title: The diadenosine homodinucleotide P18 improves in vitro myelination in experimental Charcot-Marie-Tooth type 1A.
abstract: Charcot-Marie-Tooth 1A (CMT1A) is a demyelinating hereditary neuropathy whose pathogenetic mechanisms are still poorly defined and an etiologic treatment is not yet available. An abnormally high intracellular Ca(2+) concentration ([Ca(2+)]i) occurs in Schwann cells from CMT1A rats (CMT1A SC) and is caused by overexpression of the purinoceptor P2X7. Normalization of the Ca(2+) levels through down-regulation of P2X7 appears to restore the normal phenotype of CMT1A SC in vitro. We recently demonstrated that the diadenosine 5',5'''-P1, P2-diphosphate (Ap2A) isomer P18 behaves as an antagonist of the P2X7 purinergic receptor, effectively blocking channel opening induced by ATP. In addition, P18 behaves as a P2Y11 agonist, inducing cAMP overproduction in P2Y11-overexpressing cells. Here we investigated the in vitro effects of P18 on CMT1A SC. We observed that basal levels of intracellular cAMP ([cAMP]i), a known regulator of SC differentiation and myelination, are significantly lower in CMT1A SC than in wild-type (wt) cells. P18 increased [cAMP]i in both CMT1A and wt SC, and this effects was blunted by NF157, a specific P2Y11 antagonist. Prolonged treatment of organotypic dorsal root ganglia (DRG) cultures with P18 significantly increased expression of myelin protein zero, a marker of myelin production, in both CMT1A and wt cultures. Interestingly, P18 decreased the content of non-phosphorylated neurofilaments, a marker of axonal damage, only in CMT1A DRG cultures. These results suggest that P2X7 antagonists, in combination with [cAMP]i-increasing agents, could represent a therapeutic strategy aimed at correcting the molecular derangements causing the CMT1A phenotype.
authors: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Mother and Child Sciences and CEBR, University of Genova, Genova, Italy.
authors: Lucilla
authors: L
authors: Nobbio
authors: Davide
authors: D
authors: Visigalli
authors: Elena
authors: E
authors: Mannino
authors: Fulvia
authors: F
authors: Fiorese
authors: Matthias U
authors: MU
authors: Kassack
authors: Laura
authors: L
authors: Sturla
authors: Valeria
authors: V
authors: Prada
authors: Antonio
authors: A
authors: De Flora
authors: Elena
authors: E
authors: Zocchi
authors: Santina
authors: S
authors: Bruzzone
authors: Angelo
authors: A
authors: Schenone
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D004195:Disease Models, Animal; D046149:Embryo Culture Techniques; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D012583:Schwann Cells / Q000187:drug effects* / Q000473:pathology
chemical_list: D015226:Dinucleoside Phosphates; D009185:Myelin Proteins; C073687:PMP22 protein, human; D000242:Cyclic AMP
keywords: CMT1A; DRG CULTURES; MYELINATION; P2X7; cAMP