(N-[9-fluorenylmethoxycarbonyl]-)-l-leucine (FMOC-l-leucine) and rosiglitazone, two ligands of peroxisome proliferator-activated receptor γ (PPARγ), were evaluated in mature (adult mice) and immature (pups) brain injury models. In adult magnesium-deficient mice, a model responsive to both neuroprotective and anti-seizure compounds, FMOC-l-leucine, but not rosiglitazone, protected against audiogenic seizures. The protection afforded by FMOC-l-leucine was alleviated by the PPARγ antagonist GW9662 (1–2mg/kg) and was induced in 50% animals by 4.8±1.2mg/kg. At this dose, FMOC-l-leucine modified audiogenic seizure phase durations in convulsing mice differently than prototype antiepileptic drugs did. FMOC-l-leucine (up to 100mg/kg) was inactive in the 6Hz seizure test, an adult animal model largely responsive to anti-seizure drugs. In a model of neonatal brain injury, FMOC-l-leucine (4μg/kg) was neuroprotective against cerebral ibotenate toxicity. It reduced significantly the size of lesions in grey but not in white matter, while rosiglitazone (10μg/kg) was inactive. Taken as a whole, the present data support neuroprotective potentialities of FMOC-l-leucine towards both mature and immature brain. The PPAR-based protection of immature brain is more important as it is known that classic adult brain protectants (GABA_A activators, N-methyl-d-aspartate and sodium channel blockers) may be toxic for immature brain. The PPARγ agonist FMOC-l-leucine is likely to be devoid of these classic protective mechanisms because of its inactivity in the 6Hz seizure test, its activity in the audiogenic test being explained by neuroprotective rather than intrinsic anti-seizure mechanisms. Targeting PPARs might be thus a promising way to protect immature brain.