Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge.
Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge.
复制标题
外周脂多糖激发后海马中犬尿氨酸代谢平衡被破坏。
DOI：
10.1186/s12974-016-0590-y
复制
发表时间：
2016-05-27
影响因子：
9.3
通讯作者：
O'Connor JC
中科院分区：
文献类型：
--
作者：
Parrott JM;Redus L;O'Connor JC
炎症会增加抑郁症相关症状的风险，色氨酸代谢是这些行为变化的重要媒介。外周免疫激活导致促炎细胞因子表达、小胶质细胞激活和神经毒性犬尿氨酸代谢物的产生的中枢上调。对外周免疫激活的神经炎症和犬尿氨酸代谢反应在很大程度上是在全脑水平上表征的。目前尚不清楚这种代谢反应是否具有区域特异性，尽管已知独特的吲哚胺2，3-双加氧酶（IDO）依赖性抑郁样行为是由离散的脑区控制的。因此，神经炎症和犬尿氨酸代谢的区域表征可能有助于更好地理解介导炎症相关行为变化的潜在机制。在用脂多糖（LPS）进行外周免疫攻击后，分析来自行为相关区域的脑组织的神经炎性靶标和犬尿氨酸途径酶的mRNA的变化。犬尿氨酸途径的代谢平衡也在外周循环和这些脑区域中确定。外周LPS治疗导致促炎细胞因子和神经胶质细胞标志物的脑表达的区域独立性上调，指示神经炎症反应。犬尿氨酸途径酶的表达在很大程度上也是区域独立的。虽然犬尿氨酸/色氨酸比率在血浆和评价的每个脑区域中均显著升高，但犬尿氨酸代谢的平衡偏向于在海马中产生神经毒性代谢物。上游神经炎症过程，如促炎细胞因子产生、神经胶质细胞活化和犬尿氨酸产生，在整个脑中可能是相似的。然而，下游犬尿氨酸代谢的平衡似乎是一个严格调节的脑区域依赖性过程。
Inflammation increases the risk of developing depression-related symptoms, and tryptophan metabolism is an important mediator of these behavior changes. Peripheral immune activation results in central up-regulation of pro-inflammatory cytokine expression, microglia activation, and the production of neurotoxic kynurenine metabolites. The neuroinflammatory and kynurenine metabolic response to peripheral immune activation has been largely characterized at the whole brain level. It is unknown if this metabolic response exhibits regional specificity even though the unique indoleamine 2,3-dioxygenase (IDO)-dependent depressive-like behaviors are known to be controlled by discrete brain regions. Therefore, regional characterization of neuroinflammation and kynurenine metabolism might allow for better understanding of the potential mechanisms that mediate inflammation-associated behavior changes. Following peripheral immune challenge with lipopolysaccharide (LPS), brain tissue from behaviorally relevant regions was analyzed for changes in mRNA of neuroinflammatory targets and kynurenine pathway enzymes. The metabolic balance of the kynurenine pathway was also determined in the peripheral circulation and these brain regions. Peripheral LPS treatment resulted in region-independent up-regulation of brain expression of pro-inflammatory cytokines and glial cellular markers indicative of a neuroinflammatory response. The expression of kynurenine pathway enzymes was also largely region-independent. While the kynurenine/tryptophan ratio was elevated significantly in both the plasma and in each brain regions evaluated, the balance of kynurenine metabolism was skewed toward production of neurotoxic metabolites in the hippocampus. The upstream neuroinflammatory processes, such as pro-inflammatory cytokine production, glial cell activation, and kynurenine production, may be similar throughout the brain. However, it appears that the balance of downstream kynurenine metabolism is a tightly regulated brain region-dependent process.