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Lysophosphatidic acid receptor 1 signaling initiates neonatal post-hemorrhagic hydrocephalus through ciliated ependymal cell loss

  • Author(s): Lummis, Nicole Christine
  • Advisor(s): Chun, Jerold
  • et al.
No data is associated with this publication.
Abstract

Lysophosphatidic acid (LPA) is a signaling phospholipid that binds to G protein-coupled receptors designated LPA1-LPA6. It has several activities throughout the body, including modulating cellular survival and migration. LPA circulates in the blood bound to carriers such as albumin, and LPA concentrations are increased during cases of hemorrhage or trauma. In the nervous system, LPA helps modulate development and differentiation, but high concentrations of the lipid are often involved in pathology. Post-hemorrhagic hydrocephalus is one such disorder. Hydrocephalus results from an accumulation of cerebrospinal fluid (CSF) in the brain, which expands the fluid-filled ventricles, causing permanent brain damage. This disorder is often chronic and is treated by invasive neurosurgical procedures which drain excess CSF. Here we provide evidence that LPA, introduced to the CSF in the blood, may be a key mediator of post-hemorrhagic hydrocephalus. Animals were injected with LPA at postnatal day 8 and hydrocephalus was observed by measuring increased ventriculomegaly and intracranial pressure 7 days later. Histology and immunohistochemistry demonstrated that the ciliated ependymal cells which generate CSF flow were heavily disrupted 3-6 hours post-LPA exposure. However, development of hydrocephalus and degeneration of the ependymal monolayer was prevented by knockout of LPA1, and to a lesser extent by LPA3 knockout. Pretreatment with the LPA1 antagonist AM095 also protected LPA-injected animals from developing hydrocephalus, signifying that this is a receptor-mediated phenomenon that could be prevented by timely application of a pharmacological inhibitor. As there are currently no efficacious pharmacological treatments for hydrocephalus patients or methods used to prevent hydrocephalus post-hemorrhage, the identification of LPA1-expressing ependymal cells provides a novel target for therapeutic development.

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This item is under embargo until December 19, 2020.