Session Speaker

Blood and CSF Kynurenines and their Clinical Implications in Mood Disorders
Aye Mu Myint
Germany

The changes in blood cytokines which indicated the imbalance between pro- and anti-inflammatory cytokines have been reported to occur in psychiatric disorders such as major depression, schizophrenia, bipolar mania and anxiety disorders. The proinflammatory cytokines have been shown to enhance corticotrophin releasing factor (CRF) in the hypothalamus which in turn activates hypothalamo-pituitary-adrenal (HPA) axis. This results in persistently high cortisol concentrations commonly observed in the depressed patients. This could in turn induce the glucocorticoid receptor tolerance which enhances the impairment of the negative feedback mechanism of the HPA axis, persistent hypercortisolaemia and neurodegenerative changes.

Moreover, it was reported that cytokines such as IL-2 and IFN-γ reduce the synthesis of 5-HT by stimulating the activity of indoleamine 2,3 dioxygenase (IDO), an enzyme which converts tryptophan, the precursor of 5-HT to kynurenine. Kynurenine is further metabolized to kynurenic acid (KYNA), 3-hydroxykynurenine (3OHK) and quinolinic acid (QUINA) by kynurenine aminotransferase, kynurenine 3-monooxygenase (kynurenine 3-hydroxylase)(KMO) and kynureninase(KYNASE). Both KMO and KYNASE are also shown to be activated by IFNγ. The 3OHK is neurotoxic apoptotic while QUINA is the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist. Conversely, KYNA is an antagonist of all three ionotropic excitatory amino acid receptors and α7-nicotinic acetylcholine receptor (α7-nAChR).

In the brain, tryptophan catabolism occurs in the astrocytes and microglia though 60% of brain kynurenine is contributed from the periphery. The astrocytes are shown to produce mainly KYNA whereas microglia and macrophages produced mainly 3OHK and QUINA. The astrocytes have been demonstrated to metabolise the QUINA produced by the neighbouring microglia. The protective effect of KYNA against excitotoxic effect of QUINA has also been detected in neuronal cell cultures. Tryptophan breakdown has been found to be increased but KYNA, the neuroprotective metabolite is decreased in both patients with major depression and bipolar depressed patients compared to healthy controls. However, in the patients with bipolar mania, the only the tryptophan breakdown and changes in competing amino acids are significant whereas decreased KYNA is highly significant in major depression. Such changes in these metabolites are reflected also in the cerebrospinal fluid of patients with major depression and bipolar depression.

These findings lead to the hypothesis an imbalance neuroprotection-neurodegener-ation in terms of kynurenine metabolites and their immunological and biochemical interactions in the brain might further induce the apoptosis of the neuroprotective astrocytes and the vulnerability to stress is thereby enhanced in major depressive disorders. Moreover, this might explain the chronic and recurrent nature of the disease and also the link between depression and dementia. Medication that could correct the imbalanced kynurenine metabolites could be of help depressed patients to prevent further neurotoxic changes in their neuronal network system and progression of the disease.