368 Exploring Lysophosphatidylcholine as a Therapeutic Avenue in Ischemic Stroke: The Plasma-Brain Disjunction and the Promise of Inhibition

INTRODUCTION: Lipids and their bioactive metabolites, such as Lysophosphatidylcholine (LPC), are increasingly recognized as being integral in ischemic stroke. Low levels of plasma LPC have been reported as a diagnostic biomarker for stroke, in clinical and pre-clinical studies. However, the therapeutic role for LPC supplementation in improving stroke outcomes has yet to be explored. METHODS: Adult male Sprague-Dawley rats underwent transient middle cerebral artery occlusion (tMCAO). Rats were randomly assigned to 4 groups (sham-operated, vehicle, LPC 18:1 supplementation, or LPC inhibition using a phospholipase 2 inhibitor (PLA2i). Levels of multiple LPC species within the plasma and brain were measured using HPLC-MS. Primary outcomes including cerebral perfusion, lesion volume, and neurobehavior were measured using Laser Speckle, histology, and a customized neurobehavioral battery. Secondary outcomes including neuroinflammation, oxidative stress, and apoptosis were measured using Western blot and immunofluorescent methods. RESULTS: At the acute phase of stroke, plasma levels of all LPC species significantly decreased, and brain levels increased. Supplementation of LPC 18:1 at this time increased lesion volume (29.2%, P<.05) and worsened neurological outcomes. Inhibition of LPC using PLA2i significantly improved lesion (17.9%, P<.05) and neurological outcomes, while increasing plasma LPC levels and decreasing brain levels. LPC 18:1 supplementation promoted the conversion of microglia towards an inflammatory state across the ischemic spectrum, covering mild to severe. CONCLUSIONS: Our study represents the first to explore the therapeutic potential of LPC in stroke, uncovering its harm despite its established role as a biomarker. Instead, LPC inhibition holds promise as it improved outcomes. Our results highlight the limitations of plasma LPC as a predictor of therapeutic efficacy. Furthermore, LPC’s inhibition decreases neuroinflammation, thus preserving penumbral tissue and expanding the therapeutic time window.