Complement Inhibition Reduces Post-Hemorrhagic Hydrocephalus in Mouse Neonatal Germinal Matrix Hemorrhage
Abstract IntroductionGerminal matrix hemorrhage (GMH) is a devastating disease of infancy that results in intraventricular hemorrhage, post-hemorrhagic hydrocephalus (PHH), periventricular leukomalacia and neurocognitive deficits. There are no curative treatments and limited surgical options. We developed a novel mouse model of GMH and investigated the role of complement in PHH development.MethodsWe utilized a neonatal mouse model of GMH involving injection of collagenase into the subventricular zone of post-natal day four (P4) pups. Animals were randomized into four experimental arms: Naïve, sham injured, injured and vehicle (PBS) treated, and injured and CR2Crry-treated (a pan-complement inhibitor). Histopathologic and immunofluorescence analyses were performed at P14 with a focus on parameters of neuroinflammation and neuroprotection. Survival was monitored through day 45, prior to which cognitive and motor function was analyzed.ResultsThe complement inhibitor CR2Crry, which binds C3 complement activation products, localized specifically in the brain following systemic administration after GMH. Compared to vehicle treatment, CR2Crry treatment reduced PHH and lesion size, which was accompanied by decreased perilesional complement deposition, decreased astrocytosis and microgliosis, and the preservation of dendritic and neuronal density. Progression to PHH and neuronal loss was linked to microglial phagocytosis of complement opsonized neurons, which was reversed with CR2Crry treatment. Complement inhibition also improved survival and weight gain, and improved motor performance and cognitive outcomes measured in adolescent GMH mice. ConclusionComplement plays an important role in the pathological sequelae of GMH. Complement inhibition represents a novel therapeutic approach to reduce disease progression in neonatal GMH and PHH, for which there is currently no treatment outside of surgical intervention.
