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

Abstract

Background Cerebellar hypoplasia is common problem for preterm infants, and infants that suffer 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 i.p. glycerol (3.25 to 6.5 g/kg). Controls were born at term. IVH was documented by ultrasound. Brain MRI volumes, cerebellar foliation, proliferation (Ki-67) and Purkinje cell density were done at two weeks 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. Conclusions Cerebellar hypoplasia was induced after glycerol administration in a dose-dependent manner. Given rapid tissue accumulation of glycerol, dose dependent decreased brain growth and lack of IVH effect on measured outcomes we question the validity of this model as glycerol toxicity cannot be ruled out. A more physiologic model of IVH is needed.

Heptanoate is neuroprotective in vitro but triheptanoin post-treatment did not protect against middle cerebral artery occlusion in rats

“…Since both groups were equally affected, we speculate that glycerol, which has been shown to be greatly increased (1.7 mM) following triheptanoin infusion [13], could contribute to the hemorrhage. High concentration of glycerol given systemically induce intraventricular and subarachnoid hemorrhage in neonatal rabbit models [35,36]. These findings suggest that care should be taken if considering administering lipidbased parenteral nutrition to stroke patients.…”

Moderate-Grade Germinal Matrix Haemorrhage Activates Cell Division in the Neonatal Mouse Subventricular Zone

“…Thus, in order to understand how GMH impacts NSPC and cortical development in the intermediate group, in whom outcomes appear to be most variable and who may have the most to gain from intervention, a more subtle injury model is needed. Currently available physiological techniques [52] cannot be used to model low-grade GMH as it causes widespread haemorrhage within the brain parenchyma [50] and may also be confounded by the use of glycerol, which has been shown to impact cortical development independently [54] . Similarly, the interpretation of results following the injection of collagenase into the SVZ [25] , whilst reducing bolus size, is significantly limited due to the potentially confounding affect of collagenase on the NSPC.…”

Strategies for working with a preterm rabbit model of glycerol-induced intraventricular hemorrhage: strengths and limitations

“…To the Editor: We read the Traudt et al (1) article with interest, in which the authors reported their experience with our glycerol model of intraventricular hemorrhage (IVH). The authors found a much higher mortality rate and a lower incidence of IVH in the glycerol-treated E29 rabbit pups compared to our report published in 2008 (2).…”

“…The number of P12 survivors were 7, 3, and 5 in 3.25, 4.87, and 6.5 g/kg glycerol dose groups, respectively (their Table 1) and of these, three pups with IVH were excluded from evaluation (1). In view of the small sample size of each group, unknown birthweight and growth of animals, and a presumably sick group of Correspondence Ballabh and LaGamma pups exhibiting high mortality, the authors' conclusion might be premature.…”