical application to rat sciatic nerve.

Background: Amitriptyline is a tricyclic antidepressant drug used systemically for the management of neuropathic pain. Antidepressants, as a class of drugs with direct neurologic actions, are becoming widely used for the management of chronic pain, although their mechanisms are not entirely understood. Amitriptyline exerts potent effects on reuptake of norepinephrine and serotonin and blocks alpha 2A adrenoreceptors and N-methyl-D-aspartate receptors.

Experimental spinal stenosis: relationship between degree of cauda equina compression, neuropathology, and pain.

Study Design: An analysis of pathologic changes after different degrees of cauda equina compression.

Objectives: To explore the association between the degree of the cauda equina compression and the extent of pathologic change, expression of tumor necrosis factor (TNF-alpha), and neuropathic pain. To compare with distal nerve compression injury.

TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord.

Objectives: The purpose of the current study was to evaluate changes in tumor necrosis factor-alpha (TNF-alpha ) and TNF-alpha receptor 1 (p55 receptor) using double fluorescent immunohistochemistry in glial and neural cells in the dorsal root ganglion and spinal cord after sciatic nerve injury in mice. SUMMARY OF BACKGROUND DATA.: TNF-alpha is a primary mediator of the inflammatory response and is primarily synthesized and released in the nervous system by macrophages and Schwann cells following peripheral nerve injury.