Rodent neonatal germinal matrix hemorrhage mimics the human brain injury, neurological consequences, and post-hemorrhagic hydrocephalus

Abstract

Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns. GMH causes neurological sequelae such as cerebral palsy, post-hemorrhagic hydrocephalus, and mental retardation. Despite this, there is no standardized animal model of spontaneous GMH using newborn rats to depict the condition. We asked whether stereotactic injection of collagenase type VII (0.3 U) into the ganglionic eminence of neonatal rats would reproduce the acute brain injury, gliosis, hydrocephalus, periventricular leukomalacia, and attendant neurological consequences found in humans. To test this hypothesis, we used our neonatal rat model of collagenase-induced GMH in P7 pups, and found that the levels of free-radical adducts (nitrotyrosine and 4-hyroxynonenal), proliferation (mammalian target of rapamycin), inflammation (COX-2), blood components (hemoglobin and thrombin), and gliosis (vitronectin and GFAP) were higher in the forebrain of GMH pups, than in controls. Neurobehavioral testing showed that pups with GMH had developmental delay, and the juvenile animals had significant cognitive and motor disability, suggesting clinical relevance of the model. There was also evidence of white-matter reduction, ventricular dilation, and brain atrophy in the GMH animals. This study highlights an instructive animal model of the neurological consequences after germinal matrix hemorrhage, with evidence of brain injuries that can be used to evaluate strategies in the prevention and treatment of post-hemorrhagic complications.

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

“…S4). This finding differentiates our model as being more representative of low-grade GMH, i.e., Papile grades II and III in contrast with the grade IV haemorrhage modelled by previously published studies [24][25][26] . This finding further reinforces the need for this model of low-grade GMH and implies that the global impact of grade IV haemorrhage may mask the more subtle impact that GMH/IVH has on the NSPC within the SVZ.…”

“…Following IC blood injection at P0, we observed an increased number of falls [control ( n = 15), 4.5; sham ( n = 12), 9.33; and GMH ( n = 21), 22.23; ANOVA] and significantly more fails in grip strength testing [control ( n = 15), 1.875; sham ( n = 12), 1.83; and GMH ( n = 21), 2.47; ANO-VA] from P3 to P6; however, this difference did not persist and, contrary to published models of GMH (Aquilina et al [24] , Xue et al [26] , Lekic et al [25] ), we found no persistent deficits/alterations in neuromotor development up to Fig. S4).…”

“…Given the clinical significance of GMH, numerous models in different animal species have been trialled [50] ; however, to date all models have focused on the severe end of the spectrum with extensive cortical injury where diffuse haemorrhage and marked disturbances in behaviour are seen [25,51,52] . It is well recognised that NSPC within the SVZ are exquisitely sensitive to microenvironmental cues [9,10] and further that haemorrhage within the ventricle alters the expression of NSC modulators, such as TGFβ [53] .…”

“…To date, published models of intraventricular haemorrhage (IVH) have focused on modelling severe haemorrhage, with large parenchymal defects seen [24][25][26][27] . This approach is likely to mask the more subtle developmental impact of IVH on the NSPC within the SVZ; as such, we endeavoured to produce a model with minimal cortical disruption to uncover this subtle mechanism.…”

Hydrocephalus after Intraventricular Hemorrhage: The Role of Thrombin

“…However, germinal matrix hemorrhage is common in premature infants, where it is a major cause of cerebral palsy. In a rodent neonatal germinal matrix hemorrhage model, Lekic et al 27 found that IVH resulted in an increase of thrombin and hydrocephalus. The role of thrombin and PAR-1 in hydrocephalus after neonatal IVH should be the subject of further investigation.…”