title: Cerebroprotective effects of TAK-937, a novel cannabinoid receptor agonist, in permanent and thrombotic focal cerebral ischemia in rats: therapeutic time window, combination with t-PA and efficacy in aged rats.
abstract: Some occluded arteries of acute ischemic stroke (AIS) patients are not recanalized, even if thrombolytic therapy is performed. Considering such clinical settings, we examined the potential cerebroprotective efficacy of TAK-937, a novel cannabinoid receptor agonist, in young adult and aged rats with a permanent middle cerebral artery occlusion (MCAO) model and conducted a combination study with TAK-937 and tissue type plasminogen activator (t-PA) in a rat thrombotic MCAO model. TAK-937 significantly reduced infarct volume when it was administered 3 and 5h after permanent MCAO in young adult rats. A thrombotic MCAO was induced by photo-irradiation of the middle cerebral artery with Rose Bengal administration and a permanent MCAO was produced by thermoelectric coagulation of occluded arteries. TAK-937 (10, 30 and 100μg/kg/h) was intravenously infused 1, 3, 5, or 8-24h after MCAO. t-PA (3 or 10mg/kg) was intravenously administered 1, 1.5 or 2h after MCAO. Infarct volume was determined using a 2,3,5-triphenyltetrazolium chloride staining method 24 or 48h after MCAO. The combined treatment of TAK-937 with t-PA significantly reduced the cerebral infarction compared with t-PA treatment alone in a rat thrombotic MCAO model. TAK-937 reduced infarct volume of aged rats as well, when it was administered 1h after permanent MCAO. These results suggest that TAK-937 exerts protective effects regardless of age and has a wide therapeutic time window in permanent occlusion. Furthermore, combined treatment of TAK-937 with t-PA would provide more therapeutic efficacy compared to t-PA treatment alone.
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
authors.forename: Motohisa
authors.initials: M
authors.lastname: Suzuki
authors.forename: Noriko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hamajo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Masato
authors.initials: M
authors.lastname: Shimojo
mesh_terms: D000577:Amides / Q000008:administration & dosage*; D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage*; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
chemical_list: D000577:Amides; D001572:Benzofurans; D063386:Cannabinoid Receptor Agonists; D005343:Fibrinolytic Agents; C574751:N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide; D018696:Neuroprotective Agents; D010959:Tissue Plasminogen Activator
keywords: (2-Hydroxypropyl)-β-cyclodextrin; 2,3,5-triphenyltetrazolium chloride; AIS; Age; BDNF; BT; CB; CNS; Cannabinoid receptor agonist; Combination therapy; HPBCD; HR; MABP; MCA; MCAO; Middle cerebral artery occlusion; PaCO(2); PaO(2); SD; Sprague–Dawley; TTC; Tissue-type plasminogen activator; acute ischemic stroke; body temperature; brain derived neurotrophic factor; cannabinoid; central nerve system; heart rate; mean arterial blood pressure; middle cerebral artery; middle cerebral artery occlusion; oxygen saturation; partial arterial carbon dioxide; partial arterial oxygen; sO(2); t-PA; tissue-type plasminogen activator