Lithium prevents stress-induced reduction of vascular endothelium growth factor levels
Lithium prevents stress-induced reduction of vascular endothelium growth factor levels
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DOI：
10.1016/j.neulet.2007.09.062
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发表时间：
2007-12
影响因子：
2.5
通讯作者：
Rui Silva;L. Martins;A. Longatto-Filho;O. Almeida;N. Sousa
中科院分区：
文献类型：
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作者：
Rui Silva;L. Martins;A. Longatto-Filho;O. Almeida;N. Sousa
了解调节出生后神经发生的机制正变得越来越重要，因为它的调制已被牵连在某些神经精神疾病的发病机制。锂是一种情绪稳定剂，已知可增加海马神经发生。锂还导致血管生成因子血管内皮生长因子（VEGF）水平升高。由于VEGF最近被证明具有神经原性，我们有兴趣研究是否锂管理也可能伴随着正常和应激大鼠海马中VEGF表达的改变;后一种治疗方法被引入，以重现锂用于治疗的一些精神病理学体征。在应激动物的海马中VEGF的表达低于对照组，但在同时接受锂的动物中，应激的影响显著减弱。VEGF和未成熟神经元、成熟神经元和星形胶质细胞的特异性标记物的双重染色显示，未成熟神经元对应激的VEGF抑制作用最敏感。证实了锂的这些作用中涉及已知的调节途径，我们证明了锂联合给药可防止应激诱导的糖原合成酶激酶-3 β（GSK-3β）上调和β-连环蛋白表达下调; GSK-3β是已知的主要锂靶点，这种情绪稳定剂对其的抑制导致β-连环蛋白上调，随后导致VEGF增加。我们的研究结果表明，锂的作用，以及可能作为情绪稳定剂的治疗效果也是由VEGF介导的。
Understanding the mechanisms that regulate postnatal neurogenesis is becoming increasingly relevant since its modulation has been implicated in the pathogenesis of certain neuropsychiatric disorders. Lithium is a mood stabilizer known to increase hippocampal neurogenesis. Lithium also results in increased levels of the angiogenic factor vascular endothelial growth factor (VEGF). Since VEGF was recently shown to have neurogenic properties, we were interested to examine whether lithium administration might also be accompanied by alterations in VEGF expression in the hippocampus of normal and stressed rats; the latter treatment was introduced to reproduce some of the psychopathological signs for which lithium is used therapeutically. The expression of VEGF in the hippocampus in stressed animals was lower than that in controls, but the effect of stress was significantly attenuated in animals concomitantly receiving lithium. Double staining for VEGF and specific markers for immature neurons, mature neurons and astroglia revealed that immature neurons were most sensitive to the VEGF-inhibiting effects of stress. Confirming the involvement of a known regulatory pathway in these actions of lithium, we demonstrated that lithium co-administration prevented the stress-induced upregulation of glycogen synthase kinase-3β (GSK-3β) and down-regulation of β-catenin expression; GSK-3β is a known primary lithium target and its inhibition by this mood stabilizer leads to an upregulation of β-catenin and subsequently, an increase of VEGF. Our results suggest that the actions of lithium, and possibly its therapeutic efficacy as a mood stabilizer also, are mediated by VEGF.