====== Lysophosphatidic acid ======

[[Autotaxin]] (ATX) is the [[ectoenzyme]] producing the bulk of lysophosphatidic acid (LPA) in circulation
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[[Hydrocephalus treatment]] has largely been limited to surgical [[cerebrospinal fluid]] [[diversion]], as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the [[cerebrospinal fluid]]  [[secretion]] apparatus and its regulatory properties in [[physiology]] and [[pathophysiology]].

[[Cerebrospinal fluid]] obtained from patients with [[subarachnoid hemorrhage]] (SAH) and [[rat]]s with experimentally inflicted [[intraventricular hemorrhage]] (IVH) was analyzed for lysophosphatidic [[acid]] (LPA) by alpha-LISA. Toft-Bertelsen et al. 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.

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.

Together, these 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
((Toft-Bertelsen TL, Barbuskaite D, Heerfordt EK, Lolansen SD, Andreassen SN, Rostgaard N, Olsen MH, Norager NH, Capion T, Rath MF, Juhler M, MacAulay N. [[Lysophosphatidic acid]] as a [[CSF]] [[lipid]] in [[posthemorrhagic hydrocephalus]] that drives CSF accumulation via [[TRPV4]]-induced hyperactivation of [[NKCC1]]. Fluids Barriers CNS. 2022 Sep 6;19(1):69. doi: 10.1186/s12987-022-00361-9. PMID: 36068581.)).