RESUMO
OBJECTIVE: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein 1 (YKL-40) were investigated in plasma and cerebrospinal fluid (CSF) in first-episode psychosis (FEP) patients. METHOD: CSF and blood were sampled from 42 first-episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL-40 and MCP-1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN-9000-hematology analyzer. RESULTS: We found higher plasma levels of MCP-1 and YKL-40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL-40 levels in the CSF of tobacco-free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning. CONCLUSION: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL-40 and MCP-1 in the initiation and progression of schizophrenia.
Assuntos
Quimiocina CCL2/sangue , Proteína 1 Semelhante à Quitinase-3/sangue , Monócitos , Transtornos Psicóticos/sangue , Esquizofrenia/sangue , Adulto , Quimiocina CCL2/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Feminino , Humanos , Contagem de Leucócitos , Masculino , Transtornos Psicóticos/líquido cefalorraquidiano , Transtornos Psicóticos/imunologia , Esquizofrenia/líquido cefalorraquidiano , Esquizofrenia/imunologia , Adulto JovemRESUMO
Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll-like receptors (TLRs), representing the first line of immune defence against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of this study was to investigate whether stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analysed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan. Stimulation of TLR-2, TLR-3, TLR-4, TLR-7/8 and TLR-9 was found to induce the production of kynurenine, but only stimulation of TLR-3 increased levels of further downstream metabolites, such as KYNA and QUIN. Stimulation of TLR-1, TLR-5 and TLR-6 did not induce the kynurenine pathway. Taken together, this study provides novel evidence demonstrating that TLR activation induces a pattern of downstream tryptophan degradation along the kynurenine pathway in monocytes. The results of this study may implicate that TLRs can be used as new drug targets for the regulation of aberrant tryptophan metabolism along this pathway, a potential therapeutic strategy that may be of importance in several disorders.
Assuntos
Cinurenina/imunologia , Monócitos/imunologia , Receptores Toll-Like/imunologia , Triptofano/imunologia , Flagelina/farmacologia , Regulação da Expressão Gênica , Humanos , Hidrólise , Imidazóis/farmacologia , Ácido Cinurênico/imunologia , Ácido Cinurênico/metabolismo , Cinurenina/agonistas , Cinurenina/metabolismo , Lipopeptídeos/farmacologia , Lipopolissacarídeos/farmacologia , Listeria monocytogenes/química , Monócitos/citologia , Monócitos/efeitos dos fármacos , Poli I-C/farmacologia , Cultura Primária de Células , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Ácido Quinolínico/imunologia , Ácido Quinolínico/metabolismo , Transdução de Sinais , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Triptofano/metabolismoRESUMO
The immune system has been recognized as a potential contributor to psychiatric disorders. In animals, lipopolysaccharide (LPS) is used to induce inflammation and behaviors analogous to some of the symptoms in these disorders. Recent data indicate that the kynurenine pathway contributes to LPS-induced aberrant behaviors. However, data are inconclusive regarding optimal LPS dose and treatment strategy. Here, we therefore aimed to evaluate the effects of single versus repeated administration of LPS on the kynurenine pathway. Adult C57BL6 mice were given 0.83 mg/kg LPS as a single or a repeated injection (LPS + LPS) and sacrificed after 24, 48, 72, or 120 h. Mice receiving LPS + LPS had significantly elevated brain kynurenine levels at 24 and 48 h, and elevated serum kynurenine at 24, 48 and 72 h. Brain kynurenic acid and quinolinic acid were significantly increased at 24 and 48 h in mice receiving LPS + LPS, whereas serum kynurenic acid levels were significantly decreased at 24 h. The increase of brain kynurenic acid by LPS + LPS was likely unrelated to the higher total dose as a separate group of mice receiving 1.66 mg/kg LPS as single injection 24 h prior to sacrifice did not show increased brain kynurenic acid. Serum quinolinic acid levels were not affected by LPS + LPS compared to vehicle. Animals given repeated injections of LPS showed a more robust induction of the kynurenine pathway in contrast to animals receiving a single injection. These results may be valuable in light of data showing the importance of the kynurenine pathway in psychiatric disorders.
