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Preclinical characterization of AMPA receptor potentiator TAK‐137 as a therapeutic drug for schizophrenia

The downregulation of the glutamate system may be involved in positive, negative, and cognitive symptoms of schizophrenia. Through enhanced glutamate signaling, the activation of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor, an ionotropic glutamate receptor, could be a n...

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Autores principales: Tanaka, Maiko, Kunugi, Akiyoshi, Suzuki, Atsushi, Suzuki, Noriko, Suzuki, Motohisa, Kimura, Haruhide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507438/
https://www.ncbi.nlm.nih.gov/pubmed/31086673
http://dx.doi.org/10.1002/prp2.479
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author Tanaka, Maiko
Kunugi, Akiyoshi
Suzuki, Atsushi
Suzuki, Noriko
Suzuki, Motohisa
Kimura, Haruhide
author_facet Tanaka, Maiko
Kunugi, Akiyoshi
Suzuki, Atsushi
Suzuki, Noriko
Suzuki, Motohisa
Kimura, Haruhide
author_sort Tanaka, Maiko
collection PubMed
description The downregulation of the glutamate system may be involved in positive, negative, and cognitive symptoms of schizophrenia. Through enhanced glutamate signaling, the activation of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor, an ionotropic glutamate receptor, could be a new therapeutic strategy for schizophrenia. TAK‐137 is a novel AMPA receptor potentiator with minimal agonistic activity; in this study, we used rodents and nonhuman primates to assess its potential as a drug for schizophrenia. At 10 mg kg(−1) p.o., TAK‐137 partially inhibited methamphetamine‐induced hyperlocomotion in rats, and at 3, 10, and 30 mg kg(−1) p.o., TAK‐137 partially inhibited MK‐801‐induced hyperlocomotion in mice, suggesting weak effects on the positive symptoms of schizophrenia. At 0.1 and 0.3 mg kg(−1) p.o., TAK‐137 significantly ameliorated MK‐801‐induced deficits in the social interaction of rats, demonstrating potential improvement of impaired social functioning, which is a negative symptom of schizophrenia. The effects of TAK‐137 were evaluated on multiple cognitive domains—attention, working memory, and cognitive flexibility. TAK‐137 enhanced attention in the five‐choice serial reaction time task in rats at 0.2 mg kg(−1) p.o., and improved working memory both in rats and monkeys: 0.2 and 0.6 mg kg(−1) p.o. ameliorated MK‐801‐induced deficits in the radial arm maze test in rats, and 0.1 mg kg(−1) p.o. improved the performance of ketamine‐treated monkeys in the delayed matching‐to‐sample task. At 0.1 and 1 mg kg(−1) p.o., TAK‐137 improved the cognitive flexibility of subchronic phencyclidine‐treated rats in the reversal learning test. Thus, TAK‐137‐type AMPA receptor potentiators with low intrinsic activity may offer new therapies for schizophrenia.
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spelling pubmed-65074382019-05-13 Preclinical characterization of AMPA receptor potentiator TAK‐137 as a therapeutic drug for schizophrenia Tanaka, Maiko Kunugi, Akiyoshi Suzuki, Atsushi Suzuki, Noriko Suzuki, Motohisa Kimura, Haruhide Pharmacol Res Perspect Original Articles The downregulation of the glutamate system may be involved in positive, negative, and cognitive symptoms of schizophrenia. Through enhanced glutamate signaling, the activation of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor, an ionotropic glutamate receptor, could be a new therapeutic strategy for schizophrenia. TAK‐137 is a novel AMPA receptor potentiator with minimal agonistic activity; in this study, we used rodents and nonhuman primates to assess its potential as a drug for schizophrenia. At 10 mg kg(−1) p.o., TAK‐137 partially inhibited methamphetamine‐induced hyperlocomotion in rats, and at 3, 10, and 30 mg kg(−1) p.o., TAK‐137 partially inhibited MK‐801‐induced hyperlocomotion in mice, suggesting weak effects on the positive symptoms of schizophrenia. At 0.1 and 0.3 mg kg(−1) p.o., TAK‐137 significantly ameliorated MK‐801‐induced deficits in the social interaction of rats, demonstrating potential improvement of impaired social functioning, which is a negative symptom of schizophrenia. The effects of TAK‐137 were evaluated on multiple cognitive domains—attention, working memory, and cognitive flexibility. TAK‐137 enhanced attention in the five‐choice serial reaction time task in rats at 0.2 mg kg(−1) p.o., and improved working memory both in rats and monkeys: 0.2 and 0.6 mg kg(−1) p.o. ameliorated MK‐801‐induced deficits in the radial arm maze test in rats, and 0.1 mg kg(−1) p.o. improved the performance of ketamine‐treated monkeys in the delayed matching‐to‐sample task. At 0.1 and 1 mg kg(−1) p.o., TAK‐137 improved the cognitive flexibility of subchronic phencyclidine‐treated rats in the reversal learning test. Thus, TAK‐137‐type AMPA receptor potentiators with low intrinsic activity may offer new therapies for schizophrenia. John Wiley and Sons Inc. 2019-05-09 /pmc/articles/PMC6507438/ /pubmed/31086673 http://dx.doi.org/10.1002/prp2.479 Text en © 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Tanaka, Maiko
Kunugi, Akiyoshi
Suzuki, Atsushi
Suzuki, Noriko
Suzuki, Motohisa
Kimura, Haruhide
Preclinical characterization of AMPA receptor potentiator TAK‐137 as a therapeutic drug for schizophrenia
title Preclinical characterization of AMPA receptor potentiator TAK‐137 as a therapeutic drug for schizophrenia
title_full Preclinical characterization of AMPA receptor potentiator TAK‐137 as a therapeutic drug for schizophrenia
title_fullStr Preclinical characterization of AMPA receptor potentiator TAK‐137 as a therapeutic drug for schizophrenia
title_full_unstemmed Preclinical characterization of AMPA receptor potentiator TAK‐137 as a therapeutic drug for schizophrenia
title_short Preclinical characterization of AMPA receptor potentiator TAK‐137 as a therapeutic drug for schizophrenia
title_sort preclinical characterization of ampa receptor potentiator tak‐137 as a therapeutic drug for schizophrenia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507438/
https://www.ncbi.nlm.nih.gov/pubmed/31086673
http://dx.doi.org/10.1002/prp2.479
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