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.

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.