Neurotoxicology
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The purpose of this investigation was to develop and apply case definitions of peripheral neuropathy (PN) derived from a set of individual measures of peripheral nerve function obtained in two epidemiological studies. ⋯ These results suggest improved efficiency (and avoidance of the multiple-comparisons problem) for detecting peripheral nerve effects when case definitions of PN are constructed rather when results of individual tests of PN function are compared.
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Paclitaxel, which is known to induce peripheral neuropathy in humans, was administered to BDF1 mice, and a neuropathological examination was then conducted. Paclitaxel was administered at a dose of 30 mg/kg once or several times at different intervals, 3 times, every 3 hours (q3hx3), every day (q1dx3), every 2 days (q2dx3) and 4 times, once a week (q7dx4). The spinal cord, spinal ganglion and peripheral nerves (sciatic and tibial) were then processed for neuropathological examination following perfusion of the anesthetized mice. ⋯ The severity of the degeneration was as follows: q2dx3>q1dx3>q3hx3 and q7dx4. The degeneration in the mice treated on q3hx3 and q7dx4 was very slight, but it was clear that paclitaxel also induced degeneration on these schedules. These results suggest that paclitaxel induces a predominantly sensory neuropathy in mice and the severity is obviously dependent on the treatment schedule.
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Vincristine is an effective chemotherapeutic agent for a variety of human neoplasms, but has dose-limiting neurotoxicity. Since laboratory rodents have proven to be refractive in such neurotoxicological studies, we conducted a neuropathological and behavioral assessment in rabbits treated with vincristine at doses known to be both chemotherapeutically effective and neurotoxic in humans. Rabbits (Kbl: NZW) were given vincristine intravenously at doses of 0 (saline), 200, 250 or 300 microg/kg once a week for 6 weeks, 500 microg/kg once a week for 3 weeks, or a single 500 microg/kg administration. ⋯ These alterations were observed even after a single dose of 500 microg/kg. In the group given weekly doses of 500 microg/kg, neuronal chromatolysis was also found in the spinal cord. These results suggest the rabbit is responsive to vincristine neurotoxicity producing a predominantly sensory neuropathy and confirming earlier studies.
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The excitotoxin, L-alpha-aminoadipic acid (L-AAA), kills primary astrocytes in the brain. The mechanism underlying the induction of cell death is not well understood although many possible mechanisms are theorized. Previous studies have reported that astrocytes die after prolonged exposure to L-AAA suggesting a delayed programmed cell death and apoptosis. ⋯ The inhibition of protein synthesis was partially reversible at 24 hours if cells were labeled in medium without L-AAA during the radiolabeling period. Heat shock or stress proteins, HSP70 and heme oxygenase-1 (HO-1), were analyzed after a 24 hour exposure to L-AAA and showed no significant induction of HSP70 or HO-1. The findings suggest that the prolonged inhibition of protein synthesis and associated lack of induction of HSP70 and HO-1 synthesis contributed to apoptotic cell death induced by the excitoxin L-AAA.
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The distribution of paclitaxel (Taxol) within the central and peripheral nervous system after repeated administration of this antineoplastic agent is still largely unknown. In this study we determined for the first time paclitaxel tissue concentration in the brain, spinal cord, dorsal root ganglia (DRG) and sciatic nerve using an experimental paradigm in the rat which reproduces the features of paclitaxel peripheral neurotoxicity in humans. ⋯ We demonstrated that paclitaxel has easy access to the DRG, where it accumulates, while the lowest concentrations of the drug were measured in the brain. The intermediate concentrations of paclitaxel observed in the sciatic nerve and spinal cord may be due to paclitaxel transport along the centrifugal and centripetal branches of the DRG neuron axons.