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Objectives: The kynurenine (KYN) pathway has been attracting attention as a relevant pathway in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We conducted a systematic review and meta-analysis of studies examining KYN pathway metabolites from cerebrospinal fluid (CSF) samples in SZ, BD, and MDD. Methods: The PubMed and Scopus databases were systematically searched to identify peer-reviewed case-control studies published until April 2022 that assessed KYN metabolites, namely, tryptophan (TRP), KYN, kynurenic acid (KA), quinolinic acid (QA), and 3-hydroxykynurenine (3-HK), in subjects with SZ, BD, or MDD compared with healthy controls (HC). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The random effects model method was selected for comparison of standardized mean differences (SMD) between two groups. Results: Twenty-three articles met the inclusion criteria (k = 8, k = 8, k = 11, for SZ, BD, and MDD, respectively). In SZ, KA levels were increased (SMD = 2.64, confidence interval [CI] = 1.16 to 4.13, p = 0.0005, I2 = 96%, k = 6, n=384). TRP (k = 5) and KYN (k = 4) did not differ significantly. In BD, TRP levels (k = 7) did not differ significantly. The level of KA was increased in MDD (k = 2), but the small number of studies precluded evaluation of statistical significance. Finally, in MDD, although some studies tended to show an increased level of KYN in those with remission vs. decreased levels in those with current depression, no significant difference was found in any KYN metabolite levels. Similarly, an increased level of QA was found, but the number of studies (k = 2) was small. Conclusion: KA, which has possibly neuroprotective effects, is increased in SZ. QA, which has neurotoxic effects, may be increased in MDD. There were no alterations in BD. Alterations in the KYN pathway may occur based on population characteristics and mood states. Future studies should explore the utility of these metabolites as biomarkers.
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A Doença de Huntington (Huntington's disease - HD) trata-se de uma patologia neurodegenerativa hereditária caracteriza por meio da expressão das proteínas huntingtinas mutantes (mHtt), das mortes dos neurônios espinhais médios (medium spiny neurons MSNs) GABAérgicos D2-positivos do striatum e da hipercinesia. Uma hipótese se refere à função das mHtts de potencializarem os efeitos excitotóxicos das estimulações dos receptores de NMDA (NMDAR) por meio da inibição da succinato desidrogenase, resultando em desequilibrio das [Ca2+]i, estresse oxidativo e apoptose. A adenosina agonista dos receptores purinérgicos P1 tem sido descrita por conta das suas funções neuroprotetoras e neuromodulatórias. Assim, estabelecemos dois modelos in vitro da HD fundamentados nas neurodiferenciações das linhagens murinas de célula-tronco embrionárias E14-TG2a e progenitoras neurais do hipocampo HT-22; seguidas pelos tratamentos com ácido quinolínico (QA) agonista seletivo dos NMDARs , na ausência e na presença do ácido 3-nitropropiônico (3-NP) inibidor irreversível da succinato desidrogenase. Estes modelos foram utilizados nas avaliações das funções neuroprotetoras da adenosina. Os neurônios pós-mitóticos das culturas de E14-TG2a diferenciadas foram caracterizados conforme os MSNs GABAérgicos do striatum; enquanto os neurônios HT-22 diferenciados foram caracterizados de modo inespecífico. Metodologia: imunofluorescência (microscopia e citometria); PCR em tempo real; análise das variações dos potenciais das membranas plasmáticas e das variações transientes das [Ca2+]i por microfluorimetria; e quantificações das reduções do AlamarBlue® (% de sobrevida celular) e das atividades extracelulares de LDH (U/L) (necrose) por espectrometria. Avaliamos a capacidade do 3-NP de potencializar os efeitos excitotóxicos do QA comparando dois grupos de neurônios HT-22 diferenciados: QA 8mM (EC50) (controle); e 3-NP 5mM/QA 8mM. Avaliarmos o potencial neuroprotetor da adenosina comparando quatro grupos de neurônios HT-22 diferenciados: QA 8mM; adenosina 250µM/QA 8mM; 3-NP 5mM/QA 8mM; 3-NP 5mM/adenosina 250µM/QA 8mM. Os neurônios pós-mitóticos derivados das E14TG2a foram classificados como MSNsGABAérgicos do striatum integrantes de uma cultura neuronal heterogênea semelhante às conexões nigroestriatais, corticoestriatais, striatonigral e striatopallidal. Os neurônios HT-22 diferenciados perfaziam uma cultura neuronal heterogênea, não totalmente madura, composta por neurônios glutamatérgicos, dopaminérgicos, colinérgicos e GABAérgicos. Os neurônios HT-22 diferenciados 3-NP 5mM apresentaram menores % de sobrevida celular após os tratamentos com QA 8mM por 24h (p<0.05); e maiores amplitudes das variações das [Ca2+]i dependentes do QA 8mM (p<0.05) (cinética 6 minutos). Por outro lado, os neurônios HT-22 diferenciados pré- tratados com 3-NP 5mM apresentaram menores atividades extracelulares de LDH após o tratamento com QA 8mM por 24h menor proporção de necrose. Os pré-tratamentos com adenosina 250µM indicaram uma tendência dos efeitos neuroprotetores (p>0.05) maiores % de sobrevida celular; menores atividades extracelulares de LDH; e menores amplitudes das variações transientes das [Ca2+]i. Em conjunto, nossos resultados indicam que a inibição da succinato desidrogenase potencializa os efeitos excitotóxicos dos NMDARs por meio da alteração das [Ca2+]i e, provavelmente, dos mecanismos de morte celular; enquanto a adenosina apenas tendeu à neuroproteção
