NEW YORK (Reuters Health) - The progesterone receptor of myelin-forming Schwann cells may be an appropriate target for treatment of Charcot-Marie-Tooth disease (CMT), European scientists report Nature Medicine published online November 9th.
In CMT type 1A, the most common subtype of this peripheral neuromuscular disorder, the peripheral myelin protein PMP-22 is overexpressed. Moreover, progesterone has been shown to stimulate Pmp22 expression in cultured Schwann cells, Dr. Klaus-Armin Nave and colleagues note.
To model the human disorder, Dr. Nave, at the Max-Planck Institute of Experimental Medicine in Gottingen, Germany, and his team generated Pmp-22-transgenic rats. In these animals, muscle atrophy was correlated with motor performance.
The scientists treated Pmp22 and wild-type male rats with progesterone, the pure progesterone antagonist onapristone (Schering), or vehicle, starting on postnatal day 5 and continuing for 7 weeks.
Pmp22 mRNA in the transgenic animals increased by about 30% after progesterone treatment and decreased 15% after onapristone treatment. Progesterone caused an increase in the proportion of unmyelinated axons and reduced myelin thickness compared with the other two treatments.
After treatment with the progesterone antagonist, the absolute number of axons in cross sections of sciatic nerve increased significantly compared with placebo-treated animals. The authors observed a strong correlation between Pmp22 mRNA levels and the percentage of unmyelinated axons of the same nerve.
The antagonist also improved motor performance, and the hormone decreased motor performance, on a standardized bar test.
“Our data suggest that progesterone should be taken with caution by patients with PMP22 gene duplications,” Dr. Nave’s group writes.
In the future, they hope to test other less toxic antiprogestins in their CMT1A model, extending follow-up for at least a year.
Source: Nat Med 2003. [ Google search on this article ]
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