Abstract
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 vermilion Drosophila mutants with deficient formation of Kyn due to mutation of vermilion gene (v) 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 v-CS flies (p=0.0001). KYNA did not affect life span of female Canton-S flies but decreased life span of v-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.
Highlights
Up-regulation of kynurenine (Kyn) pathway of tryptophan (Trp) metabolism is one of the mechanisms of aging and neurodegenerative disorders, including Huntington’s Disease and schizophrenia [1,2]
kynurenic acid (KYNA) effect on life span was evaluated in adult flies maintained at 28°C
KYNA effect on life cycle was studied in wild type flies, Canton-S, and in vermilion mutant of Drosophila melanogaster with deficient formation of Kyn from Trp because of mutation of vermilion gene (v) that encodes the Trp-2,3-dioxygenase (TDO), enzyme catalyzing Trp conversion into Kyn [2]
Summary
Up-regulation of kynurenine (Kyn) pathway of tryptophan (Trp) metabolism is one of the mechanisms of aging and neurodegenerative disorders, including Huntington’s Disease and schizophrenia [1,2]. KYNA effect on life cycle was studied in wild type flies, Canton-S, and in vermilion mutant of Drosophila melanogaster with deficient formation of Kyn from Trp because of mutation of vermilion gene (v) that encodes the Trp-2,3-dioxygenase (TDO), enzyme catalyzing Trp conversion into Kyn [2]. We evaluated KYNA effect on life span of adult (imago) wild type and vermilion flies maintained at 28°C. 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. Increased formation of KYNA ameliorates neurodegeneration and eclosion defect in Drosophila model of Huntington’s Disease
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