Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology
Por:
Afia AB, Vila E, MacDowell KS, Ormazabal-Herrero A, Leza JC, Haro JM, Artuch-Iriberri R, Ramos B and Garcia-Bueno B
Publicada:
12 sep 2021
Ahead of Print:
12 sep 2021
Resumen:
Background The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA). Methods This work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by high-performance liquid chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored. Results In the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzyme expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolite content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC. Conclusions Thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.
Filiaciones:
Afia AB:
Laboratory of Genetics, Biodiversity and Bioresource Valorization, Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia
Vila E:
Psiquiatria Molecular, Parc Sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Barcelona, Spain
MacDowell KS:
Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain
Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain
Ormazabal-Herrero A:
Clinical Chemistry Department, Institut de recerca Sant Joan de Déu and CIBERER-ISCIII, Passeig Sant Joan de Déu, 2. 08950, Esplugues de Llobregat, Barcelona, Spain
Leza JC:
Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain
Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain
Haro JM:
Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain
Parc Sanitari Sant Joan de Déu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Barcelona, Spain
Artuch-Iriberri R:
Clinical Chemistry Department, Institut de recerca Sant Joan de Déu and CIBERER-ISCIII, Passeig Sant Joan de Déu, 2. 08950, Esplugues de Llobregat, Barcelona, Spain
Ramos B:
Psiquiatria Molecular, Parc Sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain.
Dept. de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain.
Garcia-Bueno B:
Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain.
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