1 Department of Life Sciences and Biotechnologies, University of Ferrara, Ferrara, Italy.
2 Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Ferrara, Italy.
J Psychopharmacol. 2018 Nov;32(11):1223-1232. doi: 10.1177/0269881118805492. Epub 2018 Oct 24.
Several studies suggest a pathophysiologically relevant association between increased brain levels of the neuroinhibitory tryptophan metabolite kynurenic acid and cognitive dysfunctions in people with schizophrenia. Elevated kynurenic acid in schizophrenia may be secondary to a genetic alteration of kynurenine 3-monooxygenase, a pivotal enzyme in the kynurenine pathway of tryptophan degradation. In rats, prenatal exposure to kynurenine, the direct bioprecursor of kynurenic acid, induces cognitive impairments reminiscent of schizophrenia in adulthood, suggesting a developmental dimension to the link between kynurenic acid and schizophrenia.
The purpose of this study was to explore the possible impact of the maternal genotype on kynurenine pathway metabolism.
We exposed pregnant wild-type ( Kmo ) and heterozygous ( Kmo) mice to kynurenine (10 mg/day) during the last week of gestation and determined the levels of kynurenic acid and two other neuroactive kynurenine pathway metabolites, 3-hydroxykynurenine and quinolinic acid, in fetal brain and placenta on embryonic day 17/18.
Maternal kynurenine treatment raised kynurenic acid levels significantly more in the brain of heterozygous offspring of Kmo than in the brain of Kmo offspring. Conversely, 3-hydroxykynurenine and quinolinic acid levels in the fetal brain tended to be lower in heterozygous animals derived from kynurenine-treated Kmo mice than in corresponding Kmo offspring. Genotype-related effects on the placenta were qualitatively similar but less pronounced. Kynurenine treatment also caused a preferential elevation in cerebral kynurenic acid levels in Kmo compared to Kmo dams.
The disproportionate kynurenic acid increase in the brain of Kmo animals indicates that the maternal Kmo genotype may play a key role in the pathophysiology of schizophrenia.
多项研究表明，精神分裂症患者大脑中神经抑制性色氨酸代谢产物犬尿氨酸水平升高与认知功能障碍之间存在病理生理学相关。精神分裂症中犬尿氨酸水平升高可能继发于犬尿氨酸 3-单加氧酶（犬尿氨酸途径中关键的酶）的基因改变。在大鼠中，产前暴露于犬尿氨酸（犬尿氨酸酸的直接生物前体）可诱导成年后出现类似于精神分裂症的认知障碍，这表明犬尿氨酸酸与精神分裂症之间存在发育相关性。
本研究旨在探讨母系基因型对犬尿氨酸途径代谢的可能影响。
我们在妊娠最后一周给野生型（Kmo）和杂合型（Kmo）孕鼠暴露于犬尿氨酸（10mg/天），并在胚胎第 17/18 天测定胎脑和胎盘中犬尿酸酸和另外两种神经活性犬尿氨酸途径代谢物 3-羟基犬尿酸和喹啉酸的水平。
母源性犬尿氨酸处理使 Kmo 杂合子后代的脑内犬尿酸酸水平显著升高，而 Kmo 后代的脑内犬尿酸酸水平升高更为明显。相反，来自 Kmo 母鼠处理的 Kmo 杂合子的胎脑 3-羟基犬尿酸和喹啉酸水平较相应的 Kmo 后代降低。胎盘上的基因型相关影响是定性相似但程度较轻。犬尿氨酸处理也导致 Kmo 比 Kmo 母鼠的大脑中犬尿酸酸水平优先升高。
Kmo 动物大脑中犬尿酸酸的不成比例增加表明母系 Kmo 基因型可能在精神分裂症的病理生理学中发挥关键作用。
