Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
Core Technologies and Services, Van Andel Institute, Grand Rapids, MI, USA.
Brain Behav Immun. 2024 Jul;119:146-153. doi: 10.1016/j.bbi.2024.03.042. Epub 2024 Mar 29.
Perinatal depression (including antenatal-, postnatal-, and depression that spans both timepoints) is a prevalent disorder with high morbidity that affects both mother and child. Even though the full biological blueprints of perinatal depression remain incomplete, multiple studies indicate that, at least for antenatal depression, the disorder has an inflammatory component likely linked to a dysregulation of the enzymatic kynurenine pathway. The production of neuroactive metabolites in this pathway, including quinolinic acid (QUIN), is upregulated in the placenta due to the multiple immunological roles of the metabolites during pregnancy. Since neuroactive metabolites produced by the pathway also may affect mood by directly affecting glutamate neurotransmission, we sought to investigate whether the placental expression of kynurenine pathway enzymes controlling QUIN production was associated with both peripheral inflammation and depressive symptoms during pregnancy.
68 placentas obtained at birth were analyzed using qPCR to determine the expression of kynurenine pathway enzymes. Cytokines and metabolites were quantified in plasma using high-sensitivity electroluminescence and ultra-performance liquid chromatography, respectively. Maternal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) throughout pregnancy and the post-partum. Associations between these factors were assessed using robust linear regression with ranked enzymes.
Low placental quinolinate phosphoribosyl transferase (QPRT), the enzyme responsible for degrading QUIN, was associated with higher IL-6 and higher QUIN/kynurenic acid ratios at the 3rd trimester. Moreover, women with severe depressive symptoms in the 3rd trimester had significantly lower placental expression of both QPRT and 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD); impaired activity of these two enzymes leads to QUIN accumulation.
Overall, our data support that a compromised placental environment, featuring low expression of critical kynurenine pathway enzymes is associated with increased levels of plasma cytokines and the dysregulated kynurenine metabolite pattern observed in depressed women during pregnancy.
围产期抑郁（包括产前、产后和跨越两个时间点的抑郁）是一种发病率高的常见疾病，会影响母婴双方。尽管围产期抑郁的完整生物学蓝图尚不完全清楚，但多项研究表明，至少对于产前抑郁，这种疾病具有炎症成分，可能与色氨酸通路的酶失调有关。由于代谢产物在怀孕期间具有多种免疫作用，该通路中的神经活性代谢物（包括喹啉酸（QUIN））在胎盘内的产量增加。由于该通路产生的神经活性代谢物也可能通过直接影响谷氨酸神经传递来影响情绪，因此我们试图研究控制 QUIN 产生的色氨酸通路酶在胎盘内的表达是否与怀孕期间的外周炎症和抑郁症状有关。
使用 qPCR 分析 68 个分娩时获得的胎盘，以确定色氨酸通路酶的表达。使用高灵敏度电化学发光和超高效液相色谱法分别定量血浆中的细胞因子和代谢物。使用爱丁堡产后抑郁量表（EPDS）在整个怀孕期间和产后评估产妇的抑郁症状。使用稳健的线性回归和秩相关酶评估这些因素之间的关联。
负责降解 QUIN 的酶——胎盘喹啉酸磷酸核糖基转移酶（QPRT）表达水平低与第 3 孕期时的 IL-6 水平升高和 QUIN/犬尿氨酸比值升高有关。此外，第 3 孕期时出现严重抑郁症状的女性的 QPRT 和 2-氨基-3-羧基戊烯酸-6-半醛脱羧酶（ACMSD）的胎盘表达水平显著降低；这两种酶的活性受损会导致 QUIN 积累。
总的来说，我们的数据支持这样一种观点，即胎盘环境受损，关键色氨酸通路酶表达降低，与怀孕期间抑郁女性血浆细胞因子水平升高和色氨酸代谢物谱失调有关。