Huntington's disease (HD) is a hereditary neurodegenerative pathology characterized by mutant huntingtin proteins (mHtt) expression, striatum D2-positive GABAergic medium spiny neurons (MSNs) cell death and hyperkinetic motor symptoms development. One hypothesis refers to the principle that mHtt potentiates the excitotoxic effects of NMDA receptor (NMDAR) stimulation by the inhibition of mitochondrial succinate dehydrogenase, resulting in [Ca2+]i imbalance, oxidative stress and apoptosis. Adenosine P1 purinergic receptor agonist is related to neuroprotective and neuromodulatory functions. Thus, we established two in vitro HD models based on the neurodifferentiation of murine embryonic stem cell lines E14-TG2a and hippocampal neuroprogenitor cell line HT-22 followed by treatment with quinolinic acid (QA) selective agonist of NMDARs , in the absence and in the presence of 3-nitropropionic acid (3-NP) irreversible inhibitor of succinate dehydrogenase. These models were used to assess the neuroprotective functions of adenosine. Post-mitotic neurons from differentiated E14-TG2a cultures were characterized according to striatum's GABAergic MSNs; while the differentiated HT-22 neurons were characterized in a non-specific way. Methodology included immunofluorescence (microscopy and cytometry); real-time PCR; analysis of variations in the plasma membrane potentials and of transient variations in the [Ca2+]i by microfluorimetry; and quantification of AlamarBlue® reductions (% cell survival) and of extracellular LDH activity (U/L) (necrosis) by spectrometry. We evaluated the ability of 3-NP to potentiate the excitotoxic effects of QA by comparing two groups of differentiated HT-22 neurons: 8mM QA (control); and 5mM 3-NP/8mM QA. We evaluated the neuroprotective potential of adenosine comparing four groups of differentiated HT-22 neurons: QA 8mM; 250µM adenosine/8mM QA; 5mM 3-NP/8mM QA; 5mM 3-NP/250µM adenosine/8mM QA. Postmitotic neurons derived from E14TG2a were classified as striatums GABAergic MSNs that are part of a heterogeneous neuronal culture similar to nigrostriatal, corticostriatal, striatonigral, and striatopallidal connections. Differentiated HT-22 neurons consisted of a heterogeneous neuronal culture and not fully mature glutamatergic,dopaminergic, cholinergic and GABAergic neurons. Differentiated HT-22 neurons following 5mM 3-NP treatment showed lower % cell survival after treatments with 8mM QA for 24h (p<0.05); and higher amplitudes of the variations of [Ca2+]i induced by 8mM QA (p<0.05) (kinetics 6 minutes). On the other hand, differentiated HT-22 neurons 5mM 3-NP showed lower extracellular LDH activities after treatment with 8mM QA for 24h indicating a lower proportion of necrotic cells. Pretreatments with 250µM adenosine indicated a trend towards neuroprotective effects, such as higher percentages of cell survival; lower extracellular LDH activities; and lower amplitudes of transient variations of [Ca2+]i. Taken together, our results indicate that succinate dehydrogenase inhibition potentiated the excitotoxic effects of NMDARs by altering [Ca2+]i and, probably, cell death mechanisms, while adenosine only to neuroprotection
Subject(s)
In Vitro Techniques/methods , Quinolinic Acid/adverse effects , Huntington Disease/pathology , Models, Anatomic , Spectrum Analysis/methods , Adenosine/agonists , Receptors, N-Methyl-D-Aspartate , Neuroprotective Agents/administration & dosage , Absenteeism , Purinergic Agonists/adverse effectsABSTRACT
Major depressive disorder (MDD) is one of the world’s major chronic and disabling mental diseases. By 2030, MDD is expected to be the top of all the disease burden in the world, with high prevalence, high recurrence rate, high disability rate, and high suicide rate. Suicide is the most serious consequence of MDD. Current studies showed that inflammatory levels in the central nervous system and peripheral blood of patients with MDD were higher, and increased more significantly in depressive patients with suicidal ideation or behavior. Related researches showed that increased levels of inflammatory cytokines were associated with dysregulation of kynurenine metabolic pathway, leading to imbalances in neurometabolites, such as an excess of the neurotoxic product quinolinic acid and a decrease in the protective neuropeptide picolinic acid. This paper reviews kynurenine metabolic pathway, expecting to identify the biomarkers of MDD patients with suicide.
