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

摘要: 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 available. PXT3003 a low-dose combination baclofen, naltrexone, sorbitol which has been shown improve symptoms in Pmp22 transgenic rats, bona fide model CMT1A disease. However, superiority over its single components or dual combinations have not tested. Here, we show that dorsal root ganglion (DRG) co-culture system derived from induced myelination when compared components. Applying clinically relevant ("translational") study design adult male rats 3 months, PXT3003, but components, resulted improved performance behavioral motor sensory endpoints placebo. Unexpectedly, observed only marginally increased number myelinated axons nerves PXT3003-treated rats. electrophysiology, latencies correlated with grip strength indicating possible effect on neuromuscular junctions (NMJs) fiber pathology. Indeed, displayed perimeter individual NMJs larger functional NMJs. Moreover, muscles less neurogenic atrophy shift toward fast contracting fibers. We suggest ameliorated function result restored NMJ innervation, independent myelination.