The PPARγ agonist FMOC- l-leucine protects both mature and immature brain

Abstract

( 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 (1–2 mg/kg) and was induced in 50% animals by 4.8 ± 1.2 mg/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 100 mg/kg) was inactive in the 6 Hz seizure test, an adult animal model largely responsive to anti-seizure drugs. In a model of neonatal brain injury, FMOC- l-leucine (4 μg/kg) was neuroprotective against cerebral ibotenate toxicity. It reduced significantly the size of lesions in grey but not in white matter, while rosiglitazone (10 μg/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 6 Hz 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.