In Vivo and Ex Vivo Evaluation of L-Type Calcium Channel Blockers on Acid β-Glucosidase in Gaucher Disease Mouse ModelsReportar como inadecuado




In Vivo and Ex Vivo Evaluation of L-Type Calcium Channel Blockers on Acid β-Glucosidase in Gaucher Disease Mouse Models - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Gaucher disease is a lysosomal storage disease caused by mutations in acid β-glucosidase GCase leading to defective hydrolysis and accumulation of its substrates. Two L-type calcium channel LTCC blockers—verapamil and diltiazem—have been reported to modulate endoplasmic reticulum ER folding, trafficking, and activity of GCase in human Gaucher disease fibroblasts. Similarly, these LTCC blockers were tested with cultured skin fibroblasts from homozygous point-mutated GCase mice V394L, D409H, D409V, and N370S with the effect of enhancing of GCase activity. Correspondingly, diltiazem increased GCase protein and facilitated GCase trafficking to the lysosomes of these cells. The in vivo effects of diltiazem on GCase were evaluated in mice homozygous wild-type WT, V394L and D409H. In D409H homozygotes diltiazem 10 mg-kg-d via drinking water or 50–200 mg-kg-d intraperitoneally had minor effects on increasing GCase activity in brain and liver 1.2-fold. Diltiazem treatment 10 mg-kg-d had essentially no effect on WT and V394L GCase protein or activity levels <1.2-fold in liver. These results show that LTCC blockers had the ex vivo effects of increasing GCase activity and protein in the mouse fibroblasts, but these effects did not translate into similar changes in vivo even at very high drug doses.



Autor: Ying Sun , Benjamin Liou, Brian Quinn, Huimin Ran, You-Hai Xu, Gregory A. Grabowski

Fuente: http://plos.srce.hr/



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