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Contribution of hypothermia and CB1 receptor activation to protective effects of TAK-937, a cannabinoid receptor agonist, in rat transient MCAO model.
PLoS One. 2012; 7(7):e40889.Plos

Abstract

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.

Authors+Show Affiliations

Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22815855

Citation

Suzuki, Noriko, et al. "Contribution of Hypothermia and CB1 Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model." PloS One, vol. 7, no. 7, 2012, pp. e40889.
Suzuki N, Suzuki M, Hamajo K, et al. Contribution of hypothermia and CB1 receptor activation to protective effects of TAK-937, a cannabinoid receptor agonist, in rat transient MCAO model. PLoS One. 2012;7(7):e40889.
Suzuki, N., Suzuki, M., Hamajo, K., Murakami, K., Tsukamoto, T., & Shimojo, M. (2012). Contribution of hypothermia and CB1 receptor activation to protective effects of TAK-937, a cannabinoid receptor agonist, in rat transient MCAO model. PloS One, 7(7), e40889. https://doi.org/10.1371/journal.pone.0040889
Suzuki N, et al. Contribution of Hypothermia and CB1 Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model. PLoS One. 2012;7(7):e40889. PubMed PMID: 22815855.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contribution of hypothermia and CB1 receptor activation to protective effects of TAK-937, a cannabinoid receptor agonist, in rat transient MCAO model. AU - Suzuki,Noriko, AU - Suzuki,Motohisa, AU - Hamajo,Kazuhiro, AU - Murakami,Koji, AU - Tsukamoto,Tetsuya, AU - Shimojo,Masato, Y1 - 2012/07/16/ PY - 2012/03/04/received PY - 2012/06/14/accepted PY - 2012/7/21/entrez PY - 2012/7/21/pubmed PY - 2013/3/22/medline SP - e40889 EP - e40889 JF - PloS one JO - PLoS One VL - 7 IS - 7 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22815855/Contribution_of_hypothermia_and_CB1_receptor_activation_to_protective_effects_of_TAK_937_a_cannabinoid_receptor_agonist_in_rat_transient_MCAO_model_ L2 - https://dx.plos.org/10.1371/journal.pone.0040889 DB - PRIME DP - Unbound Medicine ER -