EFFECT OF CISPLATIN AND ACTH(4-9) ON NEURAL TRANSPORT IN CISPLATIN-INDUCED NEUROTOXICITY

Cisplatin causes a dose limiting peripheral neuropathy, however, the b iological mechanism by which this occurs is unknown. Murine N1E.115 ne uroblastoma cells and neural crest derived pigment cells have similar transport mechanisms to human neural cells and were used to study the effect of cisplatin on cellular transport. Cisplatin reduced both the number and velocity of organelles moving in the anterograde and retrog rade direction, compared to control cells. Cisplatin induced inhibitio n of transport was prevented by the simultaneous administration of ACT H(4-9). This analog alone had no effect on N1E.115 organelle, or eryth rophore granule, movement. In both N1E.115 and pigment cells cisplatin inhibited transport within 1 h of exposure to the drug. The degree of inhibition did not increase significantly if pigment cells were incub ated in cisplatin for 48 h compared to acute exposure. Microtubules in both pigment cells and N1E.115 neurites retained their structural int egrity suggesting that factors other than changes in gross microtubule morphology are responsible for cisplatin neurotoxicity. Cisplatin red uces N1E.115 neurite growth after 48 h incubation but this can be prev ented by simultaneous use of ACTH(4-9). This study demonstrates for th e first time that cisplatin and ACTH(4-9) affect fast axonal transport by specific mechanisms which appear related to their observed neuroto xic and neuroprotective roles, respectively.