Assuntos
Encéfalo/efeitos dos fármacos , Cinurenina/metabolismo , Lipopolissacarídeos/farmacologia , Ácido Quinolínico/metabolismo , Animais , Encéfalo/metabolismo , Sistema Imunitário/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ácido Cinurênico/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan that is thought to regulate cognitive functions. Previous studies have shown that levels of KYNA increase during virus infection and that this metabolite interacts with the immune system. OBJECTIVE: The aim of the study was to investigate whether patients with tick-borne encephalitis (TBE), a viral infectious disease associated with long-term cognitive impairment, have increased levels of KYNA in the cerebrospinal fluid (CSF). METHODS: CSF KYNA was analysed using high-performance liquid chromatography in 108 patients with TBE and 52 age-matched controls. Patients were classified according to the severity of TBE: mild (47%), moderate (44%) or severe (9%). RESULTS: Concentrations of CSF KYNA were considerably higher in patients with TBE (5.3 nmol L(-1) ) than in control subjects (0.99 nmol L(-1) ). KYNA concentration in the CSF varied greatly amongst individuals with TBE and increased (P < 0.05) with the severity of disease. CONCLUSIONS: This is the first study to demonstrate increased levels of CSF KYNA in patients with TBE. The importance of brain KYNA in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in TBE might play a part in the pathophysiology of the disease. A detailed knowledge of endogenous brain KYNA during the course of CNS infection might yield further insights into the neuroimmunological role of the compound and may also provide new pharmacological approaches for the treatment of cognitive symptoms.
Assuntos
Encefalite Transmitida por Carrapatos/líquido cefalorraquidiano , Ácido Cinurênico/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The N-Methyl-d-Aspartate receptor (NMDAR) antagonist kynurenic acid (KYNA) and the post-synaptic calmodulin binding protein neurogranin (Nrgn) have been implicated in neurological and neuropsychiatric conditions including Alzheimer's disease and schizophrenia. This study indicates that systemic dual-lipopolysaccharide (LPS) injections increases KYNA in the medial prefrontal cortex (mPFC), which is accompanied with increased phosphorylation of nuclear factor kappa chain of activated B cells (NFκB) and activation of the nuclear factor of activated T- cells (NFAT). Our results also indicate that dual-LPS increases Nrgn phosphorylation and concomitantly reduces phosphorylation of calmodulin kinase-II (CaMKII). We confirmed that systemic blockade of kynurenine-3 monooxygenase in conjunction with kynurenine administration results in significant increases in Nrgn phosphorylation and a significant reduction of CaMKII phosphorylation in the mPFC. Consequently, dual-LPS administration induced significant impairments in stimulus processing during Pavlovian conditioning. Taken together, our study indicates that elevations in KYNA in the mPFC can directly regulate NMDA-Nrgn-CaMKII signaling, suggesting that neuroinflammatory conditions affecting this pathway may be associated with cognitive dysfunction.
Assuntos
Ácido Cinurênico/metabolismo , Lipopolissacarídeos/toxicidade , Neurogranina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Variância , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Condicionamento Clássico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Inibição Pré-Pulso/efeitos dos fármacos , Teste de Desempenho do Rota-Rod , Sinaptossomos/efeitos dos fármacosRESUMO
The mode of action by which propofol induces anaesthesia is not fully understood, although several studies suggest that the compound acts via potentiation of brain GABA(A)-receptors. The aim of the present study is to investigate a putative GABA(B)-receptor agonistic action of propofol. For this purpose the action of propofol on a GABA-receptor mediated regulation of dopamine neurons was analyzed with extracellular single unit recordings of dopaminergic neurons of the substantia nigra in chloral hydrate anaesthetized rats. Intravenous administration of propofol (1-16 mg/kg) was found to dose-dependently decrease the firing rate and burst firing activity of nigral DA neurons. These effects by propofol were effectively antagonized by pretreatment with the selective GABA(B)-receptor antagonist CGP 35348 (200 mg/kg, i.v.) but not by pretreatment with the GABA(A)-receptor antagonist picrotoxin (4.5 mg/kg, i.v.). It is proposed that an activation of central GABA(B)-receptors may, at least partially, contribute to the anesthetic properties of propofol.
Assuntos
Anestésicos Intravenosos/farmacologia , Propofol/farmacologia , Receptores de GABA-B/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Eletrofisiologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/fisiologia , Antagonistas GABAérgicos/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacosRESUMO
Kynurenic acid (KYNA), an endogenous glutamate-receptor antagonist preferentially blocking NMDA-receptors, has analgesic properties and has also been implicated in the pathophysiology of schizophrenia. Recently, the non-steroid anti-inflammatory drug (NSAID) diclofenac was found to increase rat brain KYNA. Here, we analyze whether cyclooxygenase (COX)-1 or COX-2 modulate the levels of rat brain KYNA. The non-selective COX-inhibitor diclofenac (50 mg/kg, i.p.) or indomethacin (50 mg/kg, i.p.), a non-selective inhibitor with a preferential selectivity for COX-1, produced an elevation in brain KYNA. In contrast, the COX-2 selective inhibitors parecoxib (25 mg/kg, i.p.) or meloxicam (5 mg/kg, i.p.) decreased brain KYNA. Both elevation and lowering of brain KYNA by indomethacin or parecoxib, respectively, were prevented by the prostaglandin E1/E2 agonist misoprostol (1 mg/kg, s.c.). It is proposed that increased brain KYNA formation induced by NSAIDs displaying an inhibitory action on COX-1 contribute to their analgesic efficacy as well as to their psychiatric side effects.