Axonal transport disturbances in vincristine‐induced peripheral neuropathy

Green, Louis S.; Donoso, J. Alejandro; Heller-Bettinger, Irene; Samson, Frederick E.

doi:10.1002/ana.410010311

Cited by 70 publications

(27 citation statements)

References 23 publications

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“…In our in vivo model, we observed microtubule disorientation without concomitant reduction in the number of microtubules per axon. These data are in agreement with an earlier study of the effects of systemic vincristine on cat vagus nerve (Green et al, 1977). The authors reported no robust depolymerization or loss of axonal microtubules, but did report neurofilament aggregation, similar to that observed in this study.…”

Section: Vincristine Causes Disorientation But No Loss Of Axonal Micsupporting

confidence: 93%

“…Vinca alkaloids have been shown in vitro to depolymerize microtubules when administered at doses in the micromolar range, but only prevent microtubule assembly in the nanomolar range (Jordan et al, 1992a,b;Baas and Ahmad, 1993;Zheng et al, 1993;Wilson and Jordan, 1994;Tanaka et al, 1995). Higher concentrations of vinca alkaloids are effective in the promotion of axonal microtubule depolymerization and the formation of tubulin paracrystals (Green et al, 1977;Dustin, 1984), usually when applied locally to axons either in vitro (Green et al, 1977;Sahenk et al, 1987) or in vivo (Shelanski and Wisniewski, 1969). Whereas the precise concentration of vincristine that reaches peripheral axons in the present study is unknown, our data suggest that concentrations that reach peripheral axons are sufficient to cause microtubule disorientation, but not extensive depolymerization.…”

Section: Mechanisms Of Vincristine Action On Peripheral Nervementioning

confidence: 99%

“…Interestingly, the paresthesias and dysesthesias reported in humans are most pronounced in the distal extremities (Sandler et al, 1969;Holland et al, 1973), namely those areas innervated by the longest sensory neurons which are presumably those most sensitive to disruption of axonal transport. Although there are clear alterations in axonal microtubules following direct application of vincristine to peripheral nerve in vitro (Green et al, 1977;Sahenk et al, 1987) or in vivo (Schlaepfer, 1971), there have been no quantitative ultrastructural studies of microtubules in peripheral axons during the neuropathic hyperalgesia and nociceptor hyperresponsiveness induced by systemic administration of vincristine.…”

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confidence: 99%

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Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat

1998

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Neuropathic pain accompanies peripheral nerve injury following a variety of insults including metabolic disorders, traumatic injury, and exposure to neurotoxins such as vincristine and taxol. Vincristine, a microtubule depolymerizing drug, produces a peripheral neuropathy in humans that is accompanied by painful paresthesias and dysesthesias (Sandler et al., [1969] Neurology 19:367-374; Holland et al. [1973] Cancer Res. 33:1258-1264). The recent development of an animal model of vincristine-induced neuropathy provides an opportunity to investigate mechanisms underlying this form of neuropathic pain. Systemic vincristine (100 microg/kg) produces hyperalgesia to mechanical stimuli during the second week of administration, which persists for more than a week (Aley et al. [1996] Neuroscience 73:259-265). To test the hypothesis that changes in microtubule structure in nociceptive sensory neurons accompany vincristine-induced hyperalgesia, we analyzed unmyelinated axons in saphenous nerves of vincristine-treated rats. This study constitutes the first quantitative ultrastructural analysis of the cytoskeleton of unmyelinated axons in peripheral nerve during neuropathic hyperalgesia. There was no evidence of unmyelinated fiber loss or a decrease in the number of microtubules per axons. There was, however, a significant decrease in microtubule density in unmyelinated axons from vincristine-treated rats. This decrease in microtubule density was due to a significant increase in the cross-sectional area of unmyelinated axons, suggesting swelling of axons. In addition, vincristine-treated axons had significantly fewer microtubules cut in cross-section and significantly more tangentially oriented microtubules per axon compared to controls. These results suggest that vincristine causes disorganization of the axonal microtubule cytoskeleton, as well as an increase in the caliber of unmyelinated sensory axons.

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Section: Vincristine Causes Disorientation But No Loss Of Axonal Micsupporting

confidence: 93%

Section: Mechanisms Of Vincristine Action On Peripheral Nervementioning

confidence: 99%

mentioning

confidence: 99%

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Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat

1998

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“…We ascribe this to the perineurial sheath which may show some differences in permeation along its length. In the desheathed nerves, we did not see irregular waves of outflow activity observed in the course of transport block by the vinca alkaloids, as described by Green et al (1977). In all cases and a t all concentrations of vinca alkaloids, a smooth and more or less rapid decline of labeled activity to baseline levels was seen.…”

Section: Comparison Of Vinca Alkaloids I N Blocking Transportsupporting

confidence: 67%

Block of axoplasmic transport in vitro by vinca alkaloids

1980

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The three potent antimitotic vinca alkaloids: vincristine (VCR), vinblastine (VLB), and vindesine (VDS) were compared for their effect in blocking axoplasmic transport in vitro using a desheathed preparation of the peroneal branch of cat sciatic nerve. A range of vinca alkaloid concentrations from 1-100 microM was examined. The relative order of potency in blocking axoplasmic transport was VCR greater than VLB greater than VDS at a concentration of 25 microM. At the higher concentrations block occurred so rapidly that a statistically significant difference between these agents could not be obtained. The relation of vinca block to the transport mechanism is discussed.

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“…Ultrastructural studies have shown that VCR depolymerizes axonal microtubules dose-dependently and induces the formation of paracrystals. These studies were carried out on the vagal nerve of the cat, the optic nerve of the rabbit and the cerebral ganglia of the freshwater snail Lymnaea stagnalis [3][4][5][6]. Paracrystals have also been observed in human anterior horn cells after intrathecal administration of VCR [7].…”

Section: Introductionmentioning

confidence: 99%

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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Axonal transport disturbances in vincristine‐induced peripheral neuropathy

Cited by 70 publications

References 23 publications

Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat

Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat

Block of axoplasmic transport in vitro by vinca alkaloids

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

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