J J Xu1, P Diaz2, B Bie3, F Astruc-Diaz4, J Wu5, H Yang6, D L Brown7, M Naguib8. 1. Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: xuj3@ccf.org. 2. 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. 3. Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: bieb@ccf.org. 4. 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. 5. Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: wuj3@ccf.org. 6. Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: yangh@ccf.org. 7. Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: browndl@ccf.org. 8. Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA. Electronic address: naguibm@ccf.org.
Abstract
AIMS: 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. CONCLUSION: 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.
AIMS: 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. CONCLUSION: 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: Jijun Xu; Lingjun Zhang; Mian Xie; Yan Li; Ping Huang; Thomas L Saunders; David A Fox; Richard Rosenquist; Feng Lin Journal: J Immunol Date: 2018-04-25 Impact factor: 5.422
Authors: Cristina Martín-Escura; Alicia Medina-Peris; Luke A Spear; Roberto de la Torre Martínez; Luis A Olivos-Oré; María Victoria Barahona; Sara González-Rodríguez; Gregorio Fernández-Ballester; Asia Fernández-Carvajal; Antonio R Artalejo; Antonio Ferrer-Montiel; Rosario González-Muñiz Journal: Int J Mol Sci Date: 2022-02-28 Impact factor: 5.923