Tacrolimus and Cyclosporine A Are of No Benefit to Young Rats with Kaolin-Induced Hydrocephalus

Abstract

Hydrocephalus causes damage to periventricular axons. Tacrolimus, cyclosporine A (CsA) and calpain inhibitors have been shown to protect axons in rat models of acute traumatic brain injury. We hypothesized that these agents would ameliorate the axon damage and behavioral effects in experimental hydrocephalus. Hydrocephalus was induced in 3-week-old rats by injection of kaolin into the cisterna magna. Tests of cognitive and motor function were performed on a weekly basis. In a blinded and randomized manner, tacrolimus (FK506; 3.6 mg/kg body weight) or CsA (10 mg/kg) was administered once daily by subcutaneous injection for 2 weeks, beginning 2 weeks after induction of hydrocephalus. In a separate experiment, calpain inhibitor I (10 mg/kg/day) was administered by continuous subcutaneous infusion. The brains were subjected to histopathological and biochemical analyses after 2 weeks of treatment. There was no statistically significant protection in regard to behavior, brain structure or brain composition in any of the experiments. However, there was biochemical and histological evidence of renal injury following chronic tacrolimus and CsA administration. Calcineurin inhibition does not offer significant protection in this rat model of hydrocephalus.