Therapeutic effects of masitinib on abnormal mechanoreception in a mouse model of tourniquet-induced extremity ischemia-reperfusion.

ABSTRACT

Tourniquets are widely used to stop extremity hemorrhage, but their use and subsequent release can result in nerve damage and degeneration, leading to neurological deficits. Increasing evidence has suggested a pivotal role of inflammation in nerve damage and abnormal mechanoreception. In this study, we investigated the therapeutic effects of masitinib (Mas), an anti-neuroinflammatory drug, on the mechanoreception of sensory neurons in a mouse model of tourniquet-induced hind paw ischemia-reperfusion (tourniquet/IR). C57BL/6 mice were subjected to 3 h of ischemia by placing a rubber band at the ankle joint and evaluated for subsequent reperfusion injury on day 1, 3, 7, 14, and 28 based on the experiments. Treatment with Mas (28 mg/kg/day, i.p.) began on the day of IR induction and lasted for 1, 3, 7, 14, or 28 days. Tourniquet/IR caused sensory nerve denervation in the skin of paw pads and abolished the hind paw mechanoreception to mechanical stimulation during the first 3 days of reperfusion. Sensory nerves gradually reinnervated in the skin of paw pads and allodynia began to appear on day 7. The maximum reaction occurred on day 14 and was maintained throughout the study period. Treatment with Mas mitigated nerve damage and improved hind paw mechanoreception to mechanical stimulation by decreasing the production of reactive oxygen species (ROS) during the early stages of tourniquet/IR. Mas also alleviated allodynia and decreased inflammatory cytokines (IL-1ß and TNFα) in the skin of paw pads from days 7-28. Our data suggest that treatment with Mas significantly ameliorated paw numbness and allodynia in mouse hind paw tourniquet/IR.