Differential trophic effects of ORG 2766, an ACTH(4–9)/MSH(4–9) analogue, on peptidergic neurons and glial cells in the snail Lymnaea stagnalis

Müller, Linda; Kiburg, B.; Delft, Carry M. Moorer-van; Boer, H. H.

doi:10.1016/0196-9781(94)90183-x

Peptides

1994

DOI: 10.1016/0196-9781(94)90183-x

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Differential trophic effects of ORG 2766, an ACTH(4–9)/MSH(4–9) analogue, on peptidergic neurons and glial cells in the snail Lymnaea stagnalis

Linda Müller

B. Kiburg

Carry M. Moorer-van Delft

et al.

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Cited by 7 publications

(1 citation statement)

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“…In the pond snail Lymnaea stagnalis, an increase in the number of microtubules in the axons of the cerebral commissure has been found after treatment of isolated cerebral ganglia with ORG 2766 (Muller et al, 1992). Furthermore, in this model, glial cells seem to be activated, as indicated by a change in the chromatin pattern in the nuclei and an increase in the amount of glial tissue (Muller et al, 1993 (Muller et al, 1991 U937 and U715 cells were seeded at a final concentration of 6,000 cells per well and 8,000 cells per well respectively, in a total volume of 100 LI, in a 96 well round-bottomed microtitre plate (Greiner, 650180), for experiments which required incubations of 24 and 48 h. For incubation of 72 and 96 h, 3,000 cells per well and 4,000 cells per well of U937 and U715 were seeded respectively. All experiments were performed in triplicate.…”

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confidence: 89%

Effects of the ACTH(4-9) analogue, ORG 2766, on vincristine cytotoxicity in two human lymphoma cell lines, U937 and U715

Kiburg

Loosdrecht²,

Schweitzer³

et al. 1994

Br J Cancer

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Summary The use of cytotoxic drug vincristine (VCR) is limited by the occurrence of peripheral neuropathy. A neurotrophic ACTH(4-9) analogue, ORG 2766, is being studied for its protective effect. Possible modulatory effects of ORG 2766 on tumour cell growth and interference with the cytotoxic efficacy of VCR were studied in two human lymphoma cell lines, U937 and U715. The effects of ORG 2766 on cell growth and survival and on VCR-mediated cytotoxicity were investigated using two MTT-based assays to study direct cytotoxic effects and to assess residual growth after pretreatment. Treatment with ORG 2766 alone had no effect on cell growth and survival. Neither did this drug affect VCR cytotoxicity. However, after 96 h pretreatment with ORG 2766 and a culture period of 7 days, a reduction in residual growth and a potentiation of VCR-induced inhibition of growth capacity was observed in U715 cells, and to some extent also in U937 cells. It is concluded that ORG 2766 has no stimulatory effects on tumour growth and does not negatively interfere with VCR-mediated cytotoxicity. Rather it enhances the cytostatic effect of VCR. It is suggested that ORG 2766 can safely be used in clinical trials investigating the ability of ORG 2766 to counteract VCRinduced neurotoxicity.

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mentioning

confidence: 89%

Effects of the ACTH(4-9) analogue, ORG 2766, on vincristine cytotoxicity in two human lymphoma cell lines, U937 and U715

Kiburg

Loosdrecht²,

Schweitzer³

et al. 1994

Br J Cancer

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

Kiburg

Delft²,

Heimans

et al. 1996

J Neuro-Oncol

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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.

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Ultrastructural neuropathologic effects of Taxol on neurons of the freshwater snailLymnaea stagnalis

et al. 1995

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Cerebral ganglia of the freshwater snail Lymnaea stagnalis were incubated in vitro in 10 microM Taxol for 8 and 24 h. Cremophor EL (0.1%) was used as a diluant. The tissue was processed for electron microscopy. Various ultrastructural parameters were assessed quantitatively. Cremophor EL appeared to seriously affect the cell somata of the multipeptidergic caudodorsal cells. In the Cremophor-controls the mean area of Golgi zones, the percentage dense material (neuropeptides) in these zones, the number of large electron dense granules (these are involved in neuropeptide processing) and the mean nuclear heterochromatin clump size, were significantly smaller than in the Ringer-controls, whereas the number of lipid droplets was higher. All these parameters, except for the lipid droplets, were not different in the Cremophor-controls and the Taxol-treated specimens. After 24 h treatment, but not after 8 h, Cremophor EL furthermore induced an increase in the number of axonal microtubules. It is argued that the results might signify activation of the neurons by Cremophor EL. Taxol induced a significant increase in the number of microtubules in axons and cell somata. Furthermore an increase in the number of Golgi zones was observed, suggesting activated neuropeptide synthesis. In all groups immunostaining with antibodies to neuropeptides produced by the caudodorsal cells was normal. Release of neuropeptide (exocytosis) from axon endings was elevated after Taxol treatment, and exceptionally high in specimens cotreated with Taxol and Org 2766 (incubation time 22 h). The effect of Org 2766 and Taxol on the number of microtubules was cumulative.(ABSTRACT TRUNCATED AT 250 WORDS)

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Differential trophic effects of ORG 2766, an ACTH(4–9)/MSH(4–9) analogue, on peptidergic neurons and glial cells in the snail Lymnaea stagnalis

Cited by 7 publications

References 28 publications

Effects of the ACTH(4-9) analogue, ORG 2766, on vincristine cytotoxicity in two human lymphoma cell lines, U937 and U715

Effects of the ACTH(4-9) analogue, ORG 2766, on vincristine cytotoxicity in two human lymphoma cell lines, U937 and U715

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

Ultrastructural neuropathologic effects of Taxol on neurons of the freshwater snailLymnaea stagnalis

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