Nimodipine treatment does not benefit juvenile ferrets with kaolin-induced hydrocephalus

Abstract Prior research on 3-week hydrocephalic rats showed that behavioral deficits and white matter damage could be reduced by treatment with Ca2+ channel blocker nimodipine. We hypothesized that treatment with nimodipine would be also beneficial to young ferrets with kaolin-induced hydrocephalus. Hydrocephalus was induced at 14 days of age and animals were treated either with vehicle, low dose nimodipine (3.2 mg/kg/day), or high dose nimodipine (16 mg/kg/day) for 2 weeks from 38 to 52 days age. Hydrocephalic ferrets developed progressive ventriculomegaly, behavioral changes, and in some cases cortical blindness. These changes were not ameliorated by nimodipine. Histological examination showed damage in periventricular white matter, corpus callosum thinning, axonal damage, reactive astroglial changes, and suppressed cell proliferation compared to non-hydrocephalic controls. Treatment with nimodipine was not beneficial for any of the pathological changes mentioned above; only low dose nimodipine treatment was associated with normalized content of glial fibrillary acidic protein, despite larger ventricles. We conclude that young hydrocephalic ferrets experience behavioral impairments and structural brain damage that are not consistently improved by intermittent nimodipine treatment. Continuous delivery should be considered in further preclinical studies

Pre- and post-shunting observations in adult sheep with kaolin-induced hydrocephalus

Abstract Background The objective of this study was to examine host-shunt interactions in sheep with kaolin-induced hydrocephalus. Methods Forty-two sheep (29–40 kg) were utilized for this study. In 20 animals, various kaolin doses were injected into the cisterna magna including 10 and 50 mg/kg as well as 2–4 ml of a 25% kaolin suspension. Based on animal health and hydrocephalus development, 3 ml of a 25% kaolin suspension was chosen. In 16 animals, kaolin was administered and 6–8 days later, the animals received a custom made ventriculo-peritoneal shunt. In 8 animals ventricular CSF pressures were measured with a water manometer before kaolin administration and 7–8 days later. The sheep were allowed to survive for up to 9–12 weeks post-kaolin or until clinical status required euthanasia. Brains were assessed for morphological and histological changes. Ventricle/cerebrum cross sectional area ratios (V/C) were calculated from photographs of the sliced coronal planes immediately anterior to the interventricular foramina. Results Intraventricular pressures increased from 12.4±1.1 cm H2O to 41.3±3.5 cm H2O following kaolin injection (p 0.10) ventricular expansion. The animals lost weight between kaolin administration and shunting (33.7±1.2 kg versus 31.0±1.7 kg) with weights after shunting remaining stable up to sacrifice (31.6±2.2 kg). Of 16 shunted animals, 5 did well and were sacrificed 9–12 weeks post-kaolin. In the remainder, the study was terminated at various times due to deteriorating health. Hydrocephalus was associated with thinning of the corpus callosum, but no obvious loss of myelin staining, along with reactive astroglial (glial fibrillary acidic immunoreactive) and microglial (Iba1 immunoreactive) changes in the white matter. Ventricular shunts revealed choroid plexus ingrowth in 5/16, brain tissue ingrowth in 1/16, problems with shunt insertion in 3/16, occlusion by hemorrhagic-inflammatory material in 5/16, or no obstruction in 2/16. Free flowing CSF indicated that the peritoneal catheter was patent. Conclusions Cerebrospinal fluid shunts in hydrocephalic sheep fail in ways that are reminiscent of human neurosurgical experience suggesting that this model may be helpful in the development of more effective shunt technology