Lysophosphatidic acid, a CSF marker in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1

A range of neurological pathologies can cause secondary hydrocephalus. For decades, treatment has been limited to surgical CSF diversion, as still no pharmacological options exist due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties. We have now identified phospholipid lysophosphatidic acid (LPA) as a biomarker for posthemorrhagic hydrocephalus (PHH) in patients with subarachnoid hemorrhage (SAH) and mimicked our results in an animal model of intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and ventriculomegaly in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na+, K+, 2Cl- cotransporter (NKCC1) implicated in CSF secretion. Together, our data reveal that a biomarker present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on TRPV4 and its downstream regulation of NKCC1. TRPV4 may therefore be a promising future pharmacological target for pathologies involving disturbed brain fluid dynamics.