title: Cerebroprotective effects of TAK-937, a cannabinoid receptor agonist, on ischemic brain damage in middle cerebral artery occluded rats and non-human primates.
abstract: The pathophysiology of brain damage after ischemic stroke involves a number of mechanisms leading to neuronal damage such as the excessive release of an excitatory amino acid glutamate and inflammatory reactions. Cannabinoid (CB) receptor agonists are expected to alleviate ischemic brain damage by modulating neurotransmission and neuroinflammatory responses via CB(1) and CB(2), respectively. TAK-937 is a selective and highly potent CB(1)/CB(2) receptor agonist. In this study, the effect of TAK-937 on ischemic brain damage was examined in rat and monkey ischemic stroke models. Sprague-Dawley rats were subjected to 2h transient middle cerebral artery occlusion (t-MCAo) by inserting an intraluminal suture. TAK-937 was administered intravenously for 24h starting 2h after MCAo. Infarct volume was determined 24h after MCAo. Functional outcomes and brain atrophy were also evaluated 4weeks after MCAo. Next, cynomolgus monkeys were subjected to thromboembolic MCAo. TAK-937 was administered intravenously for 24h starting 0.5h after MCAo. Then, infarct volume and cerebrospinal fluid (CSF) S-100ß levels were determined. In the rat t-MCAo model, TAK-937 significantly reduced the infarct volume in male, female and ovariectomized rats and also improved functional outcomes and brain atrophy. In the monkey thromboembolic MCAo model, TAK-937 showed trend to reduce the infarct volume and S-100ß levels in CSF by 40%. S-100ß levels in CSF were positively correlated with infarct volume. These results suggest that TAK-937 may be useful for treatment of acute ischemic stroke. Moreover, S-100ß levels would be a useful surrogate biomarker for development of TAK-937.
authors: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Kanagawa 251-8555, Japan.
authors: Noriko
authors: N
authors: Suzuki
authors: Motohisa
authors: M
authors: Suzuki
authors: Koji
authors: K
authors: Murakami
authors: Kazuhiro
authors: K
authors: Hamajo
authors: Tetsuya
authors: T
authors: Tsukamoto
authors: Masato
authors: M
authors: Shimojo
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*
chemical_list: D000577:Amides; D001572:Benzofurans; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; C543264:Cnr1 protein, rat; C469526:Cnr2 protein, rat; C574751:N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2