Partial restoration of defective chloride conductance in ΔF508 CF mice by trimethylamine oxide

This study was designed to test the in vivo efficacy of the chemical chaperone trimethylamine oxide (TMAO) in correcting the Cl- transport defect in a mouse model of cystic fibrosis (CF). Rectal potential difference (RPD) measurements were done in matched wild-type and Delta F508 CF mice. Mice were treated by subcutaneous injections of TMAO. Wild-type mice demonstrated a forskolin-stimulated, Cl--dependent hyperpolarization of -6.4 +/- 0.8 mV (n = 11), which was significantly increased to -13.1 +/- 1.4 mV after treatment with TMAO. Delta F508 CF mice showed no significant responses to forskolin. Treatment with TMAO recovered a forskolin-activated RPD in Delta F508 CF mice (-1.1 +/- 0.2 mV; n = 17) but not in CFTR null mice. The effects of TMAO were dose dependent, resulting in a slope of -0.4 +/- 0.1 mV . g(-1) . kg(-1) in Delta F508 CF mice. The forskolin-stimulated RPD in TMAO-treated Delta F508 CF mice was partially blocked by glibenclamide and further stimulated by apigenin. The total response to forskolin plus apigenin was -2.5 +/- 0.45 mV(n = 6 mice), corresponding to 39% of the response evoked by forskolin only in wild-type mice.