The Trace Kynurenine, Cinnabarinic Acid, Displays Potent Antipsychotic-Like Activity in Mice and Its Levels Are Reduced in the Prefrontal Cortex of Individuals Affected by Schizophrenia

Abstract Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA leve...

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Published inSchizophrenia bulletin Vol. 46; no. 6; pp. 1471 - 1481
Main Authors Ulivieri, Martina, Wierońska, Joanna Monika, Lionetto, Luana, Martinello, Katiuscia, Cieslik, Paulina, Chocyk, Agnieszka, Curto, Martina, Di Menna, Luisa, Iacovelli, Luisa, Traficante, Anna, Liberatore, Francesca, Mascio, Giada, Antenucci, Nico, Giannino, Giuseppe, Vergassola, Matteo, Pittaluga, Anna, Bruno, Valeria, Battaglia, Giuseppe, Fucile, Sergio, Simmaco, Maurizio, Nicoletti, Ferdinando, Pilc, Andrzej, Fazio, Francesco
Format Journal Article
LanguageEnglish
Published US Oxford University Press 01.12.2020
Subjects
Regular
MK-801
kynurenine pathway
mood disorder
human tissue
electrophysiology
metabotropic glutamate receptor
mass
HPLC-mass
behavior
endogenous metabolite
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Abstract Abstract Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (<1 mg/kg, i.p.) showed robust efficacy in several behavioral tests useful to study antipsychotic-like activity in mice and rats and attenuated MK-801-evoked glutamate release. CA failed to display antipsychotic-like activity and inhibit excitatory synaptic transmission in mice lacking mGlu4 receptors. These findings suggest that CA is a potent endogenous antipsychotic-like molecule and reduced CA levels in the PFC might contribute to the pathophysiology of schizophrenia.
AbstractList Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (<1 mg/kg, i.p.) showed robust efficacy in several behavioral tests useful to study antipsychotic-like activity in mice and rats and attenuated MK-801-evoked glutamate release. CA failed to display antipsychotic-like activity and inhibit excitatory synaptic transmission in mice lacking mGlu4 receptors. These findings suggest that CA is a potent endogenous antipsychotic-like molecule and reduced CA levels in the PFC might contribute to the pathophysiology of schizophrenia.
Abstract Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (<1 mg/kg, i.p.) showed robust efficacy in several behavioral tests useful to study antipsychotic-like activity in mice and rats and attenuated MK-801-evoked glutamate release. CA failed to display antipsychotic-like activity and inhibit excitatory synaptic transmission in mice lacking mGlu4 receptors. These findings suggest that CA is a potent endogenous antipsychotic-like molecule and reduced CA levels in the PFC might contribute to the pathophysiology of schizophrenia.
Author Martinello, Katiuscia
Chocyk, Agnieszka
Traficante, Anna
Pittaluga, Anna
Fazio, Francesco
Lionetto, Luana
Mascio, Giada
Di Menna, Luisa
Liberatore, Francesca
Fucile, Sergio
Giannino, Giuseppe
Vergassola, Matteo
Bruno, Valeria
Iacovelli, Luisa
Simmaco, Maurizio
Cieslik, Paulina
Curto, Martina
Battaglia, Giuseppe
Nicoletti, Ferdinando
Pilc, Andrzej
Ulivieri, Martina
Wierońska, Joanna Monika
Antenucci, Nico
AuthorAffiliation 1 I.R.C.C.S. Neuromed , Pozzilli, Italy
8 School of Medicine and Psychology NESMOS Department, Sant’Andrea Hospital, Sapienza University , Rome, Italy
3 Department of Medical-Surgical Sciences and Translational Medicine, DiMA (Advanced Molecular Diagnosis), Sant’Andrea Hospital—Sapienza University , Rome, Italy
5 Department of Clinical and Molecular Medicine, Sapienza University , Rome, Italy
9 Department of Pharmacy, DiFAR, University of Genoa , Genoa, Italy
4 Department of Neurology and Psychiatry, Sapienza University , Rome, Italy
6 Bipolar & Psychotic Disorders Program, McLean Hospital , Belmont, MA
2 Institute of Pharmacology, Polish Academy of Sciences , Kraków, Poland
7 Department of Physiology and Pharmacology, Sapienza University , Rome, Italy
10 I.R.C.C.S. San Martino Hospital , Genoa, Italy
AuthorAffiliation_xml – name: 6 Bipolar & Psychotic Disorders Program, McLean Hospital , Belmont, MA
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– name: 8 School of Medicine and Psychology NESMOS Department, Sant’Andrea Hospital, Sapienza University , Rome, Italy
– name: 5 Department of Clinical and Molecular Medicine, Sapienza University , Rome, Italy
– name: 3 Department of Medical-Surgical Sciences and Translational Medicine, DiMA (Advanced Molecular Diagnosis), Sant’Andrea Hospital—Sapienza University , Rome, Italy
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Issue 6
Keywords MK-801
kynurenine pathway
mood disorder
human tissue
electrophysiology
metabotropic glutamate receptor
mass
HPLC-mass
behavior
endogenous metabolite
Language English
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Snippet Abstract Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance...
Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid...
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Title The Trace Kynurenine, Cinnabarinic Acid, Displays Potent Antipsychotic-Like Activity in Mice and Its Levels Are Reduced in the Prefrontal Cortex of Individuals Affected by Schizophrenia
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