Effects of FK506 or cyclosporine A on the developing hippocampal formation

Tacrolimus (FK506) and cyclosporin A (CsA) are immunosu-pressants widely used in transplantology. They can also protect neurons in several models of brain damage. Prolonged administration of the drugs has many negative neurological side-effects. The effects might depend on the developmental stage but appropriate investigations have been particularly rare. The present study focuses on long-term changes evoked by the drugs in the developing hippocampal formation. Six- and 30-day-old rats (P6s and P30s, respectively) were injected with FK506 or CsA in their pharmaceutical formulas containing a mixture of ethyl alcohol and Cremophor as a vehicle. Controls received the vehicle alone. When the rats were 60-day-old, sizes of their hippocampal formation, densities of calretinin-(CR+), parvalbumin-immunopositive (PV+) neurons and S100 beta protein-positive (S100 beta +) astrocytes were assessed. In P6s and P30s treated with CsA in its farmaceutical formula, the size of hippocampal formation was reduced. However, injections of the vehicle alone led to similar effects. In P30s, FK506 decreased the density of CR+ neurons but the vehicle had again the same negative effect. The only significant change in relation to vehicle-treated animals was a decrease in density of PV+ neurons in CsA-treated P30s. In P6s, FK506 dissolved in the vehicle increased the density of S100 beta + astrocytes only in relation to naive but not vehicle-treated controls. Long-term effects of FK506 or CsA in their pharmaceutical formulas were mostly negative. Interestingly, they could also be obtained by application of the vehicle alone. Therefore, clinical and experimental effects of FK506 or CsA cannot exclusively be attributed to the drugs themselves abut also to the vehicle which appears to be not biologically neutral.