title: Tolerability and efficacy study of P2X7 inhibition in experimental Charcot-Marie-Tooth type 1A (CMT1A) neuropathy.
abstract: Charcot-Marie-Tooth 1A (CMT1A) is a demyelinating hereditary neuropathy for which pharmacological treatments are not yet available. An abnormally high intracellular Ca(2+) concentration was observed in Schwann cells (SC) from CMT1A rats, caused by the PMP22-mediated overexpression of the P2X7 purinoceptor. The purpose of this study was to investigate the tolerability and therapeutic potential of a pharmacological antagonist of the P2X7 receptor (A438079) in CMT1A. A438079 ameliorated in vitro myelination of organotypic DRG cultures from CMT1A rats. Furthermore, we performed an experimental therapeutic trial in PMP22 transgenic and in wild-type rats. A preliminary dose-escalation trial showed that 3mg/kg A438079 administered via intraperitoneal injection every 24h for four weeks was well tolerated by wild type and CMT1A rats. Affected rats treated with 3mg/kg A438079 revealed a significant improvement of the muscle strength, when compared to placebo controls. Importantly, histologic analysis revealed a significant increase of the total number of myelinated axons in tibial nerves. Moreover, a significant decrease of the hypermyelination of small caliber axons and a significant increase of the frequency and diameter of large caliber myelinated axons was highlighted. An improved distal motor latencies was recorded, whereas compound muscle action potentials (CMAP) remained unaltered. A438079 reduced the SC differentiation defect in CMT1A rats. These results show that pharmacological inhibition of the P2X7 receptor is well tolerated in CMT1A rats and represents a proof-of-principle that antagonizing this pathway may correct the molecular derangements and improve the clinical phenotype in the CMT1A neuropathy.
authors.affiliation: DIMES, Section of Biochemistry, and CEBR, University of Genova, Viale Benedetto XV, 1, 16132, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sociali
authors.affiliation: DINOGMI and CEBR, University of Genova, Largo P. Daneo 3, 16132 Genova, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Visigalli
authors.affiliation: Max Planck Institute of Experimental Medicine, Research Group "Molecular and Translational Neurology", Department of Neurogenetics, Hermann-Rein-Str. 3, 37075 Göttingen, Germany; University Medical Center Göttingen, Institute of Clinical Pharmacology, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prukop
authors.affiliation: Max Planck Institute of Experimental Medicine, Research Group "Molecular and Translational Neurology", Department of Neurogenetics, Hermann-Rein-Str. 3, 37075 Göttingen, Germany.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cervellini
authors.affiliation: DIMES, Section of Biochemistry, and CEBR, University of Genova, Viale Benedetto XV, 1, 16132, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Mannino
authors.affiliation: DINOGMI and CEBR, University of Genova, Largo P. Daneo 3, 16132 Genova, Italy.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Venturi
authors.affiliation: DIMES, Section of Biochemistry, and CEBR, University of Genova, Viale Benedetto XV, 1, 16132, Italy. Electronic address: santina.bruzzone@unige.it.
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.affiliation: Max Planck Institute of Experimental Medicine, Research Group "Molecular and Translational Neurology", Department of Neurogenetics, Hermann-Rein-Str. 3, 37075 Göttingen, Germany; University Medical Center Göttingen, Department of Clinical Neurophysiology, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
authors.affiliation: DINOGMI and CEBR, University of Genova, Largo P. Daneo 3, 16132 Genova, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Schenone
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000473:pathology*; D002607:Charcot-Marie-Tooth Disease / Q000473:pathology* / Q000503:physiopathology; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*
chemical_list: D009185:Myelin Proteins; D058486:Receptors, Purinergic P2X7
keywords: CMT1A; Grip strength test; Myelination; P2X7; PMP22; SC differentiation markers