hemorrhage and how that affects post-hemorrhagic hydrocephalus. Disclosures are shown here. So germomatrix hemorrhage is a devastating disease of infancy and affects 3 and 1 half for every 1,000 live births and has no current treatments available. We know some associations, including low birth weight and early gestational age, but there is really no prevention to those. GMH is similar to TBI and stroke in that it contains a primary and a secondary injury. Primary injury having direct mechanical insult and disruption of blood vessels, while the secondary injury contains the inflammatory process with recruitment of immune cells and ultimately cyclic neuroinflammation. And this ultimately results in two major pathologies that we know of, periventricular leukomalacia and post-hemorrhagic hydrocephalus. Previous work in our lab has shown that with TBI and stroke, complement inhibition ends up reducing the deleterious effects that result from secondary injury. And therefore, we wanted to extrapolate this to our germomatrix hemorrhage model. So with our previous data from TBI and stroke, we hypothesized that inhibiting complement in the setting of germomatrix hemorrhage would reduce the secondary injury cascades that ultimately result in post-hemorrhagic hydrocephalus. In order to test our hypothesis, we developed a neonatal mouse germomatrix hemorrhage model in which we injected collagenase into the subventricular zone and used it as a stressor in a similar manner to the fragile blood vessel breakdown that happens in a natural germomatrix hemorrhage. These blood vessels were rupturing within an hour of our injection. Here, you can compare a PBS injection into the subventricular zone in the center compared to a collagenase injection on the right-hand side to confirm that the trauma from the needle insertion is not what's causing the injury. In order to better characterize our results, we had to develop an infarct grading system for these animals. And so grade 1 and 2 are essentially cortical infarcts with no ventricular involvement. Grade 3 involves the ventricle and that side. Grade 4 involves the ventricle and causes unilateral ventricular megaly. And then ultimately, grade 5 causes bilateral ventricular megaly, or also known as global hydrocephalus. So we performed a randomized study between two groups, the vehicle, which has PBS injection, and the treatment, which had a complement inhibitor, both injected intraperitoneally. And what we found was a significant reduction in the infarct lesion in the treated groups compared to the vehicle and a concurrent increase in ventricular size, or ventricular megaly, in the vehicle group. You also see a significant reduction in grade 5 injuries, which is correlate to a post-hemorrhagic hydrocephalus. So the presence of hydrocephalus was 61% in the vehicle compared to only 7% in the treated group with complement inhibition. Total brain tissue appears to be more preserved in the treatment group also compared to the vehicle group. We also looked at hippocampus sizes as a marker for cognitive development. And we see that there is a significantly higher preservation of hippocampus in treatment groups compared to the vehicle groups on both ipsilateral and contralateral hippocampi. Survival rates at 21 days were also significantly different, with 90% survival in the treated group compared to only 10% survival in the vehicle group, a very promising result. So this is a rigorous model that we've established that closely mimics the natural mechanism of germal matrix hemorrhage and provides comparable post-hemorrhagic hydrocephalus rates to human neonate in the setting of germal matrix hemorrhage. We show that complement inhibition in germal matrix hemorrhages reduces significantly the rates of post-hemorrhagic hydrocephalus, reduces the overall infarct sizes, and increases overall neonatal mouse survival. Next steps are going to be to investigate the patterns of complement deposition and the cells that are being targeted, as well as the mechanism underlying the development of hydrocephalus in the hemorrhage setting, and then ultimately look at neurocognitive outcomes in older mice that have undergone germal matrix hemorrhage induction. And then hopefully in the future, this would be a bench-to-bedside translational research project as a humanized version of CR2-CRY has already been developed. This is my group, and thank you very much for listening.

germomatrix hemorrhage

post-hemorrhagic hydrocephalus

infants

traumatic brain injury

stroke