AIMS:

Patients receiving paclitaxel often develop peripheral neuropathies. We found that a novel selectivecannabinoid 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-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.
Copyright © 2013. Published by Elsevier Ltd.

PMID:

 

24361916

 

[PubMed – as supplied by publisher]