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  • Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot-Marie-Tooth disease type 1A (CMT1A) rats.

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot-Marie-Tooth disease type 1A (CMT1A) rats.

Journal of neuroscience research (2020-06-27)
Thomas Prukop, Stephanie Wernick, Lydie Boussicault, David Ewers, Karoline Jäger, Julia Adam, Lorenz Winter, Susanne Quintes, Lisa Linhoff, Alonso Barrantes-Freer, Michael Bartl, Dirk Czesnik, Jana Zschüntzsch, Jens Schmidt, Gwenaël Primas, Julien Laffaire, Philippe Rinaudo, Anthony Brureau, Serguei Nabirotchkin, Markus H Schwab, Klaus-Armin Nave, Rodolphe Hajj, Daniel Cohen, Michael W Sereda
ABSTRACT

Charcot-Marie-Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low-dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co-culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant ("translational") study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003-treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003-treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003-treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Rabbit IgG (H+L), CF 568 antibody produced in goat, ~2 mg/mL, affinity isolated antibody
Sigma-Aldrich
Anti-Neurofilament 200 antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
Anti-PMP22 antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
SYBR® Green Extract-N-Amp Tissue PCR Kit, sufficient for 100 extractions, sufficient for 100 amplifications