In vivo modulation of vincristine-induced neurotoxicity in Lymnaea stagnalis, by the ACTH(4?9)analogue Org 2766

Abstract

The use of the cytostatic agent vincristine (VCR) is limited by the occurrence of peripheral neuropathy. This side-effect is probably caused by interference with axonal microtubules. VCR depolymerizes microtubules and reacts with tubulin to form paracrystals. The potential of a neurotrophic ACTH(4-9) analogue, Org 2766, to counteract peripheral neuropathy caused by cytostatic agents is being investigated. In the present ultrastructural study, modulatory effects of Org 2766 on VCR-induced neurotoxicity were studied in vivo in neurons of the pond snail Lymnaea stagnalis, which has been shown previously to be a suitable test system to investigate neurotoxic side-effects of cytostatic agents. 24 h after treatment with VCR (25 microM), 68.4 +/- 34.7 paracrystals were counted per cross-section of the cerebral commissure and the number of microtubules in the axons had been lowered to 46% of the control level. After a survival period of two weeks all paracrystals had disappeared. By that time, no recovery of the axonal microtubular system could be observed. However, post-treatment 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 long-lasting beneficial effects on VCR-induced neurotoxicity in vivo.

Lack of neuroprotection by an ACTH (4?9) analogue. A randomized trial in patients treated with vincristine for Hodgkin?s or non-Hodgkin?s lymphoma

“…The damaged nerve is sensitive to melanocortins only during the first week following nerve injury, which coincides with the time of the initial sprouting response. Following a VCR dose, the administration of the ACTH analogue enhances the number of neural microtubuli significantly in an animal model (Kiburg et al 1996). Unlike platin derivatives, vinca alkaloids also affect the structural integrity of microtubules.…”