Leptin is induced in the ischemic cerebral cortex and exerts neuroprotection through NF-kappaB/c-Rel-dependent transcription.
OBJECTIVE
Leptin is an adipose hormone endowed with angiopoietic, neurotrophic, and neuroprotective properties. We tested the hypothesis that leptin might act as an endogenous mediator of recovery after ischemic stroke and investigated whether nuclear transcription factors kappaB activation is involved in leptin-mediated neuroprotection.


METHODS
The antiapoptotic effects of leptin were evaluated in cultured mouse cortical neurons from wild-type or NF-kappaB/c-Rel(-/-) mice exposed to oxygen-glucose deprivation. Wild-type, c-Rel(-/-) and leptin-deficient ob/ob mice were subjected to permanent middle cerebral artery occlusion. Leptin production was measured in brains from wild-type mice with quantitative reverse transcriptase-polymerase chain reaction and immunostaining. Mice received a leptin bolus (20 microg/g) intraperitoneally at the onset of ischemia.


RESULTS
Leptin treatment activated the nuclear translocation of nuclear transcription factors kappaB dimers containing the c-Rel subunit, induced the expression of the antiapoptotic c-Rel target gene Bcl-xL in both control and oxygen-glucose deprivation conditions, and counteracted the oxygen-glucose deprivation-mediated apoptotic death of cultured cortical neurons. Leptin-mediated Bcl-xL induction and neuroprotection against oxygen-glucose deprivation were hampered in cortical neurons from c-Rel(-/-) mice. Leptin mRNA was induced and the protein was detectable in microglia/macrophage cells from the ischemic penumbra of wild-type mice subjected to permanent middle cerebral artery occlusion. Ob/ob mice were more susceptible than wild-type mice to the permanent middle cerebral artery occlusion injury. Leptin injection significantly reduced the permanent middle cerebral artery occlusion-mediated cortical damage in wild-type and ob/ob mice, but not in c-Rel(-/-) mice.


CONCLUSIONS
Leptin acts as an endogenous mediator of neuroprotection during cerebral ischemia. Exogenous leptin administration protects against ischemic neuronal injury in vitro and in vivo in a c-Rel-dependent manner.
Valerio
Alessandra
A
Department of Biomedical Sciences and Biotechnologies, Division of Pharmacology, University of Brescia, Brescia, Italy.
Dossena
Marta
M
Bertolotti
Paola
P
Boroni
Flora
F
Sarnico
Ilenia
I
Faraco
Giuseppe
G
Chiarugi
Alberto
A
Frontini
Andrea
A
Giordano
Antonio
A
Liou
Hsiou-Chi
HC
De Simoni
Maria Grazia
MG
Spano
Pierfranco
P
Carruba
Michele O
MO
Pizzi
Marina
M
Nisoli
Enzo
E
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D002544:Cerebral Infarction / Q000473:pathology; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000172:deficiency; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D000860:Hypoxia / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020738:Leptin / Q000096:biosynthesis* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics* / Q000502:physiology*; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
D020738:Leptin; D016328:NF-kappa B; D051020:bcl-X Protein; D004247:DNA; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D005947:Glucose