on November 20, 2008
Published online before print November 20, 2008, doi: 10.1161/STROKEAHA.108.528588
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Submitted on June 12, 2008
From the Division of Pharmacology, Department of Biomedical Sciences and Biotechnologies (A.V., F.B., I.S., P.F.S., M.P.), University of Brescia, Brescia, Italy; the Center for Study and Research on Obesity, Department of Pharmacology, Chemotherapy and Medical Toxicology (A.V., M.D., P.B., M.O.C., E.N.), University of Milan, Milan, Italy; the Department of Pharmacology (G.F., A.C.), University of Florence, Florence, Italy; the Institute of Normal Human Morphology (A.F., A.G.), Marche Polytechnic University, Ancona, Italy; the Department of Immunology (H.-C.L.), Weill Medical College of Cornell University, New York, NY; the Laboratory of Inflammation and Nervous System Diseases (M.G.D.S.), Mario Negri Institute, Milan, Italy; and the Istituto Auxologico Italiano (M.O.C., E.N.), Milan, Italy. * To whom correspondence should be addressed. E-mail: enzo.nisoli{at}unimi.it.
Background and Purpose—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 Methods—The antiapoptotic effects of leptin were evaluated in cultured mouse cortical neurons from wild-type or NF- Results—Leptin treatment activated the nuclear translocation of nuclear transcription factors 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.
Accepted on June 19, 2008
Leptin Is Induced in the Ischemic Cerebral Cortex and Exerts Neuroprotection Through NF-
Alessandra Valerio MD; 
B/c-Rel–Dependent Transcription
B activation is involved in leptin-mediated neuroprotection.B/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 µg/g) intraperitoneally at the onset of ischemia.B 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.
Key words: animal models • apoptosis • brain ischemia • leptin • NF-
B
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