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


METHODS
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-γ, IL-1β, IL-6, IL-10 and TNF-α) 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.


RESULTS
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.


CONCLUSIONS
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.
Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Health Sciences Center, Kuwait University, Jabriya, Kuwait.
Subramanian S
SS
Parvathy
Willias
W
Masocha
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D001921:Brain / Q000276:immunology; D039481:CD11b Antigen / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000009:adverse effects*; D016133:Polymerase Chain Reaction; D013116:Spinal Cord / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013754:Tetracyclines / Q000008:administration & dosage* / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D039481:CD11b Antigen; D018925:Chemokines; D016207:Cytokines; D061965:Matrix Metalloproteinase Inhibitors; D013754:Tetracyclines; C117155:tetracycline CMT-3; D017239:Paclitaxel