Chronic diazepam administration increases the expression of Lcn2 in the CNS.
Chronic diazepam administration increases the expression of Lcn2 in the CNS.
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DOI：
10.1002/prp2.283
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发表时间：
2017-02
影响因子：
2.6
通讯作者：
Ueno S
中科院分区：
文献类型：
--
作者：
Furukawa T;Shimoyama S;Miki Y;Nikaido Y;Koga K;Nakamura K;Wakabayashi K;Ueno S
苯二氮卓类（BZD）与γ-氨基丁酸A型受体（GABA-R）具有高亲和力结合并增强GABA的作用，被广泛用于治疗焦虑、失眠、癫痫放电和抗惊厥药。由于耐受性、依赖性、戒断反应以及认知和学习障碍等不良反应，BZD的长期使用受到限制。此外，临床报告表明，长期BZD治疗会增加阿尔茨海默病的风险。长期使用BZD可诱导异常GABA-R亚基表达和GABA-R磷酸化。然而，与这些效应相关的基因表达和信号通路尚未完全了解。在这项研究中，我们进行了微阵列分析，以调查的机制，慢性BZD管理的基因表达的影响。地西泮（DZP，一种BZD）长期给药，并分析脑中的全转录物。我们发现，mRNA的表达水平显着影响慢性DZP管理和脂质运载蛋白2（LCN 2）mRNA是最上调的基因在大脑皮层，海马和杏仁核。Lcn 2被称为铁稳态相关蛋白。在神经元、星形胶质细胞、小胶质细胞中检测到Lcn 2的免疫染色信号，并且Lcn 2蛋白表达水平持续上调。在没有促炎基因上调的情况下观察到这种上调，并且通过去铁胺甲磺酸盐（DFO）（铁螯合剂）的长期治疗来减弱。我们的研究结果表明，慢性DZP管理调节转录和上调Lcn 2的表达水平，而没有炎症反应的小鼠大脑。此外，DZP诱导的Lcn 2表达上调受到环境铁的影响。
Benzodiazepines (BZDs), which bind with high affinity to gamma‐aminobutyric acid type A receptors (GABAA‐Rs) and potentiate the effects of GABA, are widely prescribed for anxiety, insomnia, epileptic discharge, and as anticonvulsants. The long‐term use of BZDs is limited due to adverse effects such as tolerance, dependence, withdrawal effects, and impairments in cognition and learning. Additionally, clinical reports have shown that chronic BZD treatment increases the risk of Alzheimer's disease. Unusual GABAA‐R subunit expression and GABAA‐R phosphorylation are induced by chronic BZD use. However, the gene expression and signaling pathways related to these effects are not completely understood. In this study, we performed a microarray analysis to investigate the mechanisms underlying the effect of chronic BZD administration on gene expression. Diazepam (DZP, a BZD) was chronically administered, and whole transcripts in the brain were analyzed. We found that the mRNA expression levels were significantly affected by chronic DZP administration and that lipocalin 2 (Lcn2) mRNA was the most upregulated gene in the cerebral cortex, hippocampus, and amygdala. Lcn2 is known as an iron homeostasis‐associated protein. Immunostained signals of Lcn2 were detected in neuron, astrocyte, microglia, and Lcn2 protein expression levels were consistently upregulated. This upregulation was observed without proinflammatory genes upregulation, and was attenuated by chronic treatment of deferoxamine mesylate (DFO), iron chelator. Our results suggest that chronic DZP administration regulates transcription and upregulates Lcn2 expression levels without an inflammatory response in the mouse brain. Furthermore, the DZP‐induced upregulation of Lcn2 expression was influenced by ambient iron.