(N-[9-fluorenylmethoxycarbonyl]-)-
L-leucine (
FMOC-L-leucine) and
rosiglitazone, two
ligands of
peroxisome proliferator-activated receptor gamma (
PPARgamma), 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
PPARgamma 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 microg/kg) was neuroprotective against cerebral ibotenate toxicity. It reduced significantly the size of lesions in grey but not in white matter, while
rosiglitazone (10 microg/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
PPARgamma 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.