Conditional PLD1 deletion or pharmacological PLD inhibition mitigates astrocyte reactivity and promotes functional recovery after spinal cord injury.

Abstract

AIM: To investigate the effects of pharmacological PLD inhibition and astrocyte-specific PLD1 deletion on functional recovery and tissue pathology after SCI. MAIN METHODS: A contusion SCI model was established in transgenic mice with conditional astrocytic PLD1 deletion, as well as in wild-type animals treated with Five-Fluoro-2-Indolyl Des-Chlorohalopemide (FIPI), a pharmacological PLD inhibitor. Motor function recovery, tissue preservation, and astrocytic activity were assessed. In addition, lipidomic profiling was performed to evaluate metabolic alterations associated with SCI and PLD inhibition. KEY FINDINGS: Both PLD inhibition and astrocytic PLD1 deletion significantly improved motor function recovery and reduced astrocytic reactivity, partly through suppression of neurotoxic astrocyte populations. Lipidomic analysis revealed SCI-associated alterations, including increases in cholesteryl esters and free fatty acids and decreases in phosphatidylcholine and phosphatidylethanolamine. Notably, FIPI treatment partially restored lipid imbalances, particularly normalizing phosphatidylcholine and phosphatidylethanolamine levels. SIGNIFICANCE: These findings demonstrate that genetic deletion of astrocytic PLD1 or pharmacological PLD inhibition can mitigate astrocytic neurotoxicity and enhance functional recovery after SCI. Targeting PLD1 therefore represents a promising therapeutic strategy to improve outcomes in SCI.