Nimodipine therapy for juvenile ferrets with hydrocephalus

Abstract

Hydrocephalus causes damage to periventricular white matter via compression, stretching, waste material accumulation, and ischemia. Nimodipine has been shown to provide benefits clinically in subarachnoid hemorrhage and in young rats with hydrocephalus, presumably by causing vasodilatation and improving blood flow. Our hypothesis was that nimodipine would provide neuroprotection in ferret kits with induced hydrocephalus. Hydrocephalus was induced by kaolin injection into the cisterna magna of postnatal day (P14) ferrets. The drug trial started on P29 after animals were stratified using ventricle size based on magnetic resonance imaging (MRI). Kits were assigned to vehicle, low dose (3.2mg/kg/day), or high dose (16 mg/kg/day) treatment groups, which were administered in a blinded manner twice daily by subcutaneous injection. The drug trial was briefly discontinued due to toxicity caused by the solvent vehicle: dimethyl sulfoxide (DMSO). After the amount of DMSO was reduced the trial was restarted and ran for 14 days to P52. During the experiment behavioural analysis was done using two separate open field tests, every three days. Vision testing started once kits opened their eyes. There was no consistent or statistically significant difference between any of the treatment groups on either the open field tests or the visual test. We conclude that nimodipine administered in this manner does not seem to provide a neuroprotective effect in a ferret model of hydrocephalus. We cannot exclude the possibility that continuous or more frequent delivery, which would not easily be done in the animal model, might be efficacious.