Table 2.
Baseline characteristics of included studies
| Author | Year | Country | Drug | Mechanism of action | Animal | Stroke method | Therapy type | Timing of administrations | Outcome | Assessment time points | Significant improvements |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Yang et al. [14] | 2020 | China | ACEA | CB1 agonist | Sprague-Dawley rats | