The PPARgamma agonist FMOC-L-leucine protects both mature and immature brain

Biomed Pharmacother. Apr-May 2008;62(4):259-63. doi: 10.1016/j.biopha.2007.10.014. Epub 2007 Dec 3.

Abstract

(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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Anticonvulsants / pharmacology*
  • Brain / drug effects*
  • Ibotenic Acid / toxicity
  • Leucine / analogs & derivatives*
  • Leucine / pharmacology
  • Mice
  • Neuroprotective Agents / pharmacology*
  • PPAR gamma / agonists*
  • Rosiglitazone
  • Thiazolidinediones / pharmacology

Substances

  • (N-(9-fluorenylmethoxycarbonyl)-)-L-leucine
  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Anticonvulsants
  • Neuroprotective Agents
  • PPAR gamma
  • Thiazolidinediones
  • Rosiglitazone
  • Ibotenic Acid
  • Leucine