Differential effects of haloperidol and olanzapine on levels of vascular endothelial growth factor and angiogenesis in rat hippocampus
Differential effects of haloperidol and olanzapine on levels of vascular endothelial growth factor and angiogenesis in rat hippocampus
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DOI：
10.1016/j.schres.2006.06.017
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发表时间：
2006-10-01
影响因子：
4.5
通讯作者：
Mahadik, Sahebarao P.
中科院分区：
文献类型：
--
作者：
Pillai, Anilkumar;Mahadik, Sahebarao P.
与第一代抗精神病药（FGA）（如氟哌啶醇）相比，第二代抗精神病药（SGA）（如奥氮平）在改善认知能力和减少阴性症状方面具有上级优势，且无锥体外系症状（EPS）。据报道，SGAs的这些临床效果与最常见的现象有关，即脑局部血流量和血容量的有利变化。脑局部血流的变化显示出与血管生成的变化平行，血管生成主要由血管内皮生长因子（VEGF）通过其在内皮细胞上的受体Flk-1介导。因此，我们研究了氟哌啶醇和奥氮平（分别为2和10 mg/kg/天，饮用水）对成年大鼠海马VEGF及其受体Flk-1和血管生成水平的时间依赖性治疗（14和45天）的差异效应。通过Western印迹分析和ELISA测定VEGF水平，并且通过Western印迹分析测定Flk-1水平。免疫组化法检测大鼠内皮细胞抗原-1（RECA-1）和层粘连蛋白（laminin）的表达。在用氟哌啶醇和奥氮平治疗14天后，VEGF和血管生成的水平显著增加（对于两者，p < 0.001相对于载体），但是用氟哌啶醇治疗45天将它们的水平降低回到载体治疗的大鼠中的水平。然而，奥氮平治疗进一步增加了VEGF水平（p < 0.05 vs治疗14天后的水平）。Flk-1水平的变化与VEGF水平的变化一致。因此，数据表明氟哌啶醇和奥氮平具有不同的VEGF和血管生成调节的时间依赖性模式。这些变化可能提供了一个新的分子机制，以更好地解释其差异的影响，区域血流模式和相关的变化，区域体积/神经可塑性和精神病理学。(c)2006 Elsevier B. V.保留所有权利。
Compared to first-generation antipsychotics (FGAs) such as haloperidol, second-generation antipsychotics (SGAs) such as olanzapine are found superior to improve cognitive performance and reduce negative symptoms with no extrapyramidal symptoms (EPS). These clinical effects of SGAs have been reported to be associated with the most replicated phenomenon, favorable changes in brain regional blood flow and volume. The changes in brain regional blood flow are shown to parallel changes in angiogenesis, which is primarily mediated by vascular endothelial growth factor (VEGF) through its receptor, Flk-1, on endothelial cells. Therefore, we studied the differential effects of time-dependent treatment (14 and 45 days) with haloperidol and olanzapine (2 and 10 mg/kg/day, respectively, in drinking water) on hippocampal levels of VEGF, its receptor Flk-1, and angiogenesis in adult rat. The levels of VEGF were determined by both Western blot analysis and ELISA, and Flk-1 levels were determined by Western blot analysis. Immunohistochemical analysis of rat endothelial cell antigen-1 (RECA-1) and laminin were used to evaluate the changes in angiogenesis. After 14 days of treatment with both haloperidol and olanzapine, the levels of VEGF and angiogenesis were significantly increased (p < 0.001 vs vehicle for both), but 45 days of treatment with haloperidol reduced their levels back to levels in vehicle-treated rats. However, olanzapine treatment further increased VEGF levels (p < 0.05 vs levels after 14 days of treatment). Changes in the levels of Flk-1 paralleled the changes in VEGF levels. Thus, the data indicate that haloperidol and olanzapine have distinct time-dependent patterns of regulation of VEGF and angiogenesis. These changes probably provide a new molecular mechanism to better explain their differential effects on the patterns of regional blood flow and associated changes in regional volume/neuroplasticity and psychopathology. (c) 2006 Elsevier B.V. All rights reserved.