Navrotskaya Valeriya, Oxenkrug Gregory
Department of Genetics and Cytology, V.N. Karazin Kharkiv National University, Ukraine.
Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University/Tufts Medical Center, Boston, USA.
Pharmacol Drug Dev Ther. 2016;1(1). doi: 10.15761/PDDT.1000104. Epub 2016 Dec 8.
Up-regulation of tryptophan (Trp) conversion into kynurenine (Kyn) and increased formation of down-stream metabolites of Kyn is one of the mechanisms of aging and neurodegenerative disorders. Kyn is an immediate precursor of kynurenic acid (KYNA), an antagonist to NMDA and α7nAChR receptors and activator of aryl hydrocarbon receptor. Increased formation of KYNA ameliorates neurodegeneration and eclosion defect in Drosophila model of Huntington's Disease.
Effect of KYNA on pupae viability and life span was evaluated in wild type (Canton-S, CS) and Drosophila mutants with deficient formation of Kyn due to mutation of gene () that encodes the Trp-2,3-dioxygenase (TDO), enzyme catalyzing Trp conversion into Kyn.
Vermilion mutants were transferred into the Canton-S genetic background (v-CS). KYNA effect on viability (number of filial generation pupae and %% of their lethality) was assessed in pupae maintained at standard temperature (23°C). KYNA effect on life span was evaluated in adult (imago) flies maintained at 28°C (accelerated aging).
KYNA drastically increased (4 fold from 8.36 to 33.62) %% of dead pupae in Canton-S but not in -CS flies (p=0.0001). KYNA did not affect life span of female Canton-S flies but decreased life span of -CS female flies (from 17.15 to 14.29 days). KYNA increased life span of male Canton-S (from 17.92 to 19.96 days) and v-CS flies (14.52 to 17.75 days).
This the first (to the best of our knowledge) observation of the toxic effect of KYNA in Drosophila pupae. KYNA effect on high-temperature induced aging acceleration was gender dependent. Present data support the role of downstream Kyn metabolites in aging mechanisms.
色氨酸（Trp）转化为犬尿氨酸（Kyn）的上调以及Kyn下游代谢产物形成的增加是衰老和神经退行性疾病的机制之一。Kyn是犬尿喹啉酸（KYNA）的直接前体，KYNA是N-甲基-D-天冬氨酸（NMDA）和α7烟碱型乙酰胆碱受体（α7nAChR）的拮抗剂以及芳烃受体的激活剂。KYNA形成增加可改善亨廷顿舞蹈病果蝇模型中的神经退行性变和羽化缺陷。
在野生型（Canton-S，CS）果蝇以及由于编码色氨酸-2,3-双加氧酶（TDO，催化Trp转化为Kyn 的酶）的基因（）突变而导致Kyn形成缺陷的果蝇突变体中，评估KYNA对蛹活力和寿命的影响。
朱红眼突变体被转移到Canton-S遗传背景（v-CS）中。在标准温度（23°C）下饲养的蛹中，评估KYNA对活力（子代蛹的数量及其致死率的百分比）的影响。在28°C（加速衰老）下饲养的成年（成虫）果蝇中，评估KYNA对寿命的影响。
KYNA使Canton-S果蝇中死蛹的百分比大幅增加（从8.36%增至33.62%），但在v-CS果蝇中未出现这种情况（p = 0.0001）。KYNA不影响Canton-S雌性果蝇的寿命，但缩短了v-CS雌性果蝇的寿命（从17.15天降至14.29天）。KYNA延长了Canton-S雄性果蝇（从17.92天增至19.96天）和v-CS雄性果蝇（从14.52天增至17.75天）的寿命。
据我们所知，这是首次观察到KYNA对果蝇蛹的毒性作用。KYNA对高温诱导的衰老加速的影响具有性别依赖性。目前的数据支持Kyn下游代谢产物在衰老机制中的作用。
