In vivo modulation of vincristine-induced neurotoxicity in Lymnaea stagnalis, by the ACTH(4-9) analogue Org 2766.
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.
Kiburg
B
B
Graduate School Neurosciences, Amsterdam, The Netherlands.
Moorer-van Delft
C
C
Heimans
J J
JJ
Huijgens
P C
PC
Boer
H H
HH
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001369:Axons / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D003460:Crystallization; D017952:Ganglia, Invertebrate / Q000166:cytology / Q000187:drug effects; D008195:Lymnaea; D008854:Microscopy, Electron; D008870:Microtubules / Q000187:drug effects; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000494:pharmacology*; D014750:Vincristine / Q000633:toxicity*
D000927:Anticonvulsants; D000972:Antineoplastic Agents, Phytogenic; D009498:Neurotoxins; D010446:Peptide Fragments; C013765:Org 2766; D014750:Vincristine; D000324:Adrenocorticotropic Hormone