(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats

Speciale, C.; Wu, Hui; Cini, M.; Marconi, Marina; Varasi, Mario; Schwarcz, Robert

doi:10.1016/s0014-2999(96)00613-9

Cited by 90 publications

(50 citation statements)

References 19 publications

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“…It is well known that pharmacological blockade of the enzyme converting KYN to 3-hydroxykynurenine, kynurenine 3-monooxygenase (KMO), results in elevated brain KYNA levels. 19,34,[53][54][55] In addition, we recently reported that a nonsynonymous polymorphism in the KMO gene results in higher CSF KYNA levels in both healthy volunteers and patients with schizophrenia. 56 Also, a postmortem study shows decreased KMO gene expression as well as decreased KMO enzyme activity in individuals with schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia

Linderholm

Skogh

Olsson

et al. 2010

Schizophrenia Bulletin

258

208

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Background:The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP) produced in astrocytes and antagonizes N-methyl-D-aspartate and a7* nicotinic receptors. Methods: The formation of KYNA is determined by the availability of substrate, and hence, we analyzed KYNA and its precursors, kynurenine (KYN) and TRP, in the cerebrospinal fluid (CSF) of patients with schizophrenia. CSF from male patients with schizophrenia on olanzapine treatment (n 5 16) was compared with healthy male volunteers (n 5 29). Results: KYN and KYNA concentrations were higher in patients with schizophrenia (60.7 ± 4.37nM and 2.03 ± 0.23nM, respectively) compared with healthy volunteers (28.6 ± 1.44nM and 1.36 ± 0.08nM, respectively), whereas TRP did not differ between the groups. In all subjects, KYN positively correlated to KYNA. Conclusion: Our results demonstrate increased levels of CSF KYN and KYNA in patients with schizophrenia and further support the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia

Linderholm

Skogh

Olsson

et al. 2010

Schizophrenia Bulletin

258

208

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“…The metabolism of kynurenine would thus be shunted toward KYNA, similar to the outcome of administering pharmacologic compounds that block KMO. 36 The availability of kynurenine is suggested to be the determinant of KYNA synthesis. 22 One might speculate that the SNP rs1053230 is affecting the function of the KMO enzyme, as it is associated with CSF concentrations of KYNA.…”

Section: Discussionmentioning

confidence: 99%

Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

Holtze

Saetre²,

Engberg³

et al. 2012

jpn

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IntroductionIn recent years, the general view of the pathophysiology of schizophrenia (i.e., disturbances in dopamine [DA] transmission) has been expanded to also involve a glutamatergic dysfunction of the brain. Thus, clinical observations show that systemic administration of N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., phencyclidine [PCP] and ketamine) evokes schizophrenia-like symptoms in healthy individuals and provokes symptoms in patients with schizophrenia. [1][2][3] Furthermore, the glutamate deficiency theory has gained some support from genetic findings. 4 A hypoglutamatergic state of the brain can also be achieved by elevation of the endogenous NMDA receptor antagonist kynurenic acid (KYNA).5 Indeed, increased concentrations of KYNA have been found in the cerebrospinal fluid (CSF) and in the postmortem brains of patients with schizophrenia.6-8 Kynurenic acid is a metabolite of tryptophan ( Fig. 1) and acts as an antagonist at the glycine coagonist site and the glutamate recognition site of the NMDA receptor.9-12 Additionally, KYNA blocks the α7* nicotinic receptor at low concentrations.13 Elevated levels of KYNA in the rat brain are associated with . This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine. Methods: We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED. Results: We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA. Limitations: Given the limited sample size, the results are tentative until replication. Conclusion: Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA.

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“…These findings are in excellent agreement with previous in vivo electrophysiological studies (Gessa et al, 2000;Tung et al, 1991;White and Wang, 1983) and it is generally accepted that antipsychotic drugs increase DA cell firing rate by blockade of somatodendritic DA autoreceptors Grace, 1994, 1996). However, in a situation of hyperdopaminergia induced by elevation of brain KYNA Engberg, 2000, 2002;Erhardt et al, , 2001aErhardt et al, , b, 2002aSpeciale et al, 1996), the excitatory effects of clozapine observed in control rats were converted into pure inhibitory responses by the drug. In contrast, the excitatory action of haloperidol on VTA DA neurons was even more pronounced in rats with elevated levels of endogenous brain KYNA, since administration of the drug in low doses was associated with a depolarization block of all DA neurons recorded.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

Schwieler

Erhardt

2003

Neuropsychopharmacol

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The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and a7* nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.

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(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats

Cited by 90 publications

References 19 publications

Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia

Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia

Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

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