1-Methyl-4-phenylpyridinium and 3-nitropropionic acid diminish cortical synthesis of kynurenic acid via interference with kynurenine aminotransferases in rats

Luchowski, Piotr; Luchowska, Elzbieta; Turski, Waldemar A.; Urbańska, Ewa M.

doi:10.1016/s0304-3940(02)00735-8

Cited by 56 publications

(42 citation statements)

References 20 publications

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“…One of the two studies of the effects of the chronic treatment of rats with 3-NP demonstrated a significant decrease in the amount of KAT-I-immunoreactive cells, predominantly in the striatum (Csillik et al, 2002). The other study on ex vivo rat cortical slices, showed that 3-NP dose-dependently inhibited the production of KYNA and led to decreased KAT-I and KAT-II activities in the cortical tissue homogenates (Luchowski et al, 2002). No murine studies have been conducted previously to assess the effects of in vivo applied 3-NP on the KP metabolism at the metabolite level per se, and there have been no studies of KP alterations due to 3-NP intoxication in the serum, which would allow conclusions as to the possible effects Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although it seems clear that higher cumulative doses of 3-NP cause motor and cognitive impairments, the motor dysfunctions observed undergo a considerable amelioration after the cessation of toxin administration (El Massioui et al, 2001;Fernagut et al, 2002b;Li et al, 2009). Early studies raised the possibility that the KP is altered in 3-NP models (Csillik et al, 2002;Luchowski et al, 2002), but this has not yet been further investigated.…”

Section: Introductionmentioning

confidence: 99%

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Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease

Veres

Molnár

Zádori

et al. 2015

Pharmacology Biochemistry and Behavior

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Experiments on human samples and on genetic animal models of Huntington's disease (HD) suggest that a number of neuroactive metabolites in the kynurenine (KYN) pathway (KP) of the tryptophan (TRP) catabolism may play a role in the development of HD. Our goal in this study was to assess the concentrations of TRP, KYN, kynurenic acid and 3-hydroxykynurenine (3-OHK) in the serum and brain of 5-month-old C57Bl/6 mice in the widely used 3-nitropropionic acid (3-NP) toxin model of HD. We additionally investigated the behavioral changes through open-field, rotarod and Y-maze tests. Our findings revealed an increased TRP catabolism via the KP as reflected by elevated KYN/TRP ratios in the striatum, hippocampus, cerebellum and brainstem. As regards the other examined metabolites of KP, we found only a significant decrease in the 3-OHK level in the cerebellum of the 3-NP-treated mice. The open-field and rotarod tests demonstrated that treatment with 3-NP resulted in a reduced motor ability, though this had almost totally disappeared a week after the last injection, similarly as observed previously in most murine 3-NP studies. The relevance of the alterations observed in our biochemical and behavioral analyses is discussed. We propose that the identified biochemical alterations could serve as applicable therapeutic endpoints in studies of drug effects on delayed-type neurodegeneration in a relatively fast and cost-effective toxin model of HD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease

Veres

Molnár

Zádori

et al. 2015

Pharmacology Biochemistry and Behavior

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“…complex I and complex II respectively, reducing the level of available ATP and ultimately leading to a cellular energy deficit. Both toxins have been shown to inhibit KYNA synthesis via interference with KAT-I and KAT-II [149]. FK506 is a neuroimmunophilin ligand that belongs in a relatively new class of drugs, nowadays used in the clinical setting as immunosuppressants.…”

Section: Parkinson's Disease and The Kynureninesmentioning

confidence: 99%

Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders

Sas

Robotka

Toldi

et al. 2007

Journal of the Neurological Sciences

416

294

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“…A number of endogenous and exogenous factors influencing the central production of KYNA have been recognized. For example, mitochondrial toxins compromising the status of mitochondrial respiration, endogenous sulfur-containing amino acids and inhibitors of protein kinase A activity reduce formation of KYNA, whereas rise of intracellular cAMP level stimulates KYNA production (Urbanska et al 1997;Luchowski et al 2002;Kocki et al 2003;Luchowska et al 2005Luchowska et al , 2009Kloc et al 2008). It was also shown that hyperglycemia enhances the inhibitory effect of mitochondrial toxins and D,L-homocysteine on the central production of KYNA (Chmiel-Perzyńska et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Novel Aspect of Ketone Action: β-Hydroxybutyrate Increases Brain Synthesis of Kynurenic Acid In Vitro

et al. 2010

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Ketone bodies formed during ketogenic diet or non-treated diabetes mellitus may exert neuroprotective and antiepileptic effects. Here, we assessed the influence of ketone body, β-hydroxybutyrate (BHB) on the brain synthesis of kynurenic acid (KYNA), an endogenous antagonist of glutamatergic and α7-nicotinic receptors. In brain cortical slices and in primary glial cultures, BHB enhanced KYNA production. KT 5270, an inhibitor of protein kinase A, has prevented this action. At hypoglycemia, under pH 7.0 and 7.4, profound (15 mM BHB), but not mild (3 mM) ketosis increased synthesis of KYNA. In paradigm resembling diabetic ketoacidosis in vitro (30 mM glucose, pH 7.0), neither mild nor profound ketosis influenced the production of KYNA. At pH 7.4 and in 30 mM glucose though, both mild and severe ketonemia evoked an increase of KYNA production. The activity of KYNA biosynthetic enzymes, KAT I and KAT II, in cortical homogenate was not altered by BHB (0.05-10.0 mM). However, in cultured glial cells exposed to BHB (10 mM), the activity of KATs increased. This effect was reversed by the co-incubation of cells with KT 5270. Presented data reveal a novel mechanism of action of BHB. Increased synthesis of KYNA in the presence of BHB is most probably mediated by protein kinase A-dependent stimulation of KATs expression/activity leading to an increase of KYNA formation. Ensuing attenuation of the excessive excitatory glutamate-mediated neurotransmission may, at least in part, explain the neuroprotective actions of BHB.

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1-Methyl-4-phenylpyridinium and 3-nitropropionic acid diminish cortical synthesis of kynurenic acid via interference with kynurenine aminotransferases in rats

Cited by 56 publications

References 20 publications

Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease

Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease

Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders

Novel Aspect of Ketone Action: β-Hydroxybutyrate Increases Brain Synthesis of Kynurenic Acid In Vitro

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