Neuroactive metabolises of L‐tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid effect of tryptophan loading

During, Matthew J.; Freese, Andrew; Heyes, Melvyn P.; Swartz, Kenton J.; Markey, S. P.; Roth, Robert H.; Martin, Joseph B.

doi:10.1016/0014-5793(89)81387-0

Cited by 41 publications

(13 citation statements)

References 53 publications

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“…The concentrations of extracellular tryptophan, kynurenine and QUIN in naïve rats were in line with studies using various detection methods, including ECNI [31,32,40,41]. Interestingly, ambient kynurenine levels in brain microdialysates from normal rats (~500 nM when corrected for the ~20% recovery from the dialysis probe) were only slightly lower than kynurenine concentrations in rat brain tissue and serum, respectively [42,43].…”

Section: Discussionsupporting

confidence: 76%

Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain

Notarangelo

Macherone

et al. 2012

Analytical Biochemistry

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We describe here a GC/MS/MS method for the sensitive and concurrent determination of extracellular tryptophan and the kynurenine pathway metabolites kynurenine, 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) in rat brain. This metabolic cascade is increasingly linked to the pathophysiology of several neurological and psychiatric diseases. Methodological refinements, including optimization of MS conditions and addition of deuterated standards, resulted in assay linearity to the low nanomolar range. Measured in samples obtained by striatal microdialysis in vivo, basal levels of tryptophan, kynurenine and QUIN were 415, 89 and 8 nM, respectively, but 3-HK levels were below the limit of detection (<2 nM). Systemic injection of kynurenine (100 mg/kg, i.p.) did not affect extracellular tryptophan but produced detectable levels of extracellular 3-HK (peak after 2-3 h: ~50 nM) and raised extracellular QUIN levels (peak after 2 h: ~105 nM). The effect of this treatment on QUIN, but not on 3-HK, was potentiated in the NMDA-lesioned striatum. Our results indicate that the novel methodology, which allowed the measurement of extracellular kynurenine and 3-HK in the brain in vivo, will facilitate studies of brain kynurenines and of the interplay between peripheral and central kynurenine pathway function under physiological and pathological conditions.

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Section: Discussionsupporting

confidence: 76%

Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain

Notarangelo

Macherone

et al. 2012

Analytical Biochemistry

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“…The concentrations measured in the human epileptic brain (∼10 μM) were in the range of neurotoxic and seizure promoting levels (During et al, 1989). Since QA levels in the brain are topographically overlapping with abnormal epileptiform activity, we propose a scenario where multiple drug resistance not only impedes CBZ access to the brain, but also leads to exacerbation of seizures by a powerful metabolic process.…”

Section: Discussionmentioning

confidence: 99%

A pro-convulsive carbamazepine metabolite: Quinolinic acid in drug resistant epileptic human brain

Ghosh¹,

Marchi²,

Hossain³

et al. 2012

Neurobiology of Disease

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Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood–brain barrier (BBB). Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood–brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography–mass spectroscopy. Accelerated mass spectroscopy was used to identify 14C metabolites deriving from the parent 14C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from 14C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. 14C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites.

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“…One Kyn metabolite, quinolinic acid (QA), is a selective NMDA receptor agonist (reviewed in Freese et al (1990)), and a monoamine oxidase-B (MAO-B) inhibitor (Naoi et al 1987). A peripherally-administered dose of Trp which less than doubled extracellular brain 5-HT in rats increased the brain QA concentration 80-fold (During et al 1989), and QA has been shown to have stimulant (Lapin 1978) and anxiogenic (Lapin 1996) properties in animals. These data collectively suggest a potential for a large Trp bolus to alter behavior by: 1) heightened NMDA receptor activation, and 2) increased norepinephrine neurotransmission by inhibiting catecholamine elimination by MAO-B.…”

Section: Discussionmentioning

confidence: 99%

Differential Behavioral Effects of Plasma Tryptophan Depletion and Loading in Aggressive and Nonaggressive Men

Bjork¹,

Dougherty²,

Moeller³

et al. 2000

Neuropsychopharmacology

123

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Preliminary findings indicate that men with high trait hostility may be prone to aggression increases following plasma tryptophan (Trp) depletion. We measured laboratory aggression in men selected for presence (n ϭ12Substantial research has implicated decreased serotonin (5-HT) neurotransmission in human aggressive behavior (Brown et al. 1979;Coccaro et al. 1997a;Linnoila et al. 1983;Virkkunen et al. 1994). In recent neuroendocrine challenge studies, aggression has correlated negatively with plasma prolactin (PRL) elevations following the administration of the 5-HT agonist fenfluramine (Coccaro et al. 1996;Manuck et al. 1998). In another recent report, PRL responses to both fenfluramine and m -CPP were blunted in personality-disordered individuals with high self-reported hostility (Coccaro et al. 1997a). Finally, other physiological responses to serotonergic agonists fenfluramine (Coccaro et al. 1996) and ipsapirone (Moeller et al. 1998) were inversely correlated with rates of laboratory aggression.While these correlational data are compelling, the strongest support for the hypothesis that dysfunctional 5-HT neurotransmission facilitates aggression is prospectively-measured behavior change after the impairment or enhancement of the 5-HT system. This research in humans can be difficult in that serotonin-specific drugs can take days to weeks to exert any mood and/or behavior effects, and these effects may be too subtle for detection by many laboratory measures. Nevertheless, some data have shown a tendency for serotonergic drugs to decrease aggression in humans. For example, From NO . 4 fluoxetine (Coccaro et al. 1997c) and sertraline (Kavoussi et al. 1994) attenuated clinician-rated impulsive aggression in psychiatric patients. Heiligenstein et al. (1993) meta-analyzed data from thousands of patients in several clinical trials of fluoxetine and found that aggressive acts were reported in only 0.15% of fluoxetinetreated patients, but 0.65% of placebo-treated patients. When aggression was measured prospectively, fluoxetine was effective in decreasing aggression in a psychiatric outpatients selected for prominent impulsive aggression (Coccaro and Kavoussi 1997).The administration of a beverage of large neutral amino acids (LNAAs) which lacks 5-HT precursor L-tryptophan (Trp) can rapidly alter brain 5-HT (Young et al. 1985). This technique, called "tryptophan depletion," reduces brain Trp uptake in two ways: 1) LNAAs competitively inhibit active transport of Trp across the blood-brain barrier (Yuwiler et al. 1977), and 2) endogenous plasma Trp is incorporated into proteins in the hepatic response to the LNAA load (Gessa et al. 1975). Animal research has shown that Trp depletion dosedependently reduces brain levels of Trp, 5-HT, and the 5-HT metabolite 5-HIAA within a few hours (Biggio et al. 1974;Moja et al. 1989).In humans, Trp depletion has decreased synthesis rates of a 5-HT analogue in the brain in a PET scanning experiment (Nishizawa et al. 1997), and has reduced cerebrospinal fluid concentrations of 5-HIA...

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Neuroactive metabolises of L‐tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid effect of tryptophan loading

Cited by 41 publications

References 53 publications

Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain

Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain

A pro-convulsive carbamazepine metabolite: Quinolinic acid in drug resistant epileptic human brain

Differential Behavioral Effects of Plasma Tryptophan Depletion and Loading in Aggressive and Nonaggressive Men

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