Low-Level Stress Induces Production of Neuroprotective Factors in Wild-Type but Not BDNF+/- Mice: Interleukin-10 and Kynurenic Acid.
Low-Level Stress Induces Production of Neuroprotective Factors in Wild-Type but Not BDNF+/- Mice: Interleukin-10 and Kynurenic Acid.
复制标题
DOI：
10.1093/ijnp/pyv089
复制
发表时间：
2015-08-01
期刊：
影响因子：
--
通讯作者：
O'Connor JC
中科院分区：
文献类型：
--
作者：
Dugan AM;Parrott JM;Redus L;Hensler JG;O'Connor JC
脑源性神经营养因子（BDNF）缺乏会导致对压力的脆弱性，但其机制尚不清楚。 BDNF+/- 小鼠在低水平压力后表现出行为、生理和神经化学变化，这是重度抑郁症的标志。免疫攻击后，神经炎症引起的犬尿氨酸通路色氨酸代谢变化会介导抑郁样行为。我们假设 BDNF+/- 小鼠更容易受到应激引起的神经炎症和犬尿氨酸代谢的影响，因此 BDNF+/- 或野生型同窝小鼠会遭受重复的不可预测的轻度应激。测量促炎细胞因子表达和犬尿氨酸代谢物。不可预测的轻微压力不会诱发神经炎症。然而，只有野生型小鼠才能产生神经保护因子白细胞介素 10 和犬尿酸，以应对反复不可预测的温和应激。在 BDNF+/- 小鼠中，在反复发生不可预测的轻度应激后，犬尿氨酸优先代谢为神经毒性中间体 3-羟基犬尿氨酸。我们的数据表明，BDNF 可能在压力期间调节犬尿氨酸途径代谢，并为压力诱发的精神疾病的发展提供了一种新的脆弱性和恢复力的分子机制。
Brain-derived neurotrophic factor (BDNF) deficiency confers vulnerability to stress, but the mechanisms are unclear. BDNF+/- mice exhibit behavioral, physiological, and neurochemical changes following low-level stress that are hallmarks of major depression. After immune challenge, neuroinflammation-induced changes in tryptophan metabolism along the kynurenine pathway mediate depressive-like behaviors. We hypothesized that BDNF+/- mice would be more susceptible to stress-induced neuroinflammation and kynurenine metabolism, so BDNF+/- or wild-type littermate mice were subject to repeated unpredictable mild stress. Proinflammatory cytokine expression and kynurenine metabolites were measured. Unpredictable mild stress did not induce neuroinflammation. However, only wild-type mice produced the neuroprotective factors interleukin-10 and kynurenic acid in response to repeated unpredictable mild stress. In BDNF+/- mice, kynurenine was metabolized preferentially to the neurotoxic intermediate 3-hydroxykynurenine following repeated unpredictable mild stress. Our data suggest that BDNF may modulate kynurenine pathway metabolism during stress and provide a novel molecular mechanism of vulnerability and resilience to the development of stress-precipitated psychiatric disorders.