LPA 1/3 overactivation induces neonatal posthemorrhagic hydrocephalus through ependymal loss and ciliary dysfunction.

Autor: Lummis NC; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; Biomedical Sciences Graduate Program, University of California San Diego School of Medicine, La Jolla, CA, USA., Sánchez-Pavón P; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Kennedy G; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Frantz AJ; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; Biomedical Sciences Graduate Program, University of California San Diego School of Medicine, La Jolla, CA, USA., Kihara Y; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Blaho VA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Chun J; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2019 Oct 09; Vol. 5 (10), pp. eaax2011. Date of Electronic Publication: 2019 Oct 09 (Print Publication: 2019).
DOI: 10.1126/sciadv.aax2011
Abstrakt: Posthemorrhagic hydrocephalus (PHH) in premature infants is a common neurological disorder treated with invasive neurosurgical interventions. Patients with PHH lack effective therapeutic interventions and suffer chronic comorbidities. Here, we report a murine lysophosphatidic acid (LPA)-induced postnatal PHH model that maps neurodevelopmentally to premature infants, a clinically accessible high-risk population, and demonstrates ventriculomegaly with increased intracranial pressure. Administration of LPA, a blood-borne signaling lipid, acutely disrupted the ependymal cells that generate CSF flow, which was followed by cell death, phagocytosis, and ventricular surface denudation. This mechanism is distinct from a previously reported fetal model that induces PHH through developmental alterations. Analyses of LPA receptor-null mice identified LPA 1 and LPA 3 as key mediators of PHH. Pharmacological blockade of LPA 1 prevented PHH in LPA-injected animals, supporting the medical tractability of LPA receptor antagonists in preventing PHH and negative CNS sequelae in premature infants.
(Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze: MEDLINE
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