Effects of amantadine on corneal endothelium.

Abstract Purpose An adverse effect of amantadine, a drug used for Parkinson's disease, is corneal edema. While corneal endothelial cell loss is noted with amantadine toxicity, the reversibility of corneal edema suggests that amantadine affects active mechanisms regulating corneal hydration. Although mainly known as a NMDA receptor antagonist, amantadine is also a K+-channel blocker. The purpose of this study was to investigate potential mechanisms of amantadine's toxic effects on corneal endothelium. Methods Bovine corneas were used for short-circuit current measurements of corneal endothelial active ion transport to compare the effects of amantadine with an NMDA receptor agonist (NMDA) and antagonist (D-APV), and the K+-channel blockers BaCl 2 and clotrimazole. Cell death and changes in cell morphology were observed using annexin V stain, alizarin red S staining of the intercellular junctions, ZO-1 immunolocalization, and phalloidin stain of the actin cytoskeleton. Results Amantadine caused a transient decrease in the short-circuit current that mimicked the effect of clotrimazole. BaCl 2 , and the NMDA receptor agonist and antagonist had no effect on the short-circuit current. Tissue incubation with amantadine caused an increase in cell area (measured by ZO-1 localization) and cell height (measured by phalloidin stain) but did not increase apoptotic cell death (annexin V stain). Conclusions The similarity of amantadine and clotrimazole effects on the short-circuit current and the effects on cell volume suggest that amantadine's actions on corneal endothelium are mediated via K+ channels. The observed absence of cell death and transient effect on short-circuit current support the reported reversibility of amantadine–induced corneal edema. Highlights • The physiologic basis for amantadine toxicity on corneal endothelium is unknown. • Amantadine has a transient effect on the corneal endothelial short-circuit current. • The short-circuit current effect of amantadine mimics that of a K+ channel blocker, clotrimazole. • Amantadine causes an increase in corneal endothelial cell volume. • Amantadine toxicity on corneal endothelium may be mediated by K+ channels. [ABSTRACT FROM AUTHOR]