Kynurenic Acid Protects Against Reactive Glial-associated Reductions in the Complexity of Primary Cortical Neurons.

Brain glia produce neuroactive metabolites via tryptophan-kynurenine catabolism. A role for kynurenine pathway (KP) metabolites is proposed in reactive glial associated neurodegeneration. The aim of this investigation was to assess the role of KP induction and KP metabolites in driving reactive glial associated neuronal atrophy. Rat primary mixed glia, and enriched microglial and astroglial cultures were stimulated with IFNγ (10 ng/ml) for 24 hours. KP induction in mixed glial cells was confirmed by raised expression of the rate limiting KP enzyme indoleamine 2,3 dioxygenase (IDO) and raised concentrations of KP metabolites kynurenic acid (KYNA) and quinolinic acid (QUIN) in the conditioned media. Conditioned media was transferred onto immature (3 days) and mature (21 days) primary cortical neurons in vitro for 24 hours. IFNγ-stimulated mixed glial conditioned media reduced neurite outgrowth and complexity of both immature and mature neurons and co-localised expression of synaptic markers determined by immunocytochemistry. Pre-treatment of mixed glial cells with the IDO inhibitor, 1-methyltryptophan (1-MT) (L) prevented these effects of IFNγ-stimulated mixed glial conditioned media. KYNA increased complexity and synapse formation in mature cortical neurons and protected against reduced neuronal complexity and co-localised expression of synaptic markers induced by conditioned media from IFNγ-stimulated mixed glia and by treatment of neuronal cells with QUIN (1 µM). Overall, this study supports a role for the KP in driving neuronal atrophy associated with reactive glia and indicates that inhibition of the KP in glia, or raising the concentration of the astrocytic metabolite KYNA, protects against reactive microglial and QUIN-associated neuronal atrophy.

Inhibition of the kynurenine pathway protects against reactive microglial-associated reductions in the complexity of primary cortical neurons.

Brain glia possess the rate limiting enzyme indoleamine 2, 3-dioxygenase (IDO) which catalyses the conversion of tryptophan to kynurenine. Microglia also express kynurenine monooxygenase (KMO) and kynureninase (KYNU) which lead to the production of the free radical producing metabolites, 3-hydroxykynurenine and 3-hydroxyanthranillic acid respectively and subsequently production of the NMDA receptor agonist quinolinic acid. The aim of this study was to examine the effect of IFNγ-stimulated kynurenine pathway (KP) induction in microglia on neurite outgrowth and complexity, and to determine whether alterations could be abrogated using pharmacological inhibitors of the KP. BV-2 microglia were treated with IFNγ (5ng/ml) for 24h and conditioned media (CM) was placed on primary cortical neurons 3 days in vitro (DIV) for 48h. Neurons were fixed and neurite outgrowth and complexity was assessed using fluorescent immunocytochemistry followed by Sholl analysis. Results show increased mRNA expression of IDO, KMO and KYNU, and increased concentrations of tryptophan, kynurenine, and 3-hydroxykynurenine in the CM of IFNγ-stimulated BV-2 microglia. The IFNγ-stimulated BV-2 microglial CM reduced neurite outgrowth and complexity with reductions in various parameters of neurite outgrowth prevented when BV-2 microglia were pre-treated with either the IDO inhibitor, 1-methyltryptophan (1-MT) (L) (0.5mM; 30min), the KMO inhibitor, Ro 61-8048 (1µM; 30min), the synthetic glucocorticoid, dexamethasone (1µM; 2h) -which suppresses IFNγ-induced IDO - and the N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 (0.1µM; 30min). Overall this study indicates that inhibition of the KP in microglia may be targeted to protect against reactive microglial-associated neuronal atrophy.

Stress-related regulation of the kynurenine pathway: Relevance to neuropsychiatric and degenerative disorders.

The kynurenine pathway (KP), which is activated in times of stress and infection has been implicated in the pathophysiology of neurodegenerative and psychiatric disorders. Activation of this tryptophan metabolising pathway results in the production of neuroactive metabolites which have the potential to interfere with normal neuronal functioning which may contribute to altered neuronal transmission and the emergence of symptoms of these brain disorders. This review investigates the involvement of the KP in a range of neurological disorders, examining recent in vitro, in vivo and clinical discoveries highlights evidence to indicate that the KP is a potential therapeutic target in both neurodegenerative and stress-related neuropsychiatric disorders. Furthermore, this review identifies gaps in our knowledge with regard to this field which are yet to be examined to lead to a more comprehensive understanding of the role of KP activation in brain health and disease. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.

The pupil's response to affective pictures: Role of image duration, habituation, and viewing mode.

The pupil has been shown to be sensitive to the emotional content of stimuli. We examined this phenomenon by comparing fearful and neutral images carefully matched in the domains of luminance, image contrast, image color, and complexity of content. The pupil was more dilated after viewing affective pictures, and this effect was (a) shown to be independent of the presentation time of the images (from 100-3,000 ms), (b) not diminished by repeated presentations of the images, and (c) not affected by actively naming the emotion of the stimuli in comparison to passive viewing. Our results show that the emotional modulation of the pupil is present over a range of variables that typically vary from study to study (image duration, number of trials, free viewing vs. task), and encourages the use of pupillometry as a measure of emotional processing in populations where alternative techniques may not be appropriate.