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1.
Schizophr Res ; 257: 34-40, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37271040

RESUMEN

BACKGROUND: The hypothesis of dopamine dysfunction in psychosis has evolved since the mid-twentieth century. However, clinical support from biochemical analysis of the transmitter in patients is still missing. The present study assessed dopamine and related metabolites in the cerebrospinal fluid (CSF) of first-episode psychosis (FEP) subjects. METHODS: Forty first-episode psychosis subjects and twenty healthy age-matched volunteers were recruited via the Karolinska Schizophrenia Project, a multidisciplinary research consortium that investigates the pathophysiology of schizophrenia. Psychopathology, disease severity, and cognitive performance were rated as well as cerebrospinal fluid concentrations of dopamine and related metabolites were measured using a sensitive high-pressure liquid chromatography assay. RESULTS: CSF dopamine was reliably detected in 50 % of healthy controls and in 65 % of first-episode psychosis subjects and significantly higher in first-episode psychosis subjects compared to age-matched healthy controls. No difference in CSF dopamine levels was observed between drug-naive subjects and subjects with short exposure to antipsychotics. The dopamine concentrations were positively associated with illness severity and deficits in executive functioning. CONCLUSIONS: Dopamine dysfunction has long been considered a cornerstone of the pathophysiology of schizophrenia, although biochemical support for elevated brain dopamine levels has been lacking. The results of the present study, showing that FEP subjects have increased CSF dopamine levels that correlate to disease symptoms, should fill the knowledge gap in this regard.


Asunto(s)
Trastornos Psicóticos , Esquizofrenia , Humanos , Dopamina/metabolismo , Encéfalo , Cognición
3.
Mol Psychiatry ; 26(11): 6820-6832, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33976392

RESUMEN

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3-/- mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1ß, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3-/- mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.


Asunto(s)
Trastorno Bipolar , Trastornos Psicóticos , Esquizofrenia , Animales , Trastorno Bipolar/genética , Trastorno Bipolar/metabolismo , Encéfalo/metabolismo , Ácido Quinurénico/metabolismo , Ratones , Trastornos Psicóticos/genética , Trastornos Psicóticos/metabolismo , Esquizofrenia/metabolismo
4.
Microorganisms ; 9(2)2021 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557172

RESUMEN

In children, tick-borne encephalitis and neuroborreliosis are common infections affecting the central nervous system. As inflammatory pathways including cytokine expression are activated in these children and appear to be of importance for outcome, we hypothesized that induction of the kynurenine pathway may be part of the pathophysiological mechanism. Inflammatory biomarkers were analyzed in cerebrospinal fluid from 22 children with tick-borne encephalitis (TBE), 34 children with neuroborreliosis (NB) and 6 children with no central nervous system infection. Cerebrospinal fluid levels of kynurenine and kynurenic acid were increased in children with neuroborreliosis compared to the comparison group. A correlation was seen between expression of several cerebrospinal fluid cytokines and levels of kynurenine and kynurenic acid in children with neuroborreliosis but not in children with tick-borne encephalitis. These findings demonstrate a strong induction of the kynurenine pathway in children with neuroborreliosis which differs from that seen in children with tick-borne encephalitis. The importance of brain kynurenic acid (KYNA) in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in neuroborreliosis might be of importance for the pathophysiology of the disease. Drugs targeting the enzymes of this pathway may open the venue for novel therapeutic interventions.

5.
Acta Neuropsychiatr ; 32(1): 43-53, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31753057

RESUMEN

OBJECTIVE: Sustained immune activation leads to cognitive dysfunctions, depression-, and anxiety-like behaviours in humans and rodents. It is modelled by administration of lipopolysaccharides (LPS) to induce expression of pro-inflammatory cytokines that then activate indoleamine 2,3 dioxygenase (IDO1), the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Here, we ask whether chronic IDO1 inhibition by 1-methyl-tryptophan (1-MT, added at 2 g/l in the drinking water) or chronic inhibition of tryptophan 2,3 dioxygenase (TDO2), another enzyme capable of converting tryptophan to kynurenine, by 680C91 (15 mg/kg per os), can rescue LPS-induced (0.83-mg/kg intraperitoneally) anxiety and cognitive deficits. We also investigate the acute effects of 680C91 on serotonergic, dopaminergic, and kynurenine pathway metabolites. METHODS: We examined LPS-induced deficits in trace fear conditioning and anxiety in the light-dark box and elevated plus maze (EPM) in group-housed C57Bl6/N mice. Kynurenine pathway metabolites and monoamine levels were measured via high-performance liquid chromatography. RESULTS: Chronic blockade of IDO1 with 1-MT did not rescue cognitive deficits or abrogate the anxiogenic behaviour caused by LPS despite a decrease in the brain kynurenine:tryptophan ratio. However, 1-MT by itself demonstrated anxiolytic properties in the EPM. Acute and chronic inhibition of TDO2 elevated brain levels of tryptophan, while chronic inhibition of TDO2 was unsuccessful in rescuing cognitive deficits and abrogating the anxiety caused by LPS. CONCLUSIONS: In line with previous studies, we show that LPS administration induces anxiety and cognitive dysfunctions in mice that however were not reversed by chronic blockade of IDO1 or TDO2 at the doses used.


Asunto(s)
Ansiedad/prevención & control , Disfunción Cognitiva/prevención & control , Indoles/farmacología , Inflamación/inducido químicamente , Inflamación/psicología , Lipopolisacáridos/inmunología , Triptófano/análogos & derivados , Animales , Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , Quinurenina/metabolismo , Masculino , Ratones , Triptófano/metabolismo , Triptófano/farmacología
6.
Neuropharmacology ; 138: 130-139, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29879409

RESUMEN

Kynurenine 3-monooxygenase (KMO) is an essential enzyme of the kynurenine pathway, converting kynurenine into 3-hydroxykynurenine. Inhibition of KMO increases kynurenine, resulting in elevated levels of kynurenic acid (KYNA), an endogenous N-methyl-d-aspartate and α*7-nicotinic receptor antagonist. The concentration of KYNA is elevated in the brain of patients with schizophrenia, possibly as a result of a reduced KMO activity. In the present study, using in vivo single cell recording techniques, we investigated the electrophysiological characteristics of ventral tegmental area dopamine (VTA DA) neurons and their response to antipsychotic drugs in a KMO knock-out (K/O) mouse model. KMO K/O mice exhibited a marked increase in spontaneous VTA DA neuron activity as compared to wild-type (WT) mice. Furthermore, VTA DA neurons showed clear-cut, yet qualitatively opposite, responses to the antipsychotic drugs haloperidol and clozapine in the two genotypes. The anti-inflammatory drug parecoxib successfully lowered the firing activity of VTA DA neurons in KMO K/O, but not in WT mice. Minocycline, an antibiotic and anti-inflammatory drug, produced no effect in this regard. Taken together, the present data further support the usefulness of KMO K/O mice for studying distinct aspects of the pathophysiology and pharmacological treatment of psychiatric disorders such as schizophrenia.


Asunto(s)
Antipsicóticos/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/enzimología , Quinurenina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/enzimología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Relación Dosis-Respuesta a Droga , Ácido Quinurénico/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/genética , Masculino , Ratones Noqueados , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/enzimología
7.
Cell Rep ; 19(11): 2289-2303, 2017 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-28614715

RESUMEN

Molecular signatures are emerging determinants of choice of therapy for lung adenocarcinomas. An evolving therapeutic approach includes targeting metabolic dependencies in cancers. Here, using an integrative approach, we have dissected the metabolic fingerprints of lung adenocarcinomas, and we show that Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine biosynthesis, is highly expressed in a adenocarcinoma subset with poor prognosis. This subset harbors a gene signature for DNA replication and proliferation. Accordingly, models with high levels of PHGDH display rapid proliferation, migration, and selective channeling of serine-derived carbons to glutathione and pyrimidines, while depletion of PHGDH shows potent and selective toxicity to this subset. Differential PHGDH protein levels were defined by its degradation, and the deubiquitinating enzyme JOSD2 is a regulator of its protein stability. Our study provides evidence that a unique metabolic program is activated in a lung adenocarcinoma subset, described by PHGDH, which confers growth and survival and may have therapeutic implications.


Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfoglicerato-Deshidrogenasa/metabolismo , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Animales , Línea Celular Tumoral , Proliferación Celular/fisiología , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Femenino , Xenoinjertos , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Ratones SCID , Pronóstico , Serina/metabolismo
8.
Acta Neuropsychiatr ; 29(1): 54-58, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27406788

RESUMEN

OBJECTIVE: There is a growing interest in the role of kynurenine pathway and tryptophan metabolites in the pathophysiology of depression. In the present study, the metabolism of tryptophan along the kynurenine pathway was analysed in a rat model of depression. METHODS: Kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) were measured by high-performance liquid chromatography (HPLC) in prefrontal cortex (PFC) and frontal cortex (FC) in a rat model of depression, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL) rats. In addition, KYNA was also measured in hippocampus, striatum and cerebellum. RESULTS: KYNA levels were reduced in the PFC of FSL rats compared with FRL rats, but did not differ with regard to the FC, hippocampus, striatum or cerebellum. 3-HK levels in PFC and FC, representing the activity of the microglial branch of the kynurenine pathway, did not differ between the FSL and FRL strains. CONCLUSION: Our results suggest an imbalanced metabolism of the kynurenine pathway in the PFC of FSL rats.


Asunto(s)
Trastorno Depresivo/metabolismo , Ácido Quinurénico/metabolismo , Quinurenina/análogos & derivados , Corteza Prefrontal/metabolismo , Triptófano/metabolismo , Animales , Cerebelo/metabolismo , Cromatografía Liquida , Cuerpo Estriado/metabolismo , Trastorno Depresivo/genética , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Quinurenina/metabolismo , Ratas
9.
Psychoneuroendocrinology ; 71: 189-96, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27318828

RESUMEN

Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects.


Asunto(s)
Agresión/fisiología , Quinurenina/metabolismo , Triptófano/metabolismo , Adulto , Agresión/psicología , Biomarcadores/sangre , Proteína C-Reactiva , Femenino , Humanos , Inflamación/sangre , Inflamación/metabolismo , Interleucina-6 , Ácido Quinurénico/sangre , Ácido Quinurénico/metabolismo , Quinurenina/sangre , Masculino , Ácidos Picolínicos/sangre , Ácidos Picolínicos/metabolismo , Ácido Quinolínico/sangre , Ácido Quinolínico/metabolismo , Triptófano/sangre
10.
FEBS Lett ; 590(14): 2063-75, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27282934

RESUMEN

Ewing sarcoma (ES) is an aggressive pediatric tumor driven by the fusion protein EWS-FLI1. We report that EWS-FLI1 suppresses TDO2-mediated tryptophan (TRP) breakdown in ES cells. Gene expression and metabolite analyses reveal an EWS-FLI1-dependent regulation of TRP metabolism. TRP consumption increased in the absence of EWS-FLI1, resulting in kynurenine and kynurenic acid accumulation, both aryl hydrocarbon receptor (AHR) ligands. Activated AHR binds to the promoter region of target genes. We demonstrate that EWS-FLI1 knockdown results in AHR nuclear translocation and activation. Our data suggest that EWS-FLI1 suppresses autocrine AHR signaling by inhibiting TDO2-catalyzed TRP breakdown.


Asunto(s)
Comunicación Autocrina , Quinurenina/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína EWS de Unión a ARN/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Triptófano Oxigenasa/metabolismo , Triptófano/metabolismo , Línea Celular , Humanos , Quinurenina/genética , Proteínas de Fusión Oncogénica/genética , Proteína Proto-Oncogénica c-fli-1/genética , Proteína EWS de Unión a ARN/genética , Receptores de Hidrocarburo de Aril/genética , Triptófano/genética , Triptófano Oxigenasa/genética
11.
Am J Physiol Cell Physiol ; 310(10): C836-40, 2016 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-27030575

RESUMEN

Physical exercise has emerged as an alternative treatment for patients with depressive disorder. Recent animal studies show that exercise protects from depression by increased skeletal muscle kynurenine aminotransferase (KAT) expression which shifts the kynurenine metabolism away from the neurotoxic kynurenine (KYN) to the production of kynurenic acid (KYNA). In the present study, we investigated the effect of exercise on kynurenine metabolism in humans. KAT gene and protein expression was increased in the muscles of endurance-trained subjects compared with untrained subjects. Endurance exercise caused an increase in plasma KYNA within the first hour after exercise. In contrast, a bout of high-intensity eccentric exercise did not lead to increased plasma KYNA concentration. Our results show that regular endurance exercise causes adaptations in kynurenine metabolism which can have implications for exercise recommendations for patients with depressive disorder.


Asunto(s)
Ejercicio Físico/fisiología , Ácido Quinurénico/sangre , Músculo Esquelético/fisiología , Acondicionamiento Físico Humano/fisiología , Resistencia Física/fisiología , Transaminasas/metabolismo , Humanos , Masculino , Acondicionamiento Físico Humano/métodos , Regulación hacia Arriba/fisiología , Adulto Joven
12.
Diabetes Metab Res Rev ; 32(7): 754-761, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-26946084

RESUMEN

BACKGROUND: Systemic kynurenine levels are associated with resistance to stress-induced depression and are modulated by exercise. Tryptophan is a precursor for serotonin and kynurenine synthesis. Kynurenine is transformed into the neuroprotective catabolite kynurenic acid by kynurenine aminotransferases (KATs). PGC-1α1 increases KAT mRNA and induces kynurenic acid synthesis. We tested the hypothesis that skeletal muscle PGC-1α1/KAT-kynurenine pathway is altered by exercise and type 2 diabetes. METHOD: Skeletal muscle and plasma from men with normal glucose tolerance (n = 12) or type 2 diabetes (n = 12) was studied at rest, after acute exercise and during recovery. Tryptophan, Kynurenine and kynurenic acid plasma concentration were measured as well as mRNA of genes related to exercise and kynurenine metabolism. RESULTS: mRNA expression of KAT1, KAT2 and PPARα was modestly reduced in type 2 diabetic patients. In response to exercise, mRNA expression of KAT4 decreased and PGC-1α1 increased in both groups. Exercise increased plasma kynurenic acid and reduced kynurenine in normal glucose tolerance and type 2 diabetic participants. Plasma tryptophan was reduced and the ratio of [kynurenic acid] * 1000/[kynurenine] increased in both groups at recovery, suggesting an improved balance between neurotoxic and neuroprotective influences. Tryptophan and kynurenine correlated with body mass index, suggesting a relationship with obesity. CONCLUSIONS: Acute exercise directly affects circulating levels of tryptophan, kynurenine and kynurenic acid, providing a potential mechanism for the anti-depressive effects of exercise. Furthermore, exercise-mediated changes in kynurenine metabolism are preserved in type 2 diabetic patients. Copyright © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Ejercicio Físico/fisiología , Quinurenina/metabolismo , Músculo Esquelético/metabolismo , Glucemia/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , PPAR alfa/metabolismo , Pronóstico , Transaminasas/metabolismo
13.
Neuropharmacology ; 102: 42-7, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26514401

RESUMEN

Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotransferase (KAT) II, the primary enzyme for KYNA synthesis, on dopamine (DA) neurons in the ventral tegmental area (VTA). Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4-6 after administration. Pretreatment with d-cycloserine (30 mg/kg) or CGP-52432 (10 mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.). Our results show that a specific inhibition of KAT II is associated with a marked reduction in VTA DA firing activity. This effect appears to be specifically executed by NMDA-receptors and mediated indirectly via a GABA(B)-receptor-induced disinhibition of DA neurons. Our findings are in line with the view that endogenous KYNA, by modulation of the NMDA-receptor, exerts important physiological roles in the brain.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Mesencéfalo/metabolismo , Transaminasas/antagonistas & inhibidores , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Masculino , Mesencéfalo/efectos de los fármacos , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
14.
Int J Tryptophan Res ; 8: 49-52, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26448689

RESUMEN

Schizophrenia is associated with activation of the brain immune system as reflected by increased brain levels of kynurenic acid (KYNA) and proinflammatory cytokines. Although antipsychotic drugs have been used for decades in the treatment of the disease, potential effects of these drugs on brain immune signaling are not fully known. The aim of the present study is to investigate the effects of chronic treatment with antipsychotic drugs on brain levels of cytokines and KYNA. Rats were treated daily by intraperitoneally administered haloperidol (1.5 mg/kg, n = 6), olanzapine (2 mg/kg, n = 6), and clozapine (20 mg/kg, n = 6) or saline (n = 6) for 30 days. Clozapine, but not haloperidol or olanzapine-treated rats displayed significantly lower cerebrospinal fluid (CSF) levels of interleukin-8 compared to controls. Whole brain levels of KYNA were not changed in any group. Our data suggest that the superior therapeutic effect of clozapine may be a result of its presently shown immunosuppressive action. Further, our data do not support the possibility that elevated brain KYNA found in patients with schizophrenia is a result of antipsychotic treatment.

15.
Cell ; 159(1): 33-45, 2014 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-25259918

RESUMEN

Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.


Asunto(s)
Depresión/prevención & control , Quinurenina/metabolismo , Músculo Esquelético/enzimología , Estrés Psicológico/complicaciones , Factores de Transcripción/metabolismo , Animales , Barrera Hematoencefálica , Depresión/metabolismo , Perfilación de la Expresión Génica , Humanos , Ácido Quinurénico , Ratones , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , PPAR alfa/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Condicionamiento Físico Animal , Acondicionamiento Físico Humano , Transaminasas/metabolismo , Factores de Transcripción/genética
16.
Brain Behav Immun ; 36: 80-9, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24140727

RESUMEN

Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-D-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with L-kynurenine (2×200 mg/kg/day) at P7-16. In mice neonatally treated with L-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally L-kynurenine treated mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, D-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood.


Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Ácido Quinurénico/metabolismo , Quinurenina/farmacología , Infecciones por Orthomyxoviridae/fisiopatología , Anfetamina/farmacología , Animales , Animales Recién Nacidos , Química Encefálica/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Dopamina/análisis , Dopaminérgicos/farmacología , Femenino , Virus de la Influenza A , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Infecciones por Orthomyxoviridae/metabolismo
17.
Respir Physiol Neurobiol ; 189(3): 537-42, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-24013004

RESUMEN

Modulation in ventilatory settings is one of the approaches and interventions used to treat and prevent secondary brain damage after traumatic brain injury (TBI). Here we investigate the effect of hyperoxia in combination with hypoventilation on brain oxygenation, metabolism and intracranial pressure. Twelve pigs were divided into three groups; group1-100% hyperoxia (n=4), group 2-100% hyperoxia and 20% decrease in minute volume (MV) (n=4) and group 3-100% hyperoxia and 50% decrease in MV (n=4). Neither of the ventilator settings affected the lactate/pyruvate ratio significantly. However, there was a significant decrease of brain lactate (2.6±1.7 to 1.8±1.6mM) and a rapid and marked increase in brain oxygenation (7.9±0.7 to 61.3±17.6mmHg) in group 3. Intracranial pressure (ICP) was not significantly affected in this group, however, the ICP increased significantly in group 2 with 100% hyperoxia plus 20% reduction in minute volume. We conclude that hyperoxia in combination with 50% decrease in MV showed pronounced increase in partial brain oxygen tension (pbrO2) and decrease in brain lactate. The ventilatory modification, used in this study should be considered for further investigation as a possible therapeutic intervention for TBI patients.


Asunto(s)
Encéfalo/metabolismo , Hiperventilación/patología , Hipoventilación/patología , Ácido Láctico/metabolismo , Consumo de Oxígeno/fisiología , Animales , Análisis de los Gases de la Sangre , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Hiperventilación/fisiopatología , Hipoventilación/fisiopatología , Presión Intracraneal/fisiología , Masculino , Microdiálisis , Oxígeno/metabolismo , Porcinos
18.
Acta Otolaryngol ; 131(8): 802-8, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21480759

RESUMEN

CONCLUSION: The findings from this study extend the use of the local application of D-methionine (D-met) to protect against acoustic trauma and demonstrate that D-met slowly diffuses from the perilymph. OBJECTIVES: The objectives of the study were to determine the effect of D-met on auditory function and morphology after acoustic trauma and to measure the concentration of D-met in perilymph. METHODS: Auditory thresholds were determine before, immediately after, and 24 h after acoustic trauma. Cochleae were analyzed using immunocytochemistry for c-Fos, TUJI, and cytochrome c. The concentration of D-met was determined from perilymph. RESULTS: Protection against acoustic trauma (immediately and 24 h post trauma) on auditory brainstem thresholds was found at a time when the concentration of D-met in perilymph showed a fivefold increase above basal levels. The local application of D-met to the guinea pig cochlea results in elevated D-met concentrations that are maintained in the perilymph for at least 24 h.


Asunto(s)
Oído Interno/efectos de los fármacos , Pérdida Auditiva Provocada por Ruido/prevención & control , Metionina/administración & dosificación , Administración Tópica , Animales , Umbral Auditivo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Cobayas , Pérdida Auditiva Provocada por Ruido/fisiopatología , Resultado del Tratamiento
19.
Proc Natl Acad Sci U S A ; 107(46): 20087-92, 2010 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-21041631

RESUMEN

At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes.


Asunto(s)
Envejecimiento/metabolismo , Encéfalo/enzimología , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Animales , ADN Mitocondrial/genética , Regulación Enzimológica de la Expresión Génica , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5 , Ratones , Mitocondrias/enzimología , Mitocondrias/patología , Mutación/genética , Especificidad de Órganos
20.
Ups J Med Sci ; 115(4): 221-31, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20977314

RESUMEN

INTRODUCTION: Traumatic brain injury makes the brain vulnerable to secondary insults. Post-traumatic alterations in intracranial dynamics, such as reduced intracranial compliance (IC), are thought to further potentiate the effects of secondary insults. Reduced IC combined with intracranial volume insults leads to metabolic disturbances in a rat model. The aim of the present study was to discern whether a post-traumatic hypotensive insult in combination with reduced IC caused more pronounced secondary metabolic disturbances in the injured rat brain. MATERIALS AND METHODS: Rats were randomly assigned to four groups (n = 8/group): 1) trauma with hypotension; 2) trauma and reduced IC with hypotension; 3) sham injury with hypotension; and 4) sham injury and reduced IC with hypotension. A weight drop model of cortical contusion trauma was used. IC was reduced by gluing rubber film layers on the inside of bilateral bone flaps before replacement. Microdialysis probes were placed in the perimeter of the trauma zone. Hypotension was induced 2 h after trauma. Extracellular (EC) levels of lactate, pyruvate, hypoxanthine, and glycerol were analyzed. RESULTS: The trauma resulted in a significant increase in EC dialysate levels of lactate, lactate/pyruvate ratio, hypoxanthine, and glycerol. A slight secondary increase in lactate was noted for all groups but group 2 during hypotension, otherwise no late effects were seen. There were no effects of reduced IC. DISCUSSION: In conclusion, reduced IC did not increase the metabolic disturbances caused by the post-traumatic hypotensive insult. The results suggest that a mild to moderate hypotensive insult after initial post-traumatic resuscitation may be tolerated better than an early insult before resuscitation.


Asunto(s)
Lesiones Encefálicas/complicaciones , Hipotensión/fisiopatología , Animales , Encéfalo/patología , Edema Encefálico , Lesiones Encefálicas/fisiopatología , Modelos Animales de Enfermedad , Glicerol/química , Hipoxantina/química , Ácido Láctico/química , Masculino , Ácido Pirúvico/química , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
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