Journal
SCIENCE ADVANCES
Volume 5, Issue 10, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aax2011
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Funding
- NIH [NS084398, MH051699, T32GM007752, HL141880, NS103940]
- DOD [W81XWH-17-1-0455]
- AHA [16SDG27020014]
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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.
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