New Hydrocephalus Therapies Through Interruption of Lipid Signaling and Inflammatory Pathways Using Novel Drug-Like Compounds
Abstract
Lysophosphatidic acid (LPA) and its lipid precursor lysophosphatidylcholine (LPC) are abundant lipid molecules found in the blood andare released into the cerebral spinal fluid (CSF) during hemorrhage or traumatic events. Previous studies showed that when injected intothe lateral ventricles of the fetal mouse brain, LPA produced hydrocephalus and associated brain morphological abnormalities. Thepurpose of this proposal is to develop and implement fetal and neonatal models of post hemorrhagic hydrocephalus (PHH) using the LPAlipid precursor LPC towards the pursuit of developing novel therapies for the prevention and treatment of post-traumatic hydrocephalus.Key to achieving these goals, both Aims were essentially completed. LPC delivery into the lateral ventricles of neonatal mice was foundto produce hydrocephalus with comparable neuropathologies to those produced by LPA. Histological changes were refractory to autotaxin(ATX) inhibition by the compound GWJ-23; however, survival curves were markedly improved, with behavioral endpoints trending towardsat least partial utility for autotaxin inhibition in reducing PHH behavioral deficits and thus improving quality of life. Improved ATX inhibitorcompounds should be assessed in the future. Neuroimmunological chemokines were increased in cerebral spinal fluid (CSF), suggesting adistinct mechanism of damage that could also be interrupted to provide therapeutic benefit in future PHH assessments.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2021
- Accession Number
- AD1148583
Entities
People
- Jerold Chun