Abstract
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.
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KO’F and KO’R were funded by a postgraduate award from Trinity College Dublin. The authors wish to acknowledge the support of the Trinity Foundation in memory of the late Professor Thomas J. Connor (1971–2013).
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All authors had access to the data in the study and have given final approval of the version to be published. K.O’R. and A.H. take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.H.; Methodology, A.H., K.O’R, K.O’F, J.D., O.M. Y.R.; Formal Analyses, A.H., K.O’R, K.O’F. Writing—Original Draft, A.H. and K.O’R; Writing—Review and Editing A.H., K.O’F., O.M., J.D.; Supervision, A.H.
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The experimental protocols were in compliance with the European directive 2010/63/EU on the protection of animals used for scientific purposes, approved by the Animal Research Ethics Committee in Trinity College Dublin and performed under license granted by the Health Products Regulatory Authority.
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O’Reilly, K., O’Farrell, K., Midttun, O. et al. Kynurenic Acid Protects Against Reactive Glial-associated Reductions in the Complexity of Primary Cortical Neurons. J Neuroimmune Pharmacol 16, 679–692 (2021). https://doi.org/10.1007/s11481-020-09976-x
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DOI: https://doi.org/10.1007/s11481-020-09976-x