Heterozygous P0 deficiency protects mice from vincristine-induced polyneuropathy

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J Neurosci Res. 2006 May 4

Heterozygous P0 deficiency protects mice from vincristine-induced

polyneuropathy.

Uceyler N, Kobsar I, Biko L, Ulzheimer J, Levinson SR, i R,

Sommer C.

Department of Neurology, Julius-Maximilians Universitat, Wurzburg,

Germany.

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.