Electrophysiologic and morphologic changes of rat peripheral nerves induced by vincristine sulfate

Park, Kee Duk; Sunwoo, Il Nam; Koo, Heasoo

Abstract

Vincristine has been extensively need in chemotherapy to treat leukemia, lymphoma, and a variety of solid tumor. The major antitumor effect has been known to be associated with its high affinity binding to the basic protein sub unit of microtubule, tubulin, which causes disruption of the mitotic spindle apparatus and arrest of calls in metaphase. The principal side effect that has commonly limited the use of this agent is peripheral sensori-motor neuropathy, a feature probably related to the disruption of microtubule in neural tissues. There has been a need for animal experimental models w study the peripheral neuropathy induced by vincristine. However, it was not easy to develop an adequate model due to reported interspecies difference of susceptibility to vincristine. In addition, electrophysiologic test methods to confirm peripheral neuropathy in small experimental animals has not been properly addressed. The purpose of this experiment is to find out whether rat can be used as an animal experimental model of vincristine neuropathy. The authors also incorporated serial noninvasive electrophysiololgic tests, in attempt to correlate morphologic alterations induced by vincristine and functional status of peripheral nerve and muscle. Experiment Group 1 of 14 rats were given 0. 2mg/kg vincristine sulfate once a week, Group 2 of 14 rats were given same does twice a week and Group 3 of 14 rats were given 0. 4mg/kg intravenously, through tail veins for 6 weeks, to delineate the possible different effects from dosage and frequency of injections. The 14 rats for control were given only normal saline with the same methods. The electrophysiologic tests including motor nerve conduction study, sensory nerve conduction study and cervical somatosensory evoked potential were per formed 2 weeks interval. The morphologic examinations of posterior tibial nerves using light microscope and electron microscope were done 4 weeks interval up to 16 weeks. The H&E, modified Gomori-trichrome and histochemical stain(ATPase & NADH) 1. Vincristine induced peripheral neuropathy was successfully established in rat.. This was confirmed not only by morphologic measurements but also by noninvasive serial electrophysiologic examinations of peripheral nerves. 2. The vincristine neuropathy in rats was sensori-motor type similar to those in human. 3. The motor and sensory conduction velocity of posterior tibial nerve in rats fell significantly at ter 2-4 weeks in the vincristine injected groups A tendency of recovery was noted, but the conduction velocity failed to return to normal level up to 16 weeks follow up study. However, the amplitude of compound muscle action potentials as well as compound nerve action potentials showed a great deal of fluctuation during the genesis of neuropathy. Therefore, these electrophysiologic parameters were not optimal predictors in assessment of functional integrity of given nerves with the electrophysiologic test methods used in this experiments. 4, Morphologic examinations revealed that vincristine neuropathy I rats are clearly these of axonal degeneration, compatible to the findings of electrophysiologic examination. 5. The higher dose of vincristine induced the more damage to the peripheral nerves but it also resulted in high mortality rate. Administration of 0.2mg/kg/week would be adequate in generation of experimental neuropathy. 6. The examinations of gastrocnemius and soleus muscle showed same evidence of mild degree of myopathy but it was felt to be direct toxic effect, rather than secondary changes due to the neuropathy.