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The antidiabetic drug metformin has been found to have beneficial effects in various neurological disorders; however, the molecular mechanisms underlying these effects remain unclear. Here we report that metformin protects neuronal cells from quinolinic acid (QUIN)-induced excitotoxicity. For this, we pretreated N18D3 neuronal cells with metformin prior to QUIN for 24 h. We found that pretreating the cells with metformin significantly improved cell survival rate in a concentration-dependent manner and reduced apoptotic cell death, as revealed by a MTT assay and DAPI staining, respectively. Calcium imaging using fluo-4 showed that metformin (100 µM) inhibited the intracellular calcium increase that was induced by QUIN. In addition, mRNA expression of pro-apoptotic genes, p21 and Bax, was decreased and of anti-apoptotic genes, Bcl-2 and Bcl-xl, was increased with metformin treatment compared to QUIN-induced cells. The immunoreactivity of phosphorylated ERK1/2 was elevated in cells treated with metformin, indicating the ERK1/2 signaling pathway in the neuroprotective effects of metformin in QUIN-induced cell death. Collectively, our data demonstrates that metformin exerts its neuroprotective effects by inhibiting intracellular calcium increases, allowing it to regulate ERK1/2 signaling and modulate cell survival and death genes.
Subject(s)
Apoptosis , Calcium , Cell Death , Cell Survival , Genes, bcl-2 , Metformin , Nervous System Diseases , Neurons , Neuroprotection , Neuroprotective Agents , Quinolinic Acid , RNA, MessengerABSTRACT
OBJECTIVE To investigate whether quinolinic acid(QA)induces autophagy in PC12 cells and its relationship with glycogen synthase kinase-3β(GSK-3β)/β-catenin related signaling path?ways. METHODS PC12 cells were treated with QA 2.5,5.0 and 10.0 mmol·L-1 for 24 h. The cell viability was determined by MTT assay. Autophagy fluorescent spots labelled form of microtubule-associated protein 1 light chain 3(LC3)was examined by LC3 immunostaining. The expressions of GSK-3β,β-catenin,LC3 and Beclin 1 were determined by Western blotting. RESULTS QA inhibited PC12 cell survival in a concentration-dependent manner,and IC50 was 8.7 mmol · L- 1. Compared with normal control group,QA 2.5,5.0 and 10.0 mmol · L-1 increased autophagic intracellular LC3 fluorescence spots,elevated the expression ratio of LC3-Ⅱ/LC3-Ⅰ and expression of Beclin 1 in PC12 cells(P<0.05). In addition,QA enhanced GSK-3βexpression and decreasedβ-catenin expression(P<0.05,P<0.01). CONCLUSION QA induces autophagy in PC12 cells. This mechanism may be associated with the activation of GSK-3β/β-catenin related signaling pathways.
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Aim To investigate the role of HIF-1 αin PC1 2 cell injury induced by quinolinic acid.Methods PC1 2 cells were treated with quinolinic acid at the do-ses of 2.5,5 and 1 0 mmol·L -1 ,the cell viability was determined by MTT reduction assay and LDH as-say,the intracellular levels of oxygen species was measured by assessing SOD and MDA levels,cell ap-optosis was determined by Hoechst 33258 staining,the intracellular distribution of HIF-1 αwas examined by HIF-1 αimmunostaining,and the expressions of HIF-1 α,Akt,p-Akt,Bcl-2 and Bax were determined by im-munoblotting analysis.Results Quinolinic acid in-duced cell injury in PC1 2 cells in a dose-dependent manner,and potentiated oxygen radical production and cell apoptosis.In addition,quinolinic acid enhanced HIF-1 αexpression and accumulation in nuclei.The p-Akt expression and Bax/Bcl-2 ratio was increased by quinolinc acid in PC1 2 cells.Conclusions HIF-1 αand Akt mediate qunolinc acid-induced cell apoptosis in PC1 2 cells.And cellular oxidative stress may con-tribute to the injury as well.
