Neuroprotective effect of a selective peroxisome proliferator-activated receptor alpha modulator in murine cerebral ischemia.

Activation of peroxisome proliferator-activated receptor alpha (PPARα) may attenuate post-ischemic neuroinflammation. This study examined the neuroprotective potential of pemafibrate, a selective PPARα modulator (SPPARMα), in murine cerebral ischemia. Male CB-17 mice underwent transient middle cerebral artery occlusion (MCAO) for 30 min. Pemafibrate (0.1, 0.3, or 1.0 mg/kg) or vehicle was administered orally once daily for 7 days before MCAO and continued for 2 days thereafter. Pemafibrate improved neurological outcomes (median mNSS: 5.5 with vehicle, 5.0 with pemafibrate 0.1 mg/kg, 4.0 with 0.3 mg/kg, and 2.5 with 1.0 mg/kg) and reduced infarct volume (mean, mm³: 50.4 with vehicle, 40.3 with pemafibrate 0.1 mg/kg, 34.5 with 0.3 mg/kg, and 24.9 with 1.0 mg/kg) at 48 h in a dose-dependent manner. Plasma triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and glucose levels did not differ between the vehicle and pemafibrate groups. At 3 h post-MCAO, IL-6 and IL-1β mRNA levels were not significantly different between the groups. At 6 h post-MCAO, pemafibrate reduced cortical IL-1β (P = 0.008) and reduced IL-6 in both striatum (P = 0.020) and cortex (P = 0.013), with attenuation of microtubule-associated protein 2 degradation. These findings suggest that selective PPARα activation ameliorates ischemic brain injury, likely through anti-inflammatory rather than systemic metabolic effects.