Department of Pharmacobiology and University Consortium for the Study of Adaptive Disorders and Head Pain, Section of Neuropharmacology of Normal and Pathological Neuronal Plasticity, University of Calabria, Rende (CS), Italy.
Cell Death Dis. 2011 Dec 8;2(12):e238. doi: 10.1038/cddis.2011.125.
In addition to its effects in the hypothalamus to control body weight, leptin is involved in the regulation of neuronal function, development and survival. Recent findings have highlighted the neuroprotective effects of leptin against ischemic brain injury; however, to date, little is known about the role performed by the signal transducer and activator of transcription (STAT)-3, a major mediator of leptin receptor transduction pathway in the brain, in the beneficial effects of the hormone. Our data demonstrate that systemic acute administration of leptin produces neuroprotection in rats subjected to permanent middle cerebral artery occlusion (MCAo), as revealed by a significant reduction of the brain infarct volume and neurological deficit up to 7 days after the induction of ischemia. By combining a subcellular fractionation approach with immunohistofluorescence, we observe that neuroprotection is associated with a cell type-specific modulation of STAT3 phosphorylation in the ischemic cortex. The early enhancement of nuclear phospho-STAT3 induced by leptin in the astrocytes of the ischemic penumbra may contribute to a beneficial effect of these cells on the evolution of tissue damage. In addition, the elevation of phospho-STAT3 induced by leptin in the neurons after 24 h MCAo is associated with an increased expression of tissue inhibitor of matrix metalloproteinases-1 in the cortex, suggesting its possible involvement to the neuroprotection produced by the adipokine.
除了在下丘脑控制体重的作用外，瘦素还参与神经元功能、发育和存活的调节。最近的研究结果强调了瘦素对缺血性脑损伤的神经保护作用；然而，迄今为止，人们对信号转导子和转录激活子（STAT）-3在大脑中的瘦素受体转导途径中的主要介导作用所起的作用知之甚少。我们的数据表明，系统急性给予瘦素可产生对永久性大脑中动脉闭塞（MCAo）大鼠的神经保护作用，这表现在诱导缺血后 7 天内脑梗死体积和神经功能缺损显著减少。通过结合亚细胞分级分离方法和免疫荧光，我们观察到神经保护与缺血皮质中 STAT3 磷酸化的特定细胞类型调节有关。瘦素在缺血半影区星形胶质细胞中诱导的早期核磷酸化 STAT3 增强可能有助于这些细胞对组织损伤演变的有益作用。此外，MCAo 后 24 小时瘦素诱导的磷酸化 STAT3 的升高与皮质中基质金属蛋白酶组织抑制剂-1 的表达增加有关，提示其可能参与了脂肪细胞因子产生的神经保护作用。
