Systemic glycerol decreases neonatal rabbit brain and cerebellar growth independent of intraventricular hemorrhage.

ABSTRACT

BACKGROUND: Cerebellar hypoplasia is a common problem in preterm infants and infants suffering from intraventricular hemorrhage (IVH). To evaluate the effects of IVH on cerebellar growth and development, we used a neonatal rabbit model of systemic glycerol to produce IVH. METHODS: New Zealand White rabbit kits were surgically delivered 2 d preterm and treated with intraperitoneal glycerol (3.25-6.5 g/kg). Controls were born at term. IVH was documented by ultrasonography. Brain volumes determined by magnetic resonance imaging, cerebellar foliation, proliferation (Ki-67), and Purkinje cell density were assessed at 2 wk of life. Tissue glycerol and glutathione concentrations were measured. RESULTS: Glycerol increased IVH, subarachnoid hemorrhages, and mortality in a dose-dependent manner. Total cerebellar volumes, cerebellar foliation, and cerebellar proliferation were decreased in a dose-dependent manner. Glycerol accumulated rapidly in blood, brain, and liver and was associated with increased glutathione concentration. All of these results were independent of IVH status. CONCLUSION: Cerebellar hypoplasia was induced after glycerol administration in a dose-dependent manner. Given the rapid tissue accumulation of glycerol, dose-dependent decrease in brain growth, and lack of IVH effect on measured outcomes, we question the validity of this model because glycerol toxicity cannot be ruled out. A better physiological model of IVH is needed.