Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins.
Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins.
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DOI：
10.3389/fnins.2014.00457
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发表时间：
2014
影响因子：
4.3
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Dwivedi T;Zhang H
双相情感障碍（BD），最衰弱的精神障碍之一，与发病率和死亡率增加。锂是BD的一线治疗选择，通常用于维持治疗。最近，锂的神经保护作用得到了极大的关注，因为BD与大脑的结构和功能异常有关。然而，锂发挥其神经保护作用的精确分子机制尚不清楚。在海马神经元中，锂（1和2 mM）对谷氨酸诱导的细胞毒性，树突长度和数量，BDNF启动子外显子的表达和甲基化以及凋亡调控基因表达的神经元活力的影响进行了研究。在大鼠海马神经元，锂不仅增加树突的长度和数量，但对谷氨酸诱导的细胞毒性神经元的活力。虽然锂增加了BDNF以及与神经保护相关的基因（如Bcl 2和Bcl-XL）的表达，但它降低了促凋亡基因Bax、Bad和caspase 3的表达。有趣的是，锂激活特异性外显子IV的转录以诱导BDNF基因表达。这伴随着BDNF外显子IV启动子的低甲基化。这项研究描绘了锂介导其保护神经元的作用的机制。
Bipolar disorder (BD), one of the most debilitating mental disorders, is associated with increased morbidity and mortality. Lithium is the first line of treatment option for BD and is often used for maintenance therapy. Recently, the neuroprotective action of lithium has gained tremendous attention, given that BD is associated with structural and functional abnormalities of the brain. However, the precise molecular mechanism by which lithium exerts its neuroprotective action is not clearly understood. In hippocampal neurons, the effects of lithium (1 and 2 mM) on neuronal viability against glutamate-induced cytotoxicity, dendritic length and number, and expression and methylation of BDNF promoter exons and expression of apoptotic regulatory genes were studied. In rat hippocampal neurons, lithium not only increased dendritic length and number, but also neuronal viability against glutamate-induced cytotoxicity. While lithium increased the expression of BDNF as well as genes associated with neuroprotection such as Bcl2 and Bcl-XL, it decreased the expression of pro-apoptotic genes Bax, Bad, and caspases 3. Interestingly, lithium activated transcription of specific exon IV to induce BDNF gene expression. This was accompanied by hypomethylation of BDNF exon IV promoter. This study delineates mechanisms by which lithium mediates its effects in protecting neurons.