Effect of cyclosporin A or tacrolimus on the function of blood-brain barrier cells

Recently, it has been reported that continuous treatment with cyclosporin A or tacrolimus induces encephalopathy in transplant patients. The mechanism of immunosuppressant-induced encephalopathy is unclear. We investigated th e cytotoxicity to brain capillary endothelial cells and the effect of these two drugs on P-glycoprotein function using mouse brain capillary endotheli al (MBEC4) cells. The transcellular transport of [H-3]sucrose was significa ntly increased and the cellular viability, based on 3-(4, 5-dimethylthiazol -2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and trypan blue exclus ion test, was decreased by cyclosporin A (approximately 50% at 5 mu M; P < 0.005), while tacrolimus showed a much smaller effect. These findings indic ate that the toxicity of cyclosporin A was greater than that of tacrolimus. The uptake of [H-3]vincristine, a substrate of P-glycoprotein, was increas ed by these two drugs. The expression of P-glycoprotein in MBEC4 cells was reduced, but there was no effect on mdr1b mRNA levels. The decrease in the expression of P-glycoprotein may be due to the inhibition of the turnover o f P-glycoprotein, which involves translation. In conclusion, the direct cyt otoxic effect on the brain capillary endothelial cells and the inhibition o f P-glycoprotein may be partly involved in the occurrence of immunosuppress ant-induced encephalopathy. (C) 1999 Elsevier Science B.V. All rights reser ved.