losartan-potassium and Wallerian-Degeneration

Current strategies for promoting faster and more effective peripheral nerve healing have utilized a wide variety of techniques and approaches. Nerve grafts, conduits, and stem cell therapy all have their respective advantages. However, there are still some difficulties in attaining complete functional recovery with a single treatment modality. The utilization of adjuvant treatments, in combination with current standard-of-care methods, offers the potential to improve patient outcomes. This paper highlights the current landscape of adjuvant treatments for enhancing peripheral nerve repair and regeneration.

Topics: Absorbable Implants; Allografts; Autografts; Calcium Channel Blockers; Erythropoietin; Gabapentin; Humans; Immunosuppressive Agents; Lithium Compounds; Nerve Regeneration; Neuroprotective Agents; Neurosurgical Procedures; Peripheral Nerve Injuries; Peripheral Nerves; Recovery of Function; Riluzole; Stem Cell Transplantation; Valproic Acid; Veins; Wallerian Degeneration

We investigated the effect of a single administration of recombinant human erythropoietin (rhEPO) on the preservation of the ventral white matter of rats at 4 weeks after contusive spinal cord injury (SCI), a time at which functional recovery is significantly improved in comparison to the controls [Gorio A, Necati Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Enver Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99:9450-9455; Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A, Brines M (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 102:16379-16384]. Specifically, we examined, by morphological and cytochemical methods combined with light, confocal and electron microscopy, i) myelin preservation, ii) activation of adult oligodendrocyte progenitors (OPCs) identified for the expression of NG2 transmembrane proteoglycan, iii) changes in the amount of the chondroitin sulfate proteoglycans neurocan, versican and phosphacan and of their glycosaminoglycan component labeled with Wisteria floribunda lectin, and iv) ventral horn density of the serotonergic plexus as a marker of descending motor control axons. Injured rats received either saline or a single dose of rhEPO within 30 min after SCI. The results showed that the significant improvement of functional outcome observed in rhEPO-treated rats was associated with a better preservation of myelin in the ventral white matter. Moreover, the significant increase of both the number of NG2-positive OPCs and the labeling for Nogo-A, a marker of differentiated oligodendrocytes, suggested that rhEPO treatment could result in the generation of new myelinating oligodendrocytes. Sparing of fiber tracts in the ventral white matter was confirmed by the increased density of the serotonergic plexus around motor neurons. As for chondroitin sulfate proteoglycans, only phosphacan, increased in saline-treated rats, returned to normal levels in rhEPO group, probably reflecting a better maintenance of glial-axolemmal relationships along nerve fibers. In conclusion, this investigation expands previous studies supporting the pleiotropic neuroprotective effect of rhEPO on secondary degenerative response and its therapeutic pot

Topics: Animals; Antigens; Axons; Cell Membrane; Chondroitin Sulfate Proteoglycans; Erythropoietin; Male; Microscopy, Electron, Transmission; Myelin Proteins; Myelin Sheath; Nerve Fibers, Myelinated; Nerve Regeneration; Neural Pathways; Neuroprotective Agents; Nogo Proteins; Oligodendroglia; Proteoglycans; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Serotonin; Spinal Cord; Spinal Cord Injuries; Stem Cells; Treatment Outcome; Wallerian Degeneration

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. Because TNF-alpha has been implicated in the development of pain-related behaviors, we measured TNF-alpha mRNA at the nerve injury site. Systemically or locally administered rhEpo decreased TNF-alpha mRNA, compared with that observed in untreated animals. RhEpo also significantly (P < 0.05) decreased axonal degeneration. Immunohistochemistry of CCI nerve showed abundant TNF-alpha in Schwann cells, axoplasm and macrophages. In rhEpo-treated animals, TNF-alpha immunopositivity was decreased selectively in Schwann cells. These results suggest a model in which rhEpo counteracts the effects of TNF-alpha in CCI by blocking expression of TNF-alpha in Schwann cells. To further test this model, we studied primary Schwann cell cultures. RhEpo inhibited TNF-alpha expression in response to lipopolysaccharide, supporting the conclusions of our in vivo CCI experiments. In addition, rhEpo directly counteracted Schwann cell death induced by exogenously added TNF-alphain vitro. These results indicated that rhEpo regulates TNF-alpha by multiple mechanisms; rhEpo regulates TNF-alpha mRNA expression by Schwann cells but also may directly counteract TNF-alpha signaling pathways that lead to injury, chronic pain and/or death.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Blood Pressure; Cell Count; Cell Death; Disease Models, Animal; Ectodysplasins; Erythropoietin; Female; Hematocrit; Hyperalgesia; Immunohistochemistry; Lipopolysaccharides; Membrane Proteins; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Schwann Cells; Sciatic Neuropathy; Time Factors; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Wallerian Degeneration

Topics: Animals; Binding Sites; Constriction; Erythropoietin; Ganglia, Spinal; Immunohistochemistry; Immunosorbent Techniques; Janus Kinase 2; Nerve Crush; Neurons; Phosphorylation; Phosphotyrosine; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Rats; Receptors, Erythropoietin; Schwann Cells; Sciatic Nerve; Trauma, Nervous System; Wallerian Degeneration