Stimulation-associated changes in frog neuromuscular junctions. a quantitative ultrastructural comparison of rapid-frozen and chemically fixed nerve terminals

Brewer, P.A.; Lynch, Kathryn

doi:10.1016/0306-4522(86)90052-7

Cited by 24 publications

(9 citation statements)

References 33 publications

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“…As noted in prior studies, A-fibers and C-fibers in normal animals have a surprisingly high incidence of swollen and vacuolated mitochondria. There is evidence showing that swelling and vacuolation may be associated with mitochondrial stress at the time of aldehyde exposure (Brewer and Lynch, 1986). Nevertheless, the pathophysiological significance of the chemotherapy-evoked increase is ambiguous.…”

Section: Discussionmentioning

confidence: 99%

Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel

2012

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Anti-neoplastic agents in the platinum-complex, taxane, vinca alkaloid, and proteasome inhibitor classes induce a dose-limiting, chronic, distal, symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Clinical descriptions suggest that these conditions are very similar but clinical data are insufficient to determine the degree of similarity and to determine if they share common pathophysiological mechanisms. Animal models do not have the limitations of clinical studies and so we have characterized a rat model of chronic painful peripheral neuropathy induced by a platinum-complex agent, oxaliplatin, in order to compare it to a previously characterized model of chronic painful peripheral neuropathy induced by a taxane agent, paclitaxel. The oxaliplatin model evokes mechano-allodynia, mechano-hyperalgesia, and cold-allodynia that have a delayed onset, gradually increasing severity, a distinct delay to peak severity, and duration of about 2.5 months. There is no effect on heat sensitivity. EM analyses found no evidence for axonal degeneration in peripheral nerve and there is no up-regulation of activating transcription factor-3 in the lumbar dorsal root ganglia. There is a statistically significant loss of intraepidermal nerve fibers in the plantar hind paw skin. Oxaliplatin treatment causes a significant increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons, but not in their Schwann cells. Nerve conduction studies found significant slowing of sensory axons, but no change in motor axons. Single fiber recordings found an abnormal incidence of A- and C-fibers with irregular, low-frequency spontaneous discharge. Prophylactic dosing with two drugs that are known to protect mitochondria, acetyl-L-carnitine and olesoxime, significantly reduced the development of pain hypersensitivity. Our results are very similar to those obtained previously with paclitaxel and support the hypothesis that these two agents, and perhaps other chemotherapeutics, produce very similar conditions because they have a mitotoxic effect on primary afferent neurons.

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Section: Discussionmentioning

confidence: 99%

Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel

2012

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“…The reason for the presence of such mitochondria in normal axons is not understood, although there is evidence showing that swelling and vacuolation may be associated with the degree of mitochondrial activity at the time of exposure to aldehydes (Brewer and Lynch, 1986). The rarity of swollen and vacuolated mitochondria in Schwann cells shows that their presence is not a simple artifact of inadequate fixation.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat

et al. 2011

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The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, while the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.

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“…Sci. USA 96 (1999)because, during chemical fixation, exocytosis as well as fusion of vesicles with cytoplasmic organelles may take place (23)(24)(25) followed, during dehydration, by extensive extraction and redistribution of cell components (14,26,27), with ensuing uncontrolled changes of membrane compartments. To establish identification criteria for bona fide secretory organelles that had been processed by the qf-fd procedure, a frog neuromuscular preparation (24) was investigated first.…”

Section: Resultsmentioning

confidence: 99%

Multiple and diverse forms of regulated exocytosis in wild-type and defective PC12 cells

Kasai

Kishimoto

Liu

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Regulated exocytosis triggered by the photolysis of a caged Ca 2؉ compound, DM-nitrophen, was investigated by patch-clamp capacitance measurements in two clones of PC12, the first wild-type and the second (PC12-27) defective of both types of classical secretory vesicles together with the neuronal-type receptors for the attachment proteins of the N-ethylmaleimide-sensitive fusion protein, the so called SNAREs. Moreover, the electrophysiological data were correlated with the ultrastructure of resting quick-frozen-freezedried cells of the two clones. Wild-type PC12 exhibited twocomponent capacitance responses, time constants of 30-100 ms and >10 s, that previous studies had suggested to ref lect primarily the fusion of the small and large secretory vesicles, each contributing cell surface increases of Ϸ10%. Both of these components were largely and specifically inhibited whether cells previously were microinjected with tetanus toxin light chain. In the defective clone, large responses also were recorded (Ϸ19% surface expansion; time constant, Ϸ1 s) that, in contrast to those of the wild-type, were entirely resistant to the toxin. Although secretory organelles, i.e., large vesicles and also profiles of small vesicles, were abundant at the cell periphery and often docked to the plasmalemma of resting wild-type PC12, in the defective clone, no superficial accumulation of vesicles was observed. Our coordinate structural and functional results have revealed diversities between the two classical forms of regulated secretion in wild-type PC12 and have provided evidence of a toxin-insensitive form of Ca 2؉ -induced exocytosis, prominent in the defective clone, that may play an important role(s) in cellular physiology.

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Stimulation-associated changes in frog neuromuscular junctions. a quantitative ultrastructural comparison of rapid-frozen and chemically fixed nerve terminals

Cited by 24 publications

References 33 publications

Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel

Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel

Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat

Multiple and diverse forms of regulated exocytosis in wild-type and defective PC12 cells

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