Research ReportCerebroprotective effects of TAK-937, a cannabinoid receptor agonist, on ischemic brain damage in middle cerebral artery occluded rats and non-human primates

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 CB1 and CB2, respectively. TAK-937 is a selective and highly potent CB1/CB2 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 2 h transient middle cerebral artery occlusion (t-MCAo) by inserting an intraluminal suture. TAK-937 was administered intravenously for 24 h starting 2 h after MCAo. Infarct volume was determined 24 h after MCAo. Functional outcomes and brain atrophy were also evaluated 4 weeks after MCAo. Next, cynomolgus monkeys were subjected to thromboembolic MCAo. TAK-937 was administered intravenously for 24 h starting 0.5 h 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.

► TAK-937 is a selective and highly potent cannabinoid receptor agonist. ► The effect of TAK-937 was examined in rat and monkey ischemic stroke models. ► TAK-937 showed cerebroprotective effects in both models. ► TAK-937 would serve as a novel therapy for acute ischemic stroke.