Danielle S. Goulding, R. Caleb Vogel, John C. Gensel, Josh M. Morganti, Arnold J. Stromberg, and Brandon A. Miller
Neonatal intraventricular hemorrhage (IVH) leads to posthemorrhagic hydrocephalus (PHH), brain injury, and long-term disability. Current therapy for IVH is based on treating PHH but does not address the underlying brain injury. In order to develop pharmacological treatment for IVH, there must be a better understanding of the underlying pathology of this disease. This study was designed to determine the time course of the acute inflammation and oxidative stress that may underlie the progressive pathology of IVH. The authors sought to understand the temporal relationships among inflammation, oxidative stress, and white matter pathology in a rat model of IVH.
A rat model of IVH consisting of hemoglobin injection into the lateral ventricle was used. Tissue was analyzed via biochemical and histological methods to map the spatiotemporal distribution of innate immune activation and oxidative stress. White matter was quantified using both immunohistochemistry and Western blot for myelin basic protein (MBP) in the corpus callosum.
IVH led to acute induction of inflammatory cytokines, followed by oxidative stress. Oxidative stress was concentrated in white matter, adjacent to the lateral ventricles. Animals with IVH initially gained weight at a lower rate than control animals and had larger ventricles and less MBP than control animals.
Experimental IVH induces global inflammation throughout the brain and oxidative stress concentrated in the white matter. Both of these phenomena occur early after IVH. This has implications for human neonates with immature white matter that is exquisitely sensitive to inflammation and oxidative stress. Antiinflammatory or antioxidant therapy for IVH may need to be initiated early in order to protect developing white matter.
Danielle S. Goulding, R. Caleb Vogel, Chirayu D. Pandya, Crystal Shula, John C. Gensel, Francesco T. Mangano, June Goto, and Brandon A. Miller
The authors sought to determine if hydrocephalus caused a proinflammatory state within white matter as is seen in many other forms of neonatal brain injury. Common causes of hydrocephalus (such as trauma, infection, and hemorrhage) are inflammatory insults themselves and therefore confound understanding of how hydrocephalus itself affects neuroinflammation. Recently, a novel animal model of hydrocephalus due to a genetic mutation in the Ccdc39 gene has been developed in mice. In this model, ciliary dysfunction leads to early-onset ventriculomegaly, astrogliosis, and reduced myelination. Because this model of hydrocephalus is not caused by an antecedent proinflammatory insult, it was utilized to study the effect of hydrocephalus on inflammation within the white matter of the corpus callosum.
A Meso Scale Discovery assay was used to measure levels of proinflammatory cytokines in whole brain from animals with and without hydrocephalus. Immunohistochemistry was used to measure macrophage activation and NG2 expression within the white matter of the corpus callosum in animals with and without hydrocephalus.
In this model of hydrocephalus, levels of cytokines throughout the brain revealed a more robust increase in classic proinflammatory cytokines (interleukin [IL]–1β, CXCL1) than in immunomodulatory cytokines (IL-10). Increased numbers of macrophages were found within the corpus callosum. These macrophages were polarized toward a proinflammatory phenotype as assessed by higher levels of CD86, a marker of proinflammatory macrophages, compared to CD206, a marker for antiinflammatory macrophages. There was extensive structural damage to the corpus callosum of animals with hydrocephalus, and an increase in NG2-positive cells.
Hydrocephalus without an antecedent proinflammatory insult induces inflammation and tissue injury in white matter. Future studies with this model will be useful to better understand the effects of hydrocephalus on neuroinflammation and progenitor cell development. Antiinflammatory therapy for diseases that cause hydrocephalus may be a powerful strategy to reduce tissue damage.