Kynurenines impair energy metabolism in rat cerebral cortex

Abstract

Growing evidence indicates that some metabolites derived from the kynurenine pathway, the major route of L-tryptophan catabolism, are involved in the neurotoxicity associated with several brain disorders, such as Huntington's disease, Parkinson's disease and Alzheimer's disease, as well as in glutaryl-CoA dehydrogenase deficiency (GAI). Considering that the pathophysiology of the brain damage in these neurodegenerative disorders is not completely defined, in the present study, we investigated the in vitro effect of L-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on some parameters of energy metabolism, namely glucose uptake, 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate, as well as on the activities of the respiratory chain complexes I-IV and Na+,K+-ATPase activity in cerebral cortex from 30-day-old rats. We observed that all compounds tested, except L-kynurenine, significantly increased glucose uptake and inhibited 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate. In addition, the activities of complexes I, II and IV of the respiratory chain were significantly inhibited by 3HK, while 3HA inhibited complexes I and II activities and AA inhibited complexes I-III activities. Moreover, Na+,K+-ATPase activity was not modified by these kynurenines. Taken together, our present data provide evidence that various kynurenine intermediates provoke impairment of brain energy metabolism.

Fig. 1.

In vitro effect of l-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on glucose uptake in cerebral cortex from young rats. (▪) Control, (■) 0.1 μM, (□) 1 μM, (■) 10 μM, (■) 100 μM. Data are represented as mean ± SEM for six independent experiments (animals) performed in duplicate and expressed as percentage of controls. ^* p < 0.05, ^** p < 0.01, compared to control (Duncan multiple range test).

Fig. 2.

In vitro effect of l-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on ¹⁴CO₂ production from [U-¹⁴C] glucose (A), [1-¹⁴C] acetate (B) and [1,5-¹⁴C] citrate (C) in cerebral cortex from young rats. (▪) Control, (■) 0.1 μM, (□) 1 μM, (■) 10 μM, (■) 100 μM. Data are represented as mean ± SEM for six independent experiments (animals) performed in duplicate and expressed as percentage of controls. ^* p<0.05, ^** p < 0.01, ^*** p < 0.001, compared to control (Duncan multiple range test).

Fig. 2.

In vitro effect of l-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on ¹⁴CO₂ production from [U-¹⁴C] glucose (A), [1-¹⁴C] acetate (B) and [1,5-¹⁴C] citrate (C) in cerebral cortex from young rats. (▪) Control, (■) 0.1 μM, (□) 1 μM, (■) 10 μM, (■) 100 μM. Data are represented as mean ± SEM for six independent experiments (animals) performed in duplicate and expressed as percentage of controls. ^* p<0.05, ^** p < 0.01, ^*** p < 0.001, compared to control (Duncan multiple range test).

Fig. 3.

In vitro effect of l-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on the activities of the respiratory chain complexes I, I–III, II, II–III and IV in cerebral cortex homogenates or mitochondrial fractions from young rats. (▪) Control, (■) 0.1 μM, (□) 1 μM, (■) 10 μM, (■) 100 μM. Data are represented as mean ± SEM for six independent experiments (animals) performed in duplicate and expressed as mmol min⁻¹ mg of protein⁻¹. ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001, compared to control (Duncan multiple range test).