SPINAL GENE EXPRESSION PROFILING AND PATHWAYS ANALYSIS OF A CB2 AGONIST (MDA7)-TARGETED PREVENTION OF PACLITAXEL-INDUCED NEUROPATHY

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 1 mg/kg daily for four consecutive days. MDA7 was administered at a dose of 15 mg/kg 15 min before paclitaxel and then continued daily for another 10 days. 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-kappa B), transforming growth factor beta (TGF beta), 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 paclitaxelinduced peripheral allodynia in rats may be associated with genes involved in signal pathways in central sensitization, microglial activation, and neuroinflammation in the spinal cord. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.