Kynurenic acid

J Neurol Sci. 2014 Sep 15;344(1-2):94-9.

The endogenous α7 nicotinic acetylcholine receptor antagonist kynurenic acid modulates amyloid-β-induced inflammation in BV-2 microglial cells.[Pubmed: 25064444]

Amyloid-β has been shown to interact with the α7 nicotinic acetylcholine receptor on neuronal cells. Not much is known on the effect on microglial cells and whether this effect can be modulated by the endogenous α7 nicotinic acetylcholine receptor antagonist Kynurenic acid. Our aim was to investigate the effect of Kynurenic acid on amyloid-β-treated BV-2 microglial cells with respect to α7 nicotinic acetylcholine receptor expression, cell viability, cytokine production and phagocytotic abilities.
METHODS AND RESULTS:
Therefore BV-2 cells were treated with oligomeric or fibrillar forms of amyloid-β(1-40) and co-treated with Kynurenic acid. α7 nicotinic acetylcholine receptor quantity was investigated using Western blotting. Cell viability was assessed by staining cells with fluorescein diacetate and propidium iodide. Pro-inflammatory cytokines were measured in cell culture supernatants of treated cells with ELISAs; NO with Griess reagents and amyloid-β uptake were investigated with fluorescence-activated cell sorting and verified by Western blotting. Amyloid-β nor Kynurenic acid did have an effect on the protein level of the α7 nicotinic acetylcholine receptor. Amyloid-Beta induced cell mortality was unchanged after addition of Kynurenic acid. However, Kynurenic acid co-treatment reduced the pro-inflammatory cytokines tumour necrosis factor-α and IL-6 and amyloid-β phagocytosis.
CONCLUSIONS:
We provide evidence for an immunomodulating effect of the endogenous α7 nicotinic acetylcholine receptor antagonist Kynurenic acid. Our findings indicate a role for Kynurenic acid in amyloid-β associated neuroinflammation in Alzheimer disease.

J Neural Transm. 2014 Jul;121(7):725-38.

Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex.[Pubmed: 24385076]

The systemic administration of nitroglycerine induces attacks in migraineurs and is able to activate and sensitize the trigeminal system in animals involving glutamate and α7-nicotinic acetylcholine receptors, among others. Kynurenic acid is one of the endogenous glutamate receptor antagonists, and exerts inhibitory action on the α7-nicotinic acetylcholine receptors. Since Kynurenic acid penetrates the blood-brain barrier poorly, therefore a newly synthesized Kynurenic acid amide, N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KYNAa) was used with such a side-chain substitution to facilitate brain penetration in our study.
METHODS AND RESULTS:
We evaluated its modulatory effect on Kynurenic acid concentration in the cervical part of trigemino-cervical complex (C1-C2) and in the model of nitroglycerine-induced trigeminal activation using male Sprague-Dawley rats. One hour after 1 mmol/kg bodyweight KYNAa administration, the Kynurenic acid level increased significantly in C1-C2, which returned to the basal level at 300 min measured by high-performance liquid chromatography. KYNAa pre-treatment had dose-dependent, mitigating action on nitroglycerine-induced decrease in calcitonin gene-related peptide and increase in c-Fos, neuronal nitric oxide synthase and calmodulin-dependent protein kinase II alpha expression in the C1-C2. KYNAa also mitigated the behavioural changes after nitroglycerine. Thus, in this model KYNAa is able to modulate in a dose-dependent manner the changes in neurochemical markers of activation and sensitization of the trigeminal system directly and indirectly--via forming Kynurenic acid, possibly acting on peripheral and central glutamate or α7-nicotinic acetylcholine receptors.
CONCLUSIONS:
These results suggest that application of Kynurenic acid derivatives could be a useful therapeutic strategy in migraine headache in the future with a different mechanism of action.

Schizophr Res. 2013 Nov;150(2-3):392-7.

