IN-VIVO MODULATION OF VINCRISTINE-INDUCED NEUROTOXICITY IN LYMNAEA-STAGNALIS, BY THE ACTH(4-9) ANALOG ORG-2766

The use of the cytostatic agent vincristine (VCR) is limited by the oc currence of peripheral neuropathy. This side-effect is probably caused by interference with axonal microtubules. VCR depolymerizes microtubu les and reacts with tubulin to form paracrystals. The potential of a n eurotrophic ACTH((4-9)) analogue, Org 2766, to counteract peripheral n europathy caused by cytostatic agents is being investigated. In the pr esent ultrastructural study. modulatory effects of Org 2766 on VCR-ind uced neurotoxicity were studied in vivo in neurons pf the pond snail L ymnaea stagnalis, which has been shown previously to be a suitable tes t system to investigate neurotoxic side-effects of cytostatic agents. 24 h after treatment with VCR (25 mu M), 68.4+/-34.7 paracrystals were counted per cross-section of the cerebral commissure and the number o f microtubules in the axons had been lowered to 46% of the control lev el. After a survival period of two weeks all paracrystals had disappea red. By that time, no recovery of the axonal microtubular system could be observed. However, posttreatment with Org 2766 (10(-6) M) on day 6 after VCR treatment had induced a significant increase in the number of microtubules (+55%) on day 7. This beneficial effect lasted for the rest of the experimental period (14 days). These results suggest that post-treatment with Org 2766, i.e. after VCR clearance, can induce lo nglasting beneficial effects on VCR-induced neurotoxicity in vivo.