Quinolinic acid: effects on brain catecholamine and c-AMP content during L-dopa and reserpine administration

Beskid, M; Finkiewicz-Murawiejska, L

doi:10.1016/s0940-2993(11)80189-2

Cited by 6 publications

(4 citation statements)

References 12 publications

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“…3, activation of the KP neurotoxic branch can contribute to dopaminergic alterations within the neural reward circuitry via several linked processes. The KP neurotoxin, QUIN, directly alters the mesolimbic dopaminergic system and induces dopaminergic and GABAergic neuronal death (Kurachi et al 2000; Sumiyoshi et al 2004; Beskid and Finkiewicz-Murawiejska 1992; Araujo et al 2000) while KA, another KP metabolite, tightly controls the firing of midbrain dopaminergic neurons, with decreased endogenous KA resulting in decreased dopamine release (Erhardt et al 2009; Wu et al 1994). Additionally, animal studies suggest that 3-HK and 3-HAA toxicity is dependent upon transporter-mediated cellular intake with brain region selectivity; striatal and cortical neurons (key regions within the neural reward circuitry) are particularly vulnerable to these toxins (Okuda et al 1998; Heyes et al 2001).…”

Section: Discussionmentioning

confidence: 99%

The possible role of the kynurenine pathway in anhedonia in adolescents

et al. 2011

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To address the heterogeneous nature of adolescent major depression (MDD), we investigated anhedonia, a core symptom of MDD. We recently reported activation of the kynurenine pathway (KP), a central neuroimmunological pathway which metabolizes tryptophan (TRP) into kynurenine (KYN) en route to several neurotoxins, in a group of highly anhedonic MDD adolescents. In this study, we aimed to extend our prior work and examine the relationship between KP activity and anhedonia, measured quantitatively, in a group of MDD adolescents and in a combined group of MDD and healthy control adolescents. Thirty-six adolescents with MDD (22 medication-free) and 20 controls were included in the analysis. Anhedonia scores were generated based on clinician- and subject-rated assessments and a semi-structured clinician interview. Blood KP metabolites, collected in the AM after an overnight fast, were measured using high-performance liquid chromatography. The rate-limiting enzyme of the KP, indoleamine 2,3-dioxygenase (IDO), was estimated by the ratio of KYN/TRP. Pearson correlation tests were used to assess correlations between anhedonia scores and KP measures while controlling for MDD severity. IDO activity and anhedonia scores were positively correlated in the group psychotropic medication-free adolescents with MDD (r = 0.42, P = 0.05) and in a combined group of MDD subjects and healthy controls (including medicated patients: r = 0.30, P = 0.02; excluding medicated patients: r = 0.44, P = 0.004). In conclusions, our findings provide further support for the role for the KP, particularly IDO, in anhedonia in adolescent MDD. These results emphasize the importance of dimensional approaches in the investigation of psychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

The possible role of the kynurenine pathway in anhedonia in adolescents

et al. 2011

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“…19,45,46 This increased production of kynurenine metabolites alters various neurotransmitter systems within the cortical and striatal regions. [47][48][49] Kynurenine metabolites reduce dopamine levels in substantia nigra and in the striatum, 48,50 acetylcholine in the cortex, 51,52 and gamma aminobutyric acid (GABA) in rat striatum and cortex of rat brains. 47,53 Dysregulation of kynurenine metabolism associated with SD is known to impact cognitive function and to promote the development and progression of neurodegeneration.…”

Section: Sleep Deprivation Tryptophan and Kynurenine Pathwaymentioning

confidence: 99%

Effects of Sleep Deprivation on the Tryptophan Metabolism

Bhat

Pires

Tan

et al. 2020

Int J�Tryptophan�Res

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Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.

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“…An increased QUIN level disrupts the calcium ion concentration within the neurons, which results in impaired adenylyl cyclase activity. A decrease in adenylyl cyclase activity causes a decrease in the cAMP content in the rat brain. , A decrease in cAMP levels is correlated with the down-regulation of key synaptic proteins like synapsin-1, PSD-95, and synaptophysin. − These cAMP-dependent alterations in synaptic proteins decrease the synaptic plasticity and are linked to changes in CREB/BDNF and consequently reduced cognitive functions. , Increased QUIN levels are also observed in neurodegenerative disease like HD AD, PD, amyotrophic lateral sclerosis (ALS), and MS …”

Section: Introductionmentioning

confidence: 99%

“…A decrease in adenylyl cyclase activity causes a decrease in the cAMP content in the rat brain. 26,27 A decrease in cAMP levels is correlated with the down-regulation of key synaptic proteins like synapsin-1, PSD-95, and synaptophysin. 28−31 These cAMP-dependent alterations in synaptic proteins decrease the synaptic plasticity and are linked to changes in CREB/BDNF and consequently reduced cognitive functions.…”

Section: Introductionmentioning

confidence: 99%

Roflumilast, a cAMP-Specific Phosphodiesterase-4 Inhibitor, Reduces Oxidative Stress and Improves Synapse Functions in Human Cortical Neurons Exposed to the Excitotoxin Quinolinic Acid

Bhat

Tan

Heng

et al. 2020

ACS Chem. Neurosci.

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The overexpression of phosphodiesterase 4 (PDE4) enzymes is reported in several neurodegenerative diseases. PDE4 depletes cyclic 3′-5′ adenosine monophosphate (cAMP) and, in turn, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), the key players in cognitive function. The present study was undertaken to investigate the mechanism behind the protective effects of roflumilast (ROF), a cAMP-specific PDE4 inhibitor, against quinolinic acid (QUIN)-induced neurotoxicity using human primary cortical neurons. Cytotoxicity was analyzed using an MTS assay. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured by DCF-DA and JC-10 staining, respectively. Caspase 3/7 activity was measured using an ApoTox-Glo Triplex assay kit. cAMP was measured using an ELISA kit. The protein expression of CREB, BDNF, SAP-97, synaptophysin, synapsin-I, and PSD-95 was analyzed by the Western blotting technique. QUIN exposure down-regulated CREB, BDNF, and synaptic protein expression in neurons. Pretreatment with ROF increased the intracellular cAMP, mitochondrial membrane potential, and nicotinamide adenine dinucleotide (NAD + ) content and decreased the ROS and caspase 3/7 levels in QUIN-exposed neurons. ROF up-regulated the expression of synapse proteins SAP-97, synaptophysin, synapsin-I, PSD-95, and CREB and BDNF, which indicates its potential role in memory. This study suggests for the first time that QUIN causes pre-and postsynaptic protein damage. We further demonstrate the restorative effects of ROF on the mitochondrial membrane potential and antiapoptotic properties in human neurons. These data encourage further investigations to reposition ROF in neurodegenerative diseases and their associated cognitive deficits.

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Quinolinic acid: effects on brain catecholamine and c-AMP content during L-dopa and reserpine administration

Cited by 6 publications

References 12 publications

The possible role of the kynurenine pathway in anhedonia in adolescents

The possible role of the kynurenine pathway in anhedonia in adolescents

Effects of Sleep Deprivation on the Tryptophan Metabolism

Roflumilast, a cAMP-Specific Phosphodiesterase-4 Inhibitor, Reduces Oxidative Stress and Improves Synapse Functions in Human Cortical Neurons Exposed to the Excitotoxin Quinolinic Acid

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