title: Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system.
abstract: BACKGROUND
  Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB(2)) receptors are expressed in the microglia in neurodegenerative disease models.
  
  
  METHODS
  To explore the potential of CB(2) agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB(2)-selective agonist, namely, MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB(2)(+/+) and CB(2)(-/-) mice. We hypothesized that the CB(2) receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways.
  
  
  RESULTS
  We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB(2)(-/-) mice and was blocked by CB(2) antagonists, suggesting that MDA7's action directly involves CB(2) receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced toll-like receptor and CB(2) expression in the lumbar spinal cord, reduced levels of extracellular signal-regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models.
  
  
  CONCLUSIONS
  Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae.
authors.affiliation: Institute of Anesthesiology, Cleveland Clinic, 9500 Euclid Ave., NE6-306, Cleveland, OH 44195, USA. naguibm@ccf.org
authors.forename: Mohamed
authors.initials: M
authors.lastname: Naguib
authors.forename: Jijun J
authors.initials: JJ
authors.lastname: Xu
authors.forename: Philippe
authors.initials: P
authors.lastname: Diaz
authors.forename: David L
authors.initials: DL
authors.lastname: Brown
authors.forename: David
authors.initials: D
authors.lastname: Cogdell
authors.forename: Bihua
authors.initials: B
authors.lastname: Bie
authors.forename: Jianhua
authors.initials: J
authors.lastname: Hu
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craig
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001572:Benzofurans / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D006224:Cricetinae; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents; D017239:Paclitaxel / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D010812:Physical Stimulation; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis
chemical_list: C534147:1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl)piperidine; D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D010880:Piperidines; D043885:Receptor, Cannabinoid, CB2; D051195:Toll-Like Receptor 2; D017239:Paclitaxel