Depressive Effectiveness of Vigabatrin (y-Vinyl-GABA), an Antiepileptic Drug, in Intermediate-conductance Calcium-Activated Potassium Channels in Human Glioma Cells

Background: Vigabatrin (VGB, y-vinyl-GABA) is an approved non-traditional antiepileptic drug that has been revealed to have the therapeutic propensity for brain tumors; however, its ionic effects in glioma cells remain unclear to a large extent.Methods: With the aid of patch-clamp technology, we investigated the effects of VGB on various ionic currents in the glioblastoma multiforme cell line 13-06-MG.Results: In cell-attached configuration, addition of VGB concentration-dependently lessened the activity of intermediate-conductance Ca 2+ -activated K + (IK Ca ) channels, while subsequent application of DCEBIO (5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one) thwarted the VGB-induced inhibition of IK Ca channels. Neither the activity of large-conductance Ca 2+ -activated (BK Ca ) nor that of inwardly rectifying K + (K IR ) channels was adjusted by the presence of VGB in human 13-06-MG cells. However, in the continued presence of VGB, the addition of GAL-021 or BaCl 2 effectively suppressed BK Ca and K IR channels.Conclusion: The inhibitory effect of VGB on IK Ca channels demonstrated in the current study could be an unidentified but important underlying mechanism of VGB-induced antineoplastic ( e.g. , anti-glioma) actions.

In Silico, Ex Vivo and In Vivo Studies of Roflumilast as a Potential Antidiarrheal and Antispasmodic agent: Inhibition of the PDE-4 Enzyme and Voltage-gated Ca++ ion Channels

The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration–response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.