Cystic fibrosis (CF) is a genetic disease characterized by CF transmembrane regulator (CFTR) dysfunction. With over 2000 CFTR variants identified, in addition to known patient to patient variability, there is a need for personalized treatment. The discovery of CFTR modulators has shown efficacy in certain CF populations, however there are still CF populations without valid therapeutic options. With evidence suggesting that single drug therapeutics are insufficient for optimal management of CF disease, there has been an increased pursuit of combinatorial therapies. Our aim was to test cyclic AMP (cAMP) modulation, through ATP Binding Cassette Transporter C4 (ABCC4) and phosphodiesterase-4 (PDE-4) inhibition, as a potential add-on therapeutic to a clinically approved CFTR modulator, VX-770, as a method for increasing CFTR activity. Human airway epithelial cells (Calu-3) were used to test the efficacy of cAMP modulation by ABCC4 and PDE-4 inhibition through a series of concentration-response studies. Our results showed that cAMP modulation, in combination with VX-770, led to an increase in CFTR activity via an increase in sensitivity when compared to treatment of VX-770 alone. Our study suggests that cAMP modulation has potential to be pursued as an add-on therapy for the optimal management of CF disease.

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Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells

Background: The use of low-frequency electrical stimulation (LFS) as a therapy for epilepsy is
currently being studied in experimental animals and patients with epilepsy. In the present study, we
investigated the role of serine/threonine protein phosphatases in the inhibitory effects of LFS on
perforant path kindling acquisition.
Materials and Methods: Sixty four male Wistar rats were stimulated by perforant path
stimulation in a rapid kindling manner (6 stimulations per day). The LFS (1 Hz) was applied
immediately after termination of each kindling stimulation. The FK506 (1μM; i.c.v.), a
serine/threonine protein phosphatase PP2B inhibitor and okadaic acid (1μM;i.c.v.), a
serine/threonine protein phosphatases PP1/2A inhibitor, were daily microinjected into the left
ventricle 10 min before starting the stimulation protocol. A two-way ANOVA was done to compare
the seizure parameters of different groups. The effect of LFS on behavioral seizure scores was
analyzed using the nonparametric Kruskal Wallis and Mann Whitney U tests. P value less than
0.05 was considered as the level of significance.
Results: Appling LFS immediately after kindling stimulation significantly retarded the kindling
acquisition and delayed the expression of different kindled seizure stages. In addition, LFS
significantly reduced the increment of daily after-discharge duration during kindling development.
Microinjection of neither FK506 nor okadaic acid had significant effect on the antiepileptogenic
effect of LFS on kindling parameters.
Conclusion: Our findings showed that activation of PP1/2A and PP2B, which play a critical
role in LFS, induced down-regulation of synaptic strength, had no role in mediating the inhibitory
effects of LFS on perforant path kindled seizures.

The role of serine/threonine protein phosphatases in the inhibitory effects of low frequency stimulasion in perforant path kindled seizures acquisition

Seyed javad Mirnajafizadeh

Papers

The role of serine/threonine protein phosphatases in the inhibitory effects of low frequency stimulasion in perforant path kindled seizures acquisition