Matrix metalloproteinase inhibitor COL-3 prevents the development of paclitaxel-induced hyperalgesia in mice

ABSTRACT

To study the potential of chemically modified tetracycline-3 [COL-3], a potent matrix metalloproteinase [MMP] inhibitor, to protect against the development of paclitaxel-induced painful neuropathy and its immunomodulatory effects. The reaction latency to thermal stimuli [hot plate test] of female BALB/c mice was recorded before and after treatment with paclitaxel [2 mg/kg i.p.], paclitaxel plus COL-3 [4, 20 or 40 mg/kg p.o.] or their vehicles for 5 consecutive days. Gene transcripts of CD11b [marker for microglia], 5 cytokines [IFN-gamma, IL-1 beta, IL-6, IL-10 and TNF- alpha] and 3 chemokines [CCL2, CXCL10 and CX3CL1] were quantified by real-time PCR in the brains, spinal cords and spleens of mice sacrificed on day 7 after treatment. Treatment with paclitaxel reduced the reaction latency time to thermal stimuli [thermal hyperalgesia] for 4 weeks, with maximum effect on days 7 and 10. The coadministration of paclitaxel with COL-3 40 mg/kg, but not lower doses, prevented the development of paclitaxel-induced thermal hyperalgesia. Treatment with paclitaxel alone or coadministration with COL-3 increased CD11b transcript levels in the brain but not in the spinal cord. Treatment with paclitaxel reduced IL-6 transcript levels in the spinal cord but did not alter the transcript levels of other cytokines or chemokines in the brain, spinal cord or spleen. The coadministration of COL-3 with paclitaxel significantly increased the transcript levels of IL-6 in the spleen and decreased CX3CL1 transcripts in the brain in comparison to treatment with paclitaxel alone. Our results indicate that the MMP inhibitor COL-3 protected against paclitaxel-induced thermal hyperalgesia and, thus, could be useful in the prevention of chemotherapy-induced painful neuropathy