Moxidectin toxicity in senescence-accelerated prone and resistant mice

Abstract

Moxidectin has been used safely as an antiparasitic in many animal species, including for the eradication of the mouse fur mite, Mycoptes musculinus. Although no side effects of moxidectin have previously been reported to occur in mice, 2 strains of the senescence-accelerated mouse (SAMP8 and SAMR1) sustained considerable mortality after routine prophylactic treatment. To investigate the mechanism underlying this effect, moxidectin toxicosis in these mice was evaluated in a controlled study. Moxidectin was applied topically (0.015 mg), and drug concentrations in both brain and serum were analyzed by using HPLC coupled with mass spectrometry. The moxidectin concentration in brain of SAMP8 mice was 18 times that in controls, and that in brain of SAMR1 mice was 14 times higher than in controls, whereas serum moxidectin concentrations did not differ significantly among the 3 strains. Because deficiency of the blood-brain barrier protein P-glycoprotein leads to sensitivity to this class of drugs in other SAM mice, Pgp immunohistochemistry of brain sections from a subset of mice was performed to determine whether this commercially available analysis could predict sensitivity to this class of drug. The staining analysis showed no difference among the strains of mice, indicating that this test does not correlate with sensitivity. In addition, no gross or histologic evidence of organ toxicity was found in brain, liver, lung, or kidney. This report shows that topically applied moxidectin at a standard dose accumulates in the CNS causing toxicosis in both SAMP8 and SAMR1 mice.

Figure 1.

Tissue levels of moxidectin as determined by LC–MS/MS. Results are expressed as mean ± SEM (n = 5). The brain tissue levels were significantly higher in both of the SAM strains than in the AKR/J mice. Serum moxidectin concentrations were not significantly different among the 3 strains.

Figure 2.

Immunohistochemical staining of brain sections by using C219 monoclonal antibody: (A) a CF1 mouse that had no signs of toxicity after moxidectin application and (B) SAMR1 and (C) SAMP8 mice that were found moribund after moxidectin application. The black arrows indicate positive dark-brown staining in the capillary endothelial cells. No difference in P-glycoprotein expression was observed in the capillaries of the SAMP8, SAMR1, and CF1 mice). Hematoxylin counterstain; magnification, ×400 (×40 objective and ×10 ocular).