Leptin Is Induced in the Ischemic Cerebral Cortex and Exerts Neuroprotection Through NF-κB/c-Rel-Dependent Transcription

被引:81
作者
Valerio, Alessandra [6 ,7 ]
Dossena, Marta [6 ]
Bertolotti, Paola [6 ]
Boroni, Flora [7 ]
Sarnico, Ilenia [7 ]
Faraco, Giuseppe [5 ]
Chiarugi, Alberto [5 ]
Frontini, Andrea [4 ]
Giordano, Antonio [4 ]
Liou, Hsiou-Chi [3 ]
De Simoni, Maria Grazia [2 ]
Spano, PierFranco [7 ]
Carruba, Michele O. [1 ,6 ]
Pizzi, Marina [7 ]
Nisoli, Enzo [1 ,6 ]
机构
[1] Ist Auxol Italiano, Milan, Italy
[2] Mario Negri Inst Pharmacol Res, Lab Inflammat & Nervous Syst Dis, I-20157 Milan, Italy
[3] Cornell Univ, Weill Med Coll, Dept Immunol, New York, NY 10021 USA
[4] Marche Polytech Univ, Inst Normal Human Morphol, Ancona, Italy
[5] Univ Florence, Dept Pharmacol, Florence, Italy
[6] Univ Milan, Dept Pharmacol Chemotherapy & Med Toxicol, Ctr Study & Res Obes, I-20129 Milan, Italy
[7] Univ Brescia, Dept Biomed Sci & Biotechnol, Div Pharmacol, Brescia, Italy
关键词
animal models; apoptosis; brain ischemia; leptin; NF-kappa B; C-REL; DEFICIENT ADULTS; BRAIN; INJURY; GENE; ACTIVATION; PROTEIN; MOUSE; REPLACEMENT; EXPRESSION;
D O I
10.1161/STROKEAHA.108.528588
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 kappa B 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-kappa 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 mu g/g) intraperitoneally at the onset of ischemia. Results-Leptin treatment activated the nuclear translocation of nuclear transcription factors kappa 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. 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. (Stroke. 2009;40:610-617.)
引用
收藏
页码:610 / 617
页数:8
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