anisomycin and Arthritis

Dexmedetomidine (DEX) has showed significant analgesic effects in neuropathic pain, but the underlying mechanism has remained elusive. Our present study aimed to explore the effect of DEX on hyperalgesia with the involvement of p38MAPK signaling pathway in a rat model of monoarthritis (MA).. MA rat model was induced by injection of Complete Freund's Adjuvant (CFA). Pathological changes of MA rats were observed by HE staining and Safranin-O/Fast Green staining. Ankle circumference, paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) were measured to judge the degree of hyperalgesia in MA rats. Immunohistochemistry and ELISA were applied to observe the degree of inflammation in rats. Western blot analysis was conducted to detect expression of p38MAPK signaling pathway-related factors. The mechanism of p38MAPK signaling pathway in MA rats was observed. After 8 h of CFA induction, joint swelling and hyperalgesia occurred in rats. There were obvious pathological changes in the joint cavity, the joint cavity space became narrow and synovial bursa became rough. A large number of inflammatory cell infiltration was observed under microscope. After injection of DEX and SB203580, PWT and PWL were prolonged, the expression of serum inflammatory factors was decreased, and the expression of p38MAPK signaling pathway-related factors was decreased; while all the detected indexes were recovered in MA rats after treated with DEX and Anisomycin.. Our study provided evidence that DEX could alleviate hyperalgesia in arthritis rats through inhibition of the p38MAPK signaling pathway.

Topics: Animals; Anisomycin; Arthritis; Dexmedetomidine; Freund's Adjuvant; Hyperalgesia; Inflammation; MAP Kinase Signaling System; Rats; Rats, Sprague-Dawley

The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.

Topics: Amino Acids; Animals; Anisomycin; Arthritis; Carboxylesterase; Cell Line, Tumor; Cell Proliferation; Cytokines; Drug Delivery Systems; Enzyme Inhibitors; Esterases; Esters; HSP90 Heat-Shock Proteins; Humans; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Macrophages; Magnetic Resonance Spectroscopy; Mice; Mice, Transgenic; Monocytes; p38 Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Signal Transduction; Tumor Necrosis Factor-alpha