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Contribution of Hypothermia and CB(1) Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model

BACKGROUND: Cannabinoid (CB) receptor agonists are expected to alleviate ischemic brain damage by modulating neurotransmission and neuroinflammatory responses via CB(1) and CB(2) receptors, respectively. In a previous study, TAK-937, a novel potent and selective CB(1) and CB(2) receptor agonist, was...

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Detalles Bibliográficos
Autores principales: Suzuki, Noriko, Suzuki, Motohisa, Hamajo, Kazuhiro, Murakami, Koji, Tsukamoto, Tetsuya, Shimojo, Masato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397930/
https://www.ncbi.nlm.nih.gov/pubmed/22815855
http://dx.doi.org/10.1371/journal.pone.0040889
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author Suzuki, Noriko
Suzuki, Motohisa
Hamajo, Kazuhiro
Murakami, Koji
Tsukamoto, Tetsuya
Shimojo, Masato
author_facet Suzuki, Noriko
Suzuki, Motohisa
Hamajo, Kazuhiro
Murakami, Koji
Tsukamoto, Tetsuya
Shimojo, Masato
author_sort Suzuki, Noriko
collection PubMed
description BACKGROUND: Cannabinoid (CB) receptor agonists are expected to alleviate ischemic brain damage by modulating neurotransmission and neuroinflammatory responses via CB(1) and CB(2) receptors, respectively. In a previous study, TAK-937, a novel potent and selective CB(1) and CB(2) receptor agonist, was shown to exert significant cerebroprotective effects accompanied by hypothermia after transient middle cerebral artery occlusion (MCAO) in rats. Sustained hypothermia itself induces significant neuroprotective effects. In the present studies, we examined the relative contribution of hypothermia and CB(1) receptor activation to the cerebroprotective effects of TAK-937. METHODOLOGY/PRINCIPAL FINDINGS: Using a multichannel brain temperature controlling system we developed, the brain temperature of freely moving rats was telemetrically monitored and maintained between 37 and 38°C during intravenous infusion of TAK-937 (100 µg/kg/h) or vehicle for 24 h after 2 h MCAO. AM251, a selective CB(1) receptor antagonist, was administered intraperitoneally at 30 mg/kg 30 min before starting intravenous infusion of TAK-937 (100 µg/kg/h) for 24 h. Rats were sacrificed and their brains were isolated 26 h after MCAO in both experiments. When the hypothermic effect of TAK-937 was completely reversed by a brain temperature controlling system, the infarct-reducing effect of TAK-937 was attenuated in part, but remained significant. On the other hand, concomitant AM251 treatment with TAK-937 completely abolished the hypothermic and infarct-reducing effects of TAK-937. CONCLUSIONS/SIGNIFICANCE: We conclude that the cerebroprotective effects of TAK-937 were at least in part mediated by induction of hypothermia, and mainly mediated by CB(1) receptor activation.
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spelling pubmed-33979302012-07-19 Contribution of Hypothermia and CB(1) Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model Suzuki, Noriko Suzuki, Motohisa Hamajo, Kazuhiro Murakami, Koji Tsukamoto, Tetsuya Shimojo, Masato PLoS One Research Article BACKGROUND: Cannabinoid (CB) receptor agonists are expected to alleviate ischemic brain damage by modulating neurotransmission and neuroinflammatory responses via CB(1) and CB(2) receptors, respectively. In a previous study, TAK-937, a novel potent and selective CB(1) and CB(2) receptor agonist, was shown to exert significant cerebroprotective effects accompanied by hypothermia after transient middle cerebral artery occlusion (MCAO) in rats. Sustained hypothermia itself induces significant neuroprotective effects. In the present studies, we examined the relative contribution of hypothermia and CB(1) receptor activation to the cerebroprotective effects of TAK-937. METHODOLOGY/PRINCIPAL FINDINGS: Using a multichannel brain temperature controlling system we developed, the brain temperature of freely moving rats was telemetrically monitored and maintained between 37 and 38°C during intravenous infusion of TAK-937 (100 µg/kg/h) or vehicle for 24 h after 2 h MCAO. AM251, a selective CB(1) receptor antagonist, was administered intraperitoneally at 30 mg/kg 30 min before starting intravenous infusion of TAK-937 (100 µg/kg/h) for 24 h. Rats were sacrificed and their brains were isolated 26 h after MCAO in both experiments. When the hypothermic effect of TAK-937 was completely reversed by a brain temperature controlling system, the infarct-reducing effect of TAK-937 was attenuated in part, but remained significant. On the other hand, concomitant AM251 treatment with TAK-937 completely abolished the hypothermic and infarct-reducing effects of TAK-937. CONCLUSIONS/SIGNIFICANCE: We conclude that the cerebroprotective effects of TAK-937 were at least in part mediated by induction of hypothermia, and mainly mediated by CB(1) receptor activation. Public Library of Science 2012-07-16 /pmc/articles/PMC3397930/ /pubmed/22815855 http://dx.doi.org/10.1371/journal.pone.0040889 Text en Suzuki et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Suzuki, Noriko
Suzuki, Motohisa
Hamajo, Kazuhiro
Murakami, Koji
Tsukamoto, Tetsuya
Shimojo, Masato
Contribution of Hypothermia and CB(1) Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model
title Contribution of Hypothermia and CB(1) Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model
title_full Contribution of Hypothermia and CB(1) Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model
title_fullStr Contribution of Hypothermia and CB(1) Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model
title_full_unstemmed Contribution of Hypothermia and CB(1) Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model
title_short Contribution of Hypothermia and CB(1) Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model
title_sort contribution of hypothermia and cb(1) receptor activation to protective effects of tak-937, a cannabinoid receptor agonist, in rat transient mcao model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397930/
https://www.ncbi.nlm.nih.gov/pubmed/22815855
http://dx.doi.org/10.1371/journal.pone.0040889
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