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Our study investigated the neurotoxicity of quinolinic acid(QA)to spiral ganglion cells(SGCs),observed the protective effects of N-methyl-D-aspartatc(NMDA)receptor antagonist MK-801and magnesium ions on the QA-induced injury to SGCs,and analyzed the role of QA in otitis media with effusion(OME)-induced sensorineural hearing loss(SNHL).After culture in vitro for 72 h,SGCs were exposed to different media and divided into 4 groups: the blank control group,the QA injury group,the MK-801 treatment group,and the MgCl2 protection group.The apoptosis rate of SGCs was analyzed by Annexin V and PI double staining under the fluorescence microscopy 24 h later.SGCs were cultured in vitro for 72 h and divided into four groups: the low concentration QA group,the high concentration QA group,the MK-801 group,the MgCl2 group.The transient changes of intracellular calcium concentration were observed by the laser scanning confocal microscopy.Apoptosis rate in QA injury group was higher than that in blank control group and MgCl2 protection group(both P<0.05),but there was no significant difference between MK-801 treatment group and blank control group(P>0.05).In high concentration QA group,there was an obvious increase of the intracelhilar calcium concentration in SGCs,which didn't present in low concentration QA group.In MgCl2 group,the peak values of the intracellular calcium concentration in SGCs were reduced and the duration was shortened,but the intracellular calcium concentration in SGCs had no significant change in MK-801 group.It was concluded that QA could injure SGCs by excessively activating NMDA receptors on the cell membrane,which might be the mechanism by which OME induced SNHL,while Mg2+could protect the SCGs from the neurotoxicity of QA.
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Stem cells provide an important means for regenerative medicine due to the capacity to generate multiple types of differentiated cells and at the same time to maintain self-renewal. To identify the therapeutic effect of the transplantation of neural stem cells, differentiation and migration capacity of the neural stem cells that were isolated from E14 rat embryo and maintained in culture were examined after transplantation to the striatum of the quinolinic acid (QA)-induced Huntington's disease rat model. in vitro co-culture of the neural stem cells with the mixture of primary neurons and astrocytes promoted the maturation and the synapse formation of neuronal progenies of neural stem cells. Following the implantation, the neural stem cells survived, differentiated, and migrated in the damaged striatum region, exhibiting immunoreactivities against nestin, Tuj-1, GFAP, GAD(67) and synapsin 1 to a varying degree. These data provide clear evidence supporting that the neural stem cells isolated from the rat embryo and maintained in the primary culture have a multiple capacity to differentiate into neurons or glial cells both in vitro and in vivo.
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Animals , Rats , Astrocytes , Brain , Coculture Techniques , Embryonic Structures , Huntington Disease , Intermediate Filament Proteins , Nerve Tissue Proteins , Neural Stem Cells , Neuroglia , Neurons , Quinolinic Acid , Regenerative Medicine , Synapses , TransplantsABSTRACT
The kynurenine metabolic pathway involves in a cascade of enzyme reaction generated multiple biologically-active compounds.These metabolites are called"kynurenines" which participate in diverse pathophysiological processes,particularly in the central nervous system.The kynurenines have important physiological functions.For example.quinolinic acid is an Nmethyl-D-aspartate(NMDA)receptor agonist.and it can be largely accumulated in the central nervous system in many infectious nervous system diseases,resulting in neuronal excitotoxicity and death.Kynurenic acid antagonizes excitatory glutamate receptors to reduce excitotoxicityinduced neuronal death.This article reviews the related researches of the effects of kynurenine metabolic pathway on the central nervous system.
