KAEMPFEROL TARGETS LIPID BALANCE, ENDOCANNABINOID PATHWAYS, AND PPAR-α IN THE RAT CEREBRAL CORTEX AFTER TRANSIENT BILATERAL COMMON CAROTID ARTERY OCCLUSION AND REPERFUSION

Transient bilateral common carotid artery occlusion and reperfusion (BCCAO/R) has previously been established as an effective model for replicating early brain inflammation triggered by acute hypoperfusion and subsequent reperfusion events. Recognizing the significant role of diet and nutrition in shaping brain neuroplasticity, this investigation explored the neuroprotective impact of kaempferol (KAM), a dietary flavonoid, within a rat BCCAO/R paradigm. Adult Wistar rats received a single oral dose of KAM (40 mg) 6 h prior to surgery. Extensive lipidomic and molecular assessments were performed on frontal and temporal-occipital cortical tissues in addition to plasma samples. In the frontal cortex, KAM treatment led to increased concentrations of anti-inflammatory N-acylethanolamines – namely palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and docosahexaenoylethanolamide (DHAEA) – while diminishing levels of oxidized arachidonic acid derivatives. KAM further suppressed cyclooxygenase-2 (COX-2) protein and selectively reduced the endocannabinoid 2-arachidonoylglycerol (2-AG), reflecting alterations in arachidonic acid metabolism. These molecular effects were accompanied by elevated peroxisome proliferator-activated receptor alpha (PPARα) and cannabinoid receptors CB1R and CB2R, supporting activation of anti-inflammatory pathways at both nuclear and membrane levels. No marked changes emerged in the temporal-occipital cortex. In plasma, DHAEA levels increased in parallel with cortical findings, whereas PEA and OEA elevations were restricted to shamoperated KAM-treated subjects, implying potential central redistribution during hypoperfusion/reperfusion stress. Collectively, these results indicate that KAM confers anti-inflammatory protection by both suppressing COX-2- mediated prostanoid production and enhancing PPARα-dependent lipid signaling. This dual mechanism underscores KAM’s promise as a dietary strategy to mitigate neuroinflammation following hypoperfusion– reperfusion injury.