The effect of transient increases in kynurenic acid and quinolinic acid levels early in life on behavior in adulthood: Implications for schizophrenia.[Pubmed: 24091034 ]

Kynurenic acid is a tryptophan metabolite that is synthesized and released in the brain by astrocytes and acts as an antagonist of nicotinic acetylcholine receptors and N-methyl-d-aspartate glutamate receptors, both of which are critically involved in cognition as well as neural plasticity and brain development. The concentration of Kynurenic acid is increased in the brains of persons with schizophrenia and this increase has been implicated in the cognitive and social impairments associated with the disease. In addition, growing evidence suggests that the increase in Kynurenic acid may begin early in life. For example, exposure to influenza A virus during development results in a transient increase in Kynurenic acid concentration that could disrupt normal brain development and lead to cognitive deficits later in life. Changes in Kynurenic acid may thus provide a link between developmental exposure to viruses and the increased risk of subsequently developing schizophrenia.
METHODS AND RESULTS:
To test this, we mimicked the effects of influenza A exposure by treating rats with kynurenine, the precursor of Kynurenic acid, on postnatal days 7-10. We observed a transient increase in both Kynurenic acid and quinolinic acid during treatment. When rats were subsequently behaviorally tested as adults, those previously treated with kynurenine exhibited decreased social behavior and locomotor activity. In contrast, attentional function and fear conditioning were not affected.
CONCLUSIONS:
Together with other recent findings, these data have several implications for understanding how viral-induced changes in tryptophan metabolism during development may contribute to schizophrenia-related symptoms later in life.

Cell. 2015 Jan 15;160(1-2):119-31.

Kynurenic acid is a nutritional cue that enables behavioral plasticity.[Pubmed: 25594177]

The kynurenine pathway of tryptophan metabolism is involved in the pathogenesis of several brain diseases, but its physiological functions remain unclear.
METHODS AND RESULTS:
We report that Kynurenic acid, a metabolite in this pathway, functions as a regulator of food-dependent behavioral plasticity in C. elegans. The experience of fasting in C. elegans alters a variety of behaviors, including feeding rate, when food is encountered post-fast. Levels of neurally produced Kynurenic acid are depleted by fasting, leading to activation of NMDA-receptor-expressing interneurons and initiation of a neuropeptide-y-like signaling axis that promotes elevated feeding through enhanced serotonin release when animals re-encounter food. Upon refeeding, Kynurenic acid levels are eventually replenished, ending the elevated feeding period.
CONCLUSIONS:
Because tryptophan is an essential amino acid, these findings suggest that a physiological role of Kynurenic acid is in directly linking metabolism to activity of NMDA and serotonergic circuits, which regulate a broad range of behaviors and physiologies.

Pol J Vet Sci. 2014;17(3):453-8.

The in vitro effect of kynurenic acid on the rainbow trout (Oncorhynchus mykiss) leukocyte and splenocyte activity.[Pubmed: 25286653]

Kynurenic acid (KYNA), an endogenous neuroprotectant formed along the kynurenine pathway of tryptophan degradation, is a selective ligand of the GPR35 receptor, which can be found on the surface of various populations of human immune cells. In infections and inflammations, KYNA produces an anti-inflammatory effect through this receptor, by depressing the synthesis of reactive oxygen species and pro-inflammatory cytokines. However, it is still unrecognized whether receptors for Kynurenic acid are also localized on immune cells of poikilothermic animals, or whether KYNA is able to affect these cells.
METHODS AND RESULTS:
The objective of this study has been to determine the effect of different concentrations of Kynurenic acid (12.5 microM to 10 mM) on the viability and mitogenic response of lymphocytes and on the activity of phagocytic cells isolated from blood and the spleen of rainbow trout. The results imply low toxicity of Kynurenic acid towards fish immune cells, and the proliferative effect observed at the two lowest concentrations of KYNA (12.5 microM and 25 microM) seems indicative of endogenous Kynurenic acid being capable of activating fish lymphocytes. Non-toxic, micromole concentrations of KYNA, however, had no influence on the mitogenic response of lymphocytes nor on the activity of phagocytes in rainbow trout under in vitro conditions. There is some likelihood that such an effect could be observed at lower, nanomole concentrations of KYNA.