Background A range of neurological pathologies may lead to secondary hydrocephalus. Treatment has largely been limited to surgical cerebrospinal fluid (CSF) diversion, as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties in physiology and pathophysiology. Methods CSF obtained from patients with subarachnoid hemorrhage (SAH) and rats with experimentally inflicted intraventricular hemorrhage (IVH) was analyzed for lysophosphatidic acid (LPA) by alpha-LISA. We employed the in vivo rat model to determine the effect of LPA on ventricular size and brain water content, and to reveal the effect of activation and inhibition of the transient receptor potential vanilloid 4 (TRPV4) ion channel on intracranial pressure and CSF secretion rate. LPA-mediated modulation of TRPV4 was determined with electrophysiology and an ex vivo radio-isotope assay was employed to determine the effect of these modulators on choroid plexus transport. Results Elevated levels of LPA were observed in CSF obtained from patients with subarachnoid hemorrhage (SAH) and from rats with experimentally-inflicted 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. Conclusions Together, our data reveal that a serum lipid 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 brain water accumulation.

Introduction Posthemorrhagic hydrocephalus (PHH) often develops following hemorrhagic events such as intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Treatment is limited to surgical diversion of the cerebrospinal fluid (CSF) since no efficient pharmacological therapies are available. This limitation follows from our incomplete knowledge of the molecular mechanisms underlying the ventriculomegaly characteristic of PHH. Here, we aimed to elucidate the molecular coupling between a hemorrhagic event and the subsequent PHH development, and reveal the inflammatory profile of the PHH pathogenesis. Methods CSF obtained from patients with SAH was analyzed for inflammatory markers using the proximity extension assay (PEA) technique. We employed an in vivo rat model of IVH to determine ventricular size, brain water content, intracranial pressure, and CSF secretion rate, as well as for transcriptomic analysis. Ex vivo radio-isotope assays of choroid plexus transport were employed to determine the direct effect of choroidal exposure to blood and inflammatory markers, both with acutely isolated choroid plexus and after prolonged exposure obtained with viable choroid plexus kept in tissue culture conditions. Results The rat model of IVH demonstrated PHH and associated CSF hypersecretion. The Na+/K+-ATPase activity was enhanced in choroid plexus isolated from IVH rats, but not directly stimulated by blood components. Inflammatory markers that were elevated in SAH patient CSF acted on immune receptors upregulated in IVH rat choroid plexus and caused Na+/K+/2Cl- cotransporter 1 (NKCC1) hyperactivity in ex vivo experimental conditions. Conclusions CSF hypersecretion may contribute to PHH development, likely due to hyperactivity of choroid plexus transporters. The hemorrhage-induced inflammation detected in CSF and in the choroid plexus tissue may represent the underlying pathology. Therapeutic targeting of such pathways may be employed in future treatment strategies towards PHH patients.

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