minocycline and propentofylline

Neuropathic pain is one of the most important types of chronic pain. It is caused by neuronal damage. Clinical and experimental studies suggest a critical role for neuroimmune interactions in the development of neuropathic pain. In this article, we have shown that the cytoplasmic receptor Nod-like receptor-2, NOD2, and its adaptor-signaling molecule RIPK2 participate in the development of neuropathic pain after peripheral nerve injury (spared nerve injury model). The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of pronociceptive cytokines (tumor necrosis factor and IL-1β). This study found that peripheral nerve injury promoted a systemic increase in the NOD2 ligand. These results highlight a previously undetermined role for NOD2 signaling in the development of neuropathic pain, suggesting a new potential target for preventing neuropathic pain.

Topics: Animals; Bone Marrow Transplantation; Carrageenan; Disease Models, Animal; Inflammation; Interleukin 1 Receptor Antagonist Protein; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Minocycline; Neuralgia; Neuroprotective Agents; Nod2 Signaling Adaptor Protein; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Tumor Necrosis Factor, Type I; RNA, Small Interfering; Signal Transduction; Toll-Like Receptor 4; Xanthines

Microglia exhibit various activation phenotypes in the spinal cord after peripheral nerve injury, and promote neuropathic pain. Ibudilast is a phosphodiesterase inhibitor with anti-inflammatory activity, but its effect on activated microglia in chronic neuropathic pain is poorly understood. We investigated whether ibudilast was effective on established allodynia associated with activated microglial phenotypes in two rat models of peripheral and central neuropathic pain. A single intrathecal injection of ibudilast (25 μg) inhibited established allodynia on days 7-21 after sciatic nerve injury in rats. Repeated injections of ibudilast (25 μg/day) reduced the numbers of phosphorylated p38-positive cells without changing hypertrophic microglia, whereas minocycline (100 μg/day) decreased the numbers of hypertrophic microglia associated with phosphorylated p38 levels in the spinal cord. Gene analysis revealed that minocycline, but not ibudilast, increased the expression of anti-inflammatory cytokine genes Il10 and Tgfβ1 in the spinal cord. Propentofylline (100 μg/day) was less effective on microglial phenotypes and established allodynia. Ibudilast inhibited persistent allodynia after the recovery of motor deficits in experimental autoimmune encephalomyelitis rats. Therefore, ibudilast might be effective for chronic neuropathic pain after peripheral and central nerve damage. Ibudilast mediated these effects on activated microglia using a different mechanism compared with minocycline and propentofylline.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Hyperalgesia; Injections, Spinal; Male; Microglia; Minocycline; Neuralgia; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Pain Measurement; Peripheral Nerve Injuries; Phosphodiesterase Inhibitors; Phosphorylation; Pyridines; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord; Xanthines

Microglial cells are hematopoietically derived monocytes of the CNS and serve important neuromodulatory, neurotrophic, and neuroimmune roles. Following insult to the CNS, microglia develop a reactive phenotype, migrate to the site of injury, proliferate, and release a range of proinflammatory, anti-inflammatory, and neurotrophic factors. Isolation of primary microglial cell cultures has been an integral step in elucidating the many roles of these cells. In addition to primary microglial cells, several immortalized cell lines have been created to model primary microglia in vitro, including murine-derived BV-2 cells and rat derived highly aggressive proliferating immortalized (HAPI) cells. Here, we compare rat primary microglial, BV-2, and HAPI cells in experiments assessing migration, expression of activation markers, and production and release of nitric oxide, cytokines, and chemokines. BV-2 and HAPI cells responded similarly to primary microglia in experiments assessing migration, ionized calcium binding adaptor molecule 1 expression, and nitric oxide release. However, BV-2 and HAPI cells did not model primary microglia in experiments assessing tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and monocyte chemoattractant protein-1 expression and release and phospho-extracellular signal-regulated kinase 44/42 expression following lipopolysaccharide treatment. These results indicate that BV-2 and HAPI cell cultures only partially model primary microglia and that their use should therefore be carefully considered.

Topics: Animals; Animals, Newborn; Calcium-Binding Proteins; Cell Movement; Cells, Cultured; Cerebral Cortex; Cytokines; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases; Lipopolysaccharides; Mice; Microfilament Proteins; Microglia; Minocycline; Neuroprotective Agents; Nitric Oxide; Rats; Time Factors; Xanthines