RT Journal Article SR Electronic T1 Parallel Improvement of Sodium and Chloride Transport Defects by Miglustat (n-Butyldeoxynojyrimicin) in Cystic Fibrosis Epithelial Cells JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1016 OP 1023 DO 10.1124/jpet.107.135582 VO 325 IS 3 A1 Sabrina Noël A1 Martina Wilke A1 Alice G. M. Bot A1 Hugo R. De Jonge A1 Frédéric Becq YR 2008 UL http://jpet.aspetjournals.org/content/325/3/1016.abstract AB Cystic fibrosis, an autosomal recessive disease frequently diagnosed in the Caucasian population, is characterized by deficient Cl- transport due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A second major hall-mark of the disease is Na+ hyperabsorption by the airways, mediated by the epithelial Na+ channel (ENaC). In this study, we report that in human airway epithelial CF15 cells treated with the CFTR corrector miglustat (n-butyldeoxynojyrimicin), whole-cell patch-clamp experiments showed reduced amiloride-sensitive ENaC current in parallel with a rescue of defective CFTR Cl- channel activity activated by forskolin and genistein. Similar results were obtained with cells maintained in culture at 27°C for 24 h before electrophysiology experiments. With monolayers of polarized CF15 cells, short-circuit current (Isc) measurements also show normalization of Na+ and Cl- currents. In excised nasal epithelium of cftrF508del/F508del mice, like with CF15 cells, we found normalization of amiloride-sensitive Isc. Moreover, oral administration of miglustat (6 days) decreased the amiloride-sensitive Isc in cftrF508del/F508del mice but had no effect on cftr-/- mice. Our results thus show that rescuing the trafficking-deficient F508del-CFTR by miglustat down-regulates Na+ absorption. A miglustat-based treatment of CF patients may thus have a beneficial effect both on Cl- and Na+ transports. The American Society for Pharmacology and Experimental Therapeutics