title: Heterozygous P0 deficiency protects mice from vincristine-induced polyneuropathy.
abstract: Patients with hereditary neuropathies are more susceptible to vincristine (VIN)-induced neuropathy than patients without this comorbidity. The heterozygous P0(+/-) mouse is an animal model of a distinct form of inherited neuropathies. These mice produce only 50% of the major myelin protein protein zero (P0) and display signs of demyelination in motor nerves at 4 months of age. Here we investigated the development of neuropathic signs in P0(+/-) and wild-type (wt) mice after VIN treatment. Neuropathy was induced by daily intraperitoneal injections of VIN (0.5 mg/kg body weight) over 10 days. Behavioral and electrophysiological tests were performed at regular time points. Wt mice developed significant hypersensitivity to heat and mechanical stimuli between days 7 and 38 after the first VIN injection. Surprisingly, P0(+/-) mice did not show sensory or motor signs of neuropathy over the whole testing period. Immunohistochemical analysis showed an increase in macrophage numbers in sciatic nerve sections of wt mice after VIN, whereas P0(+/-) mice had higher baseline levels of macrophages without changes after VIN treatment. Semithin sections revealed a decrease in the number of small-diameter myelinated fibers in the sciatic nerves of wt mice after VIN application, whereas P0(+/-) mice had higher baseline values of this fiber subtype that did not change under treatment. Dorsal root ganglion neurons of both genotypes showed an up-regulation of voltage-gated sodium channel immunoreactivity after VIN application without differences between the genotypes. Thus, the P0(+/-) phenotype seems to be protected against VIN-induced neuropathy. The mechanism of this neuroprotection remains elusive.
authors: Department of Neurology, Julius-Maximilians Universität, Würzburg, Germany. ueceyler_n@klinik.uni-wuerburg.de
authors: Nurcan
authors: N
authors: Uçeyler
authors: Igor
authors: I
authors: Kobsar
authors: Lydia
authors: L
authors: Biko
authors: Jochen
authors: J
authors: Ulzheimer
authors: S Rock
authors: SR
authors: Levinson
authors: Rudolf
authors: R
authors: Martini
authors: Claudia
authors: C
authors: Sommer