TRPV4 antagonist efficacy in a post-hemorrhagic hydrocephalus pig model

Abstract

Hydrocephalus occurs across the age spectrum but is particularly prevalent in young and old individuals. One form of this disease is post-hemorrhagic hydrocephalus (PHH), which is a life-threatening sequela of intraventricular hemorrhage (IVH). There are no effective non-surgical interventions for the treatment of PHH or other forms of hydrocephalus. Progress has been limited by the lack of gyrencephalic animal models that exhibit high fidelity to human conditions. Here, we establish a pathophysiologically relevant novel swine model of IVH that recapitulates key features of severe PHH, including sustained ventriculomegaly, elevated intracranial pressure (ICP), neuroinflammation and white matter injury. Using this model, we test the therapeutic potential of pharmacologic inhibition of the transient receptor potential vanilloid 4 (TRPV4) non-specific cationic channel. The orally bioavailable TRPV4 antagonist GSK2789917 penetrates the blood-brain barrier, and prevents progression to PHH when administered 2 days after IVH. Specifically, GSK2789917 prevents the development of ventriculomegaly, suppresses early ICP elevations and prevents or reverses inflammasome activation. These findings establish a clinically relevant large-animal model of PHH and identify TRPV4 antagonism as a promising treatment for hydrocephalus.