title: Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy.
abstract: OBJECTIVE
  Patients receiving paclitaxel often develop peripheral neuropathies. We found that a novel selective cannabinoid CB2 receptor agonist (MDA7) prevents paclitaxel-induced mechanical allodynia in rats and mice. Here we investigated gene expression profiling in the lumbar spinal cord after 14-day treatment of MDA7 in paclitaxel animals and analyzed possible signaling pathways underlying the preventive effect of MDA7 on paclitaxel-induced neuropathy.
  
  
  METHODS
  Peripheral mechanical allodynia was induced in rats or mice receiving intraperitoneal (i.p.) injection of paclitaxel at a dose of 1mg/kg daily for four consecutive days. MDA7 was administered at a dose of 15mg/kg 15min before paclitaxel and then continued daily for another 10days. Whole-genome gene expression profiling in the lumbar spinal cord of MDA7 and paclitaxel-treated rats was investigated using microarray analysis. The Ingenuity pathway analysis was performed to determine the potential relevant canonical pathways responsible for the effect of MDA7 on paclitaxel-induced peripheral neuropathy.
  
  
  RESULTS
  We observed that the inflammatory molecular networks including tumor necrosis factor (TNF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), transforming growth factor beta (TGFβ), and mitogen-activated protein kinases (MAPK) signaling are most relevant to the preventive effect of MDA7 on paclitaxel-induced peripheral neuropathy. In addition, genes encoding molecules that are important in central sensitization such as glutamate transporters and N-methyl-d-aspartate receptor 2B (NMDAR2B), and neuro-immune-related genes such as neuronal nitric oxide synthase (nNOS1), chemokine CX3CL1 (a mediator for microglial activation), toll-like receptor 2 (TLR2), and leptin were differentially modulated by MDA7.
  
  
  CONCLUSIONS
  The preventive effect of MDA7 on paclitaxel-induced peripheral allodynia in rats may be associated with genes involved in signal pathways in central sensitization, microglial activation, and neuroinflammation in the spinal cord.
authors.affiliation: Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: xuj3@ccf.org.
authors.forename: J J
authors.initials: JJ
authors.lastname: Xu
authors.affiliation: The Department of Biomedical and Pharmaceutical Sciences, Core Laboratory for Neuromolecular Production, The University of Montana, Missoula, MT 59812, USA. Electronic address: philippe.diaz@mso.umt.edu.
authors.forename: P
authors.initials: P
authors.lastname: Diaz
authors.affiliation: Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: bieb@ccf.org.
authors.forename: B
authors.initials: B
authors.lastname: Bie
authors.affiliation: The Department of Biomedical and Pharmaceutical Sciences, Core Laboratory for Neuromolecular Production, The University of Montana, Missoula, MT 59812, USA. Electronic address: fanny.diaz@umontana.edu.
authors.forename: F
authors.initials: F
authors.lastname: Astruc-Diaz
authors.affiliation: Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: wuj3@ccf.org.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: yangh@ccf.org.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: browndl@ccf.org.
authors.forename: D L
authors.initials: DL
authors.lastname: Brown
authors.affiliation: Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: naguibm@ccf.org.
authors.forename: M
authors.initials: M
authors.lastname: Naguib
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008161:Lumbosacral Region; D051379:Mice; D017239:Paclitaxel / Q000633:toxicity*; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: C534147:1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl)piperidine; D001572:Benzofurans; D010880:Piperidines; D043885:Receptor, Cannabinoid, CB2; D017239:Paclitaxel
keywords: ATF3; CB; CB(2); FDR; GFAP; LPS; MAPK; N-methyl-d-aspartate; NF-κB; NMDA; Quantitative real-time reverse transcription polymerase chain reaction; TAK1; TGFβ; TGFβ-activated kinase 1; TLR; TNF; activating transcription factor 3; cannabinoid; false discovery rate; glial fibrillary acidic protein; lipopolysaccharide; microglial activation; mitogen-activated protein kinases; nNOS; neuroinflammation; neuronal nitric oxide synthase; neuropathy; nuclear factor kappa-light-chain-enhancer of activated B cells; paclitaxel; qRT-PCR; toll-like receptor; transforming growth factor beta; tumor necrosis factor