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Aim To observe the effects of Xiatianwu tota l alkaloids ( XA ) on learning and memory impairment and the central cholinergic f unction in rats with quinolinic acid microinjected into bilateral hippocampus. Methods Alzheimers disease (AD) rat models were made by damagin g bilateral hippocampus with quinolinic acid (150 nmol in 2 ?l for each hippoca mpus). XA 0.25, 0.5, 1 mg?kg -1 was administrated ig from 1 week before model established to 3 weeks after model established. Y-maze was used to measur e the learning and memory ability. The activity of the acetylcholinesterase ( AC hE ) in hippocampus and the contents of acetylcholine ( ACh ) was determined by spectrophotometry. Results Microinjection of quinolinic acid in to the rats hippocampus induced learning and memory dysfunction (P
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Objective: To investigate the anti-inflammatory effects of quinolinic acid.Methods: Kunming mouse or Wistar rat was selected to proceed experiments.Influences of quinolinic acid on tumidness caused by dimethylbenzene in mouse's ear,on wandering of rat WBC caused by CMC injection,on increasement of mouse capillary vessel permeability caused by acetic acid,on granuloma in rat's armpit caused by tampon and phagocytosis of mouse were investigated,respectively.Results: Obvious suppression of all the inflammatory models was observed.Conclusion:Exogenous quinolinic acid is endowed with quite evident anti-inflammatory effects on either acute or subacute animal models with somewhat immunological inhibition.
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Objective To explore the effect of estrogen on striatal neurons damage in rats induced by quinolinic acid (QA).Methods Ovariectomized rats were divided into two groups:non-replacement treatment group (recievied intrastriatal application of QA alone) and replacement treatment group (received both QA and 17-? estradiol). Striatal neurons injury was evaluated using NADPH-diaphorase histochemistry and the rotation number of rats induced by apomorphine was recorded. Activity of SOD and contents of MDA in striatum was measured by xanthine oxidase and thio-barbital method, respectively.Results Compared with non-replacement treatment group, there was a significant increase in the number of NADPH-diaphorase positive neurons ( P
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The effect of GABA ergic system in the brain in mediating convulsions induced by quinolinic acid (QA) was studied. Muscimol,an agonist of GABAA-receptor, and aminooxyacetic acid (AOAA),an inhibitor of GABA transami-nase(GABA-T) ,and alprazolam which increased the affinity of GABA-receptor as it binds with benzodiazepine-receptor, were used to increase GABAergic function in the brain. Results showed that the above substances antagonized QA-induced convulsions. In contrast, bicu-culline,an antagonist of GABAA-receptor, and 3-mercaptopropionic acid (3-MP), an inhibitor of both GABA synthesis and its release, were used to decrease GABA ergic function in the CNS. They were found to potentiate QA-induced seizures. All these results suggest that GABA ergic system in brain plays an important role in modulating QA-induced convulsions.
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Aim To study the protection of tetrandrine(Tet) from the excitotoxicity of quinolinic acid(QA) on the cultured hippocampal neurons of new-borne rats.Method Excitoxocity injury was induced by QA in cultured hippocampal neurons.The cell viability was measured by MTT assay, extracellular LDH contents were also measured and the pathomorphology of neurons was observed. Result Tet with 10 -6 mol?L -1 and 10 -7 mol?L -1 could significantly blunt the death of the primary hippocampal neurons induced by QA,prevent leakage of LDH and improve the pathomorphology of neurons. Conclusion Tet (10 -6 mol?L -1 and 10 -7 mol?L -1)provids protection on QA induced cytotoxicity in cultured hippocampal neurons of new-borne rats.
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AIM To observe the effect of aspirin on a model of Alzheimers disease in rats and its molecular mechanism. METHODS The AD pathological model was made by hippocampal CA 1 lesions with stereotaxic mini-injection of quinolinic acid;the rats learning and memory was observed by Y-maze; the apoptosis of hippocampal cells were detected by using flow cytometry and electronic microscope; the content of calcium in AD rats hippocampus was determined by atomic absortion spectrophotometer. RESULTS Aspirin was shown to improve learning and memory deficiency in rats with bilateral hippocampal lesions induced by quinolinc acid, to decrease apoptosis rate in hippocampal cells significantly and to reduce the concentration of calcium in hippocampus. CONCLUSION The protective effects of aspirin on a model of AD in rats may be involved in antagonism of calcium and inhibition of apoptosis in hippocampal cells induced by quinolinic acid.
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Objective To establish a sensitive and accurate gas chromatography-mass spectrometry method for determination of quinolinic acid in rat serum.Methods The objective compound was purified and derivatized to its dihexafluoroisopropyl ester before quantitative determination by scanning method and quantitative determination by SIM method.Results The endogenous substances in serum had no interference on the measurement of quinolinic acid in the sample.Assay linearity was obtained in the range of 0.05-20 ?mol/L with limit of quantitation(LOQ)of 0.05 ?mol/L.The intra-day relative standard deviation(RSD)was lower than 15%.The inter-day relative standard deviation was lower than 12%.Conclusion It is a sensitive,accurate and convenient method.The dihexafluoroisopropyl ester of quinolinic acid is quite stable,but the serum should not be preserved for a long time before derivation.