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Induction of Apoptosis in Human Lens Epithelial Cells by the Calcium Channel Antagonist Mibefradil in Vitro to Prevent Posterior Capsule Opacification

1Kunz F., 1Nebe B., 2Beck R., 3Noack T., 1Rychly J., 2Guthoff R.,
1Universität Rostock, Klinik für Innere Medizin, Abteilung Klinische Forschung (Rostock)
2Universität Rostock, Augenklinik (Rostock)
3Universität Rostock, Institut für Physiologie (Rostock)

Purpose: Posterior capsule opacification (PCO) is the most common complication of cataract surgery, with an incidence of up to 50% by 2 years postoperatively. To block human lens epithelial cell (hLEC) function, interfering with intracellular signal transduction appears to be a suitable approach.
Method: Mibefradil, a T-type calcium channel blocker was used in studies with hLEC obtained during cataract surgery. Apoptosis (Annexin V-FITC and TUNEL test), actin cytoskeleton and integrin receptor distribution were examined by immunofluorescence using confocal microscopy. Integrin expression was measured by flow cytometry. To study the mechanisms of Mibefradil action we investigated the membrane properties of hLEC with patch clamp technique.
Results: The calcium channel antagonist Mibefradil induced apoptosis within 24 h as shown by phospatidylserine exposure at the cell surface followed by DNA-cleavage into oligonucleosomal length DNA fragments. The apoptotic process is accompanied by fragmentation of the actin cytoskeleton which occurs prior to DNA-cleavage. In addition, adhesion related mechanisms were impaired. The normally uniform distribution of the integrin receptor β1α3 was lost and the integrin expression was reduced due to Mibefradil treatment. Our first experiments using the patch clamp technique identified potassium and calcium channels in hLEC. The inwardly directed current was completely inhibited by Mibefradil (10 µM). In connection with the rapid kinetics and the activation threshold the inwardly directed current was carried mainly by T-type calcium channels.
Conclusions: The induction of apoptosis by Mibefradil promises a new pharmaceutical approach to inhibit PCO. Further experiments have to address the detailed mechanisms of the action of the calcium antagonist Mibefradil.

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