Valerio Alessandra, Dossena Marta, Bertolotti Paola, Boroni Flora, Sarnico Ilenia, Faraco Giuseppe, Chiarugi Alberto, Frontini Andrea, Giordano Antonio, Liou Hsiou-Chi, De Simoni Maria Grazia, Spano Pierfranco, Carruba Michele O, Pizzi Marina, Nisoli Enzo
Department of Biomedical Sciences and Biotechnologies, Division of Pharmacology, University of Brescia, Brescia, Italy.
Stroke. 2009 Feb;40(2):610-7. doi: 10.1161/STROKEAHA.108.528588. Epub 2008 Nov 20.
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.
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.
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.
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.
瘦素是一种脂肪激素，具有血管生成、神经营养和神经保护特性。我们检验了瘦素可能作为缺血性中风后恢复的内源性介质这一假说，并研究了核转录因子κB激活是否参与瘦素介导的神经保护作用。
在暴露于氧糖剥夺的野生型或NF-κB/c-Rel(-/-)小鼠的培养小鼠皮质神经元中评估瘦素的抗凋亡作用。野生型、c-Rel(-/-)和瘦素缺陷型ob/ob小鼠接受永久性大脑中动脉闭塞。用定量逆转录聚合酶链反应和免疫染色法检测野生型小鼠脑中的瘦素产生。小鼠在缺血开始时腹腔注射一剂瘦素（20微克/克）。
瘦素治疗激活了含有c-Rel亚基的核转录因子κB二聚体的核转位，在对照和氧糖剥夺条件下均诱导了抗凋亡c-Rel靶基因Bcl-xL的表达，并抵消了氧糖剥夺介导的培养皮质神经元的凋亡死亡。来自c-Rel(-/-)小鼠的皮质神经元中，瘦素介导的Bcl-xL诱导和对氧糖剥夺的神经保护作用受到阻碍。在接受永久性大脑中动脉闭塞的野生型小鼠缺血半暗带的小胶质细胞/巨噬细胞中，瘦素mRNA被诱导且可检测到蛋白。ob/ob小鼠比野生型小鼠更易受永久性大脑中动脉闭塞损伤。瘦素注射显著减少了野生型和ob/ob小鼠中永久性大脑中动脉闭塞介导的皮质损伤，但在c-Rel(-/-)小鼠中未减少。
瘦素在脑缺血期间作为神经保护的内源性介质起作用。外源性给予瘦素以c-Rel依赖的方式在体外和体内保护免受缺血性神经元损伤。
