Schedule dependency of paclitaxel-induced neuropathy in mice: a morphological study

Paclitaxel, which is known to induce peripheral neuropathy in humans, was administered to BDF1 mice, and a neuropathological examination was then conducted. Paclitaxel was administered at a dose of 30 mg/kg once or several times at different intervals, 3 times, every 3 hours (q3hx3), every day (q1dx3), every 2 days (q2dx3) and 4 times, once a week (q7dx4). The spinal cord, spinal ganglion and peripheral nerves (sciatic and tibial) were then processed for neuropathological examination following perfusion of the anesthetized mice. The effect on the peripheral nerves was evaluated by counting the number of abnormal nerve fibers in the preparations of teased nerve fibers and in the epoxy resin 1-microm-thick sections. The drug-induced degeneration, such as axonal and myelin fragmentations and phagocytosis in the nerve fibers, was detected in the dorsal funiculus, the dorsal spinal roots and the peripheral nerves (sciatic and tibial). No drug-related degeneration was observed in the motor neurons in the spinal cord nor in the ventral spinal roots. The single treatment did not induce any changes. The severity of the degeneration was as follows: q2dx3>q1dx3>>q3hx3 and q7dx4. The degeneration in the mice treated on q3hx3 and q7dx4 was very slight, but it was clear that paclitaxel also induced degeneration on these schedules. These results suggest that paclitaxel induces a predominantly sensory neuropathy in mice and the severity is obviously dependent on the treatment schedule.