LPA1/3 overactivation induces neonatal posthemorrhagic hydrocephalus through ependymal loss and ciliary dysfunction.
Sci Adv
; 5(10): eaax2011, 2019 10.
Article
in En
| MEDLINE
| ID: mdl-31633020
ABSTRACT
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 LPA1 and LPA3 as key mediators of PHH. Pharmacological blockade of LPA1 prevented PHH in LPA-injected animals, supporting the medical tractability of LPA receptor antagonists in preventing PHH and negative CNS sequelae in premature infants.
Full text:
1
Database:
MEDLINE
Main subject:
Receptors, Lysophosphatidic Acid
/
Infant, Premature, Diseases
Limits:
Animals
Language:
En
Year:
2019
Type:
Article