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Quantitative Ultrastructural Effects of Cisplatin (Platinol), Carboplatin (JM8), and Iproplatin (JM9) on Neurons of Freshwater Snail Lymnaea stagnalis¹

Department of Biology, Vrije Universiteit, De Boelelaan 1087, 1081 HV Amsterdam [L. J. M., C. M. M., H. H. B.], Department of Animal Physiology, University of Nijmegen, Toernooiveld 6525 ED Nijmegen [E. W. R.], and Department of Oncology, Vrije Universiteit Hospitaal, P. O. Box 7057, 1007 HB Amsterdam [J. B. V.], The Netherlands

Qualitative and quantitative ultrastructural effects of the platinum compounds cisplatin (Platinol), carboplatin (JM8), and iproplatin (JM9) were studied on two types of identified peptidergic neuron (caudodorsal cells, light green cells) in the pond snail Lymnaea stagnalis. Depending on the parameter under investigation, either one or both cell types were studied. Central nervous systems of the snail were incubated for 5 and 20 h in various identical and equitoxic drug concentrations. Cisplatin had the most severe effects. Platinol, i.e., cisplatin dissolved in NaCl solution with the addition of HCl (pH 2.0–3.0), as well as cisplatin dissolved in snail Ringer's solution (pH 7.8), caused swelling of axons and distensions of the intercellular spaces. This drug induced an increase in chromatin clump size in the caudodorsal cells (20-h incubation), while carboplatin and iproplatin induced the formation of many small chromatin clumps. Incubation in snail Ringer's solution (controls) and cisplatin affect the morphology of the nucleoli. At high dosages of cisplatin, the nucleoli of light green cells were transformed into homogeneous dense structures. The data indicate that platinum compounds react with nuclear and nucleolar DNA. All three drugs affected the activity and organization of the rough endoplasmic reticulum and the Golgi apparatus of the peptidergic neurons studied (qualitative observations). These effects, which point to a reduced neuropeptide synthesis, may be secondary, i.e., exerted via inhibition of RNA synthesis and ribosome formation (nucleoli). The fact that the number of neuropeptide granules in the cytoplasm of the cells remained constant (both cell types) may indicate that granule transport was also inhibited. Cisplatin and iproplatin induced an increase in the number of lysosomes in the light green cells. The number of lipid droplets in these cells was not affected by drug treatment.

The results corroborate clinical data indicating that cisplatin is highly neurotoxic. Despite conflicting clinical data, observations on the snail neurons suggest that iproplatin is also neurotoxic, although less than cisplatin. Carboplatin is minimally neurotoxic, which is in accordance with clinical data. The central nervous system of Lymnaea is a suitable model for studying possible neurotoxic effects of platinum compounds.

¹ This study was subsidized by the Netherlands Cancer Fund, NKB (IKA VU 85-8).

² To whom requests for reprints should be addressed, at the Faculty of Biology, Vrije Universiteit, de Boelelaan 1087, 1081 HV Amsterdam-Buitenveldert, The Netherlands.

Received 4/29/91. Accepted 12/ 2/91.

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