Soluble Epoxide Hydrolase Inhibition Confers Neuroprotection via PPAR-α Activation During Intracerebral Hemorrhage

Epoxyeicosatrienoic acids (EETs), are known to possess potent anti-inflammatory and antioxidant neuroprotective properties. However, the molecular mechanisms responsible for these effects are not well understood. In this work, we aimed to evaluate the neuroprotective role of EETs in a hemorrhagic stroke model and the possible involvement of PPAR-α activation in this neuroprotection. Hemorrhagic damage was induced in mice through the intracerebral administration of collagenase VII in the striatum. The neuroprotective effect of EETs was tested in mice by pre-treatments of 2 h with TPPU, an inhibitor of the EETs metabolism. TPPU was administered intraperitoneally at a dose of 0.5, 1.0, or 2 mg/kg. Brain damage was evaluated based on measurements of motor activity, hematoma volume, brain water content, and blood-brain barrier (BBB) permeability. Additionally, the levels of enzymes involved in the oxidative stress balance, such as NADPH oxidase 2 (NOX-2) and superoxide dismutase (SOD), were determined by Western blot analysis. Our results showed that EETs exert neuroprotective effects by significantly decreasing all parameters related to brain damage, improving motor function and promoting an antioxidant state, as evidenced by increased levels of SOD and reduced levels of NOX enzymes. Subsequently, PPAR-α involvement was evaluated through the administration of GW6471, a PPAR-α antagonist. Pre-treating mice with GW6471 for 30 min, reverted all neuroprotective effects, including the observed changes in SOD and NOX levels. Our results demonstrate that EETs confer neuroprotection in hemorrhagic brain injury, and this effect is dependent on PPAR-α activation.