Molecular Mechanisms of CSF Hypersecretion in Intraventricular Hemorrhage-associated Hydrocephalus

Abstract

Intraventricular hemorrhage (IVH), is the accumulation of blood within the ventricles, and is associated with high morbidity and mortality via IVH-associated hydrocephalus (IVHH). IVHH distorts the surrounding brain tissue, resulting in cognitive and motor impairments, or death. IVHH is attributed to impaired CSF reabsorption at the arachnoid granulations; however, the contribution of CSF hypersecretion is unknown. NKCC1 is regulated by SPAK via phosphorylation, and is critical to the formation of CSF. A novel method to measure the rate of CSF secretion was used to study the role of the SPAK-NKCC1 pathway in IVHH. IVH resulted in ventriculomegaly, due to a 3-fold increase in CSF secretion, determined to be due to SPAK-mediated phosphorylation of NKCC1. Methods to inhibit phosphorylation of NKCC1 significantly attenuated the hypersecretion of CSF and ventriculomegaly associated with IVHH. These results provide evidence that the SPAK-NKCC1 pathway drives the pathogenesis of IVHH and is a potential therapeutic target.