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

Eur J Pharmacol. 1999 May 21;372(3):287-95. doi: 10.1016/s0014-2999(99)00247-2.

Abstract

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 the cytotoxicity to brain capillary endothelial cells and the effect of these two drugs on P-glycoprotein function using mouse brain capillary endothelial (MBEC4) cells. The transcellular transport of [3H]sucrose was significantly increased and the cellular viability, based on 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and trypan blue exclusion test, was decreased by cyclosporin A (approximately 50% at 5 microM; P<0.005), while tacrolimus showed a much smaller effect. These findings indicate that the toxicity of cyclosporin A was greater than that of tacrolimus. The uptake of [3H]vincristine, a substrate of P-glycoprotein, was increased 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 of P-glycoprotein, which involves translation. In conclusion, the direct cytotoxic effect on the brain capillary endothelial cells and the inhibition of P-glycoprotein may be partly involved in the occurrence of immunosuppressant-induced encephalopathy.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • Animals
  • Biological Transport / drug effects
  • Blood-Brain Barrier / drug effects*
  • Cell Survival / drug effects
  • Cyclosporine / pharmacology*
  • Endothelium, Vascular / drug effects*
  • Immunosuppressive Agents / pharmacology*
  • L-Lactate Dehydrogenase / metabolism
  • Mice
  • Mice, Inbred BALB C
  • RNA, Messenger / metabolism
  • Sucrose / metabolism
  • Tacrolimus / pharmacology*
  • Tritium
  • Vincristine / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • P-glycoprotein 2
  • RNA, Messenger
  • Tritium
  • Sucrose
  • Vincristine
  • Cyclosporine
  • L-Lactate Dehydrogenase
  • Tacrolimus