Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the <scp>l</scp>‐kynurenine and quinolinic acid pools in brain

Kita, Tomoyuki; Morrison, Paul F.; Heyes, Melvyn P.; Markey, Sanford P.

doi:10.1046/j.1471-4159.2002.00955.x

Cited by 112 publications

(89 citation statements)

References 32 publications

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“…We must also consider the limitations posed by only having peripheral and not central measures of tryptophan and kynurenine levels. Tryptophan and kynurenine both cross the blood-brain barrier; the majority of kynurenine in the brain is derived from blood, especially in conditions of systemic inflammation (Kita et al, 2002;Schwarcz et al, 2012). However, peripheral levels of tryptophan and kynurenine are not necessarily informative about the activity of IDO/TDO activity in the brain, nor do they provide information on the relative balance of kynurenine versus kynurenic acid produced by glial cells.…”

Section: Discussionmentioning

confidence: 99%

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Chiappelli

Postolache

Kochunov

et al. 2016

Neuropsychopharmacol

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Schizophrenia is associated with abnormalities in the structure and functioning of white matter, but the underlying neuropathology is unclear. We hypothesized that increased tryptophan degradation in the kynurenine pathway could be associated with white matter microstructure and biochemistry, potentially contributing to white matter abnormalities in schizophrenia. To test this, fasting plasma samples were obtained from 37 schizophrenia patients and 38 healthy controls and levels of total tryptophan and its metabolite kynurenine were assessed. The ratio of kynurenine to tryptophan was used as an index of tryptophan catabolic activity in this pathway. White matter structure and function were assessed by diffusion tensor imaging (DTI) and 1 H magnetic resonance spectroscopy (MRS). Tryptophan levels were significantly lower (po0.001), and kynurenine/tryptophan ratios were correspondingly higher (p = 0.018) in patients compared with controls. In patients, lower plasma tryptophan levels corresponded to lower structural integrity (DTI fractional anisotropy) (r = 0.347, p = 0.038). In both patients and controls, the kynurenine/tryptophan ratio was inversely correlated with frontal white matter glutamate level (r = − 0.391 and − 0.350 respectively, p = 0.024 and 0.036). These results provide initial evidence implicating abnormal tryptophan/ kynurenine pathway activity in changes to white matter integrity and white matter glutamate in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Chiappelli

Postolache

Kochunov

et al. 2016

Neuropsychopharmacol

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“…Biossíntese do ácido quinolínico a partir do triptofano receptor NMDA, a síntese de novas moléculas capazes de inibir uma dessas enzimas, impedindo assim a formação deste ácido, poderia ter um valor terapêutico no tratamento ou na prevenção de demência associada à infecção pelo HIV. Pesquisas estão em desenvolvimento nesta área 11 . Por exemplo, foi constatado que o derivado 4-cloro do ácido 3-hidroxiantranílico 5 é um inibidor da 3-hidroxiantranílico desoxigenase (Esquema 1) e diminui efetivamente a taxa do ácido quinolínico no líquido céfalo-raquidiano 12 .…”

Section: Receptores Do Glutamatounclassified

Métodos de preparação e atividade biológica do ácido quinolínico e derivados

Souza¹,

Almeida²,

Hyaric³

et al. 2003

Quím. Nova

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. In 1981 2,3-pyridine dicarboxylic acid (quinolinic acid) was discovery to be a selective agonist for the N-methyl -D-aspartic acid (NMDA) receptor. As a consequence it possesses neurotoxic activity resulting from overstimulation of the receptor. Quinolinic acid is implicated as an etiological factor in a range of neurodegenerative disease including AIDS related dementia, Huntington´s disease and Lyme disease. In the design of novel therapies to treat these diseases, some molecules have been identified as an important target. In this paper we described different methods to prepare quinolinic acid and derivatives.Keywords: quinolinic acid; NMDA receptor; AIDS related dementia. INTRODUÇÃOMais de um terço dos pacientes infectados pelo HIV sofrem de problemas neurológicos. Os sintomas incluem deficiência cognitiva e motora, conhecido como "AIDS dementia complex", mielopatia, neuropatia periférica e disfunções visuais 1 . A proporção de pacientes que sofrem de tais sintomas tende a aumentar à medida que as infecções oportunistas progridem. Segundo a maioria dos especialistas, uma vacina preventiva anti-HIV ou ainda um medicamento ideal é um objetivo a longo prazo e, todavia, incerto, sendo portanto necessário encontrar meios de curar os graves efeitos cognitivos associados à infecção causada pelo HIV. Este artigo aborda um suposto mecanismo da neurotoxicidade ligada ao HIV, assim como méto-dos de preparação do ácido quinolínico e de alguns de seus derivados, visando a prevenção ou a diminuição dos problemas cognitivos e motores provocados pelo HIV. Mecanismo da neurotoxidade associada à infecção pelo HIVOs problemas neurológicos associados ao HIV aparecem mesmo na ausência de infecções oportunistas e não são conseqüências de uma infecção direta dos neurônios pelo HIV 2 . Como se pode constatar a destruição ou danos dos neurônios no decorrer da doença, conclui-se que existe a liberação de um ou mais agente(s) neurotóxico(s) pelas células infectadas. Supõe-se que um destes agentes neurotóxicos seja o ácido quinolínico 6 (Esquema 1). Este composto endogênico, produto da degradação enzimática do triptofano 1, é de concentração particularmente elevada no líquido céfalo-raquidiano de pacientes portadores da AIDS 3 . Além desta evidência, o aumento da taxa de ácido quinolínico resulta em um forte aumento da taxa de cálcio nos neurônios, devido à sua interação direta ou indireta com o receptor ácido-N-metil-Daspártico (NMDA) 4-6 , uma das sub-classes dos receptores do glutamato no cérebro. Receptores do glutamatoO ácido L-glutâmico 7 é o principal neurotransmissor do sistema nervoso central dos mamíferos Entre estes três receptores ionotrópicos do glutamato, o receptor NMDA 8 é o mais estudado. Os receptores do glutamato estão implicados em processos fisiológicos fundamentais, tais como os fenô-menos de plasticidade sináptica e de memória 9 . É também conhecido que os aminoácidos excitadores podem causar efeitos neurotóxicos; estas moléculas provocam uma degenerescência neuronal em razão de uma liberação excessiva de cálcio...

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“…IDO is known to be induced by proinflammatory cytokines, including interferon-γ, interleukin (IL)-1β, and tumor necrosis factor-α [19, 20]. Brain KYN is linked to, and influenced by, the peripheral KYN pathway [21]. Both systemic and central immune stimulation, including cytokine-induced IDO activation, may contribute to activation of the cerebral KYN pathway in neurological disorders [22].…”

Section: Introductionmentioning

confidence: 99%

Kynurenine Pathway in Autism Spectrum Disorders in Children

et al. 2017

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Background: There is increasing evidence that altered immune responses play a role in the pathogenesis of autism spectrum disorders (ASD), together with dysfunction of the serotonergic and glutamatergic systems. Since the kynurenine (KYN) pathway that degrades tryptophan (TRP) is activated in various neuroinflammatory states, we aimed to determine whether this pathway is activated in ASD. Methods: Sixty-five pediatric ASD patients (including 52 boys) were enrolled from an epidemiological survey covering 2 counties in Norway; 30 (46.5%) of these patients were diagnosed with childhood autism, 16 (24.6%) with Asperger syndrome, 12 (18.5%) with atypical autism, 1 (1.5%) with Rett syndrome, and 6 (9.2%) with other ASD. The serum levels of the following markers were measured in the children with ASD and compared to those in 30 healthy children: TRP, KYN, kynurenic acid (KA), 3-hydroxykynurenine, and quinolinic acid. Results: The mean serum level of KA was significantly lower in the ASD group than in the healthy controls (28.97 vs. 34.44 nM, p = 0.040), while the KYN/KA ratio was significantly higher in the ASD group (61.12 vs. 50.39, p = 0.006). The same relative values were found when comparing the childhood autism subgroup with the controls. Also, the mean serum level of TRP was significantly lower in children with a subdiagnosis of childhood autism than in those with Asperger syndrome (67.26 vs. 77.79 μM, p = 0.020). Conclusion: Our study indicates that there is an increased neurotoxic potential and also a possible lower KYN aminotransferase activity in ASD.

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Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the l‐kynurenine and quinolinic acid pools in brain

Cited by 112 publications

References 32 publications

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Métodos de preparação e atividade biológica do ácido quinolínico e derivados

Kynurenine Pathway in Autism Spectrum Disorders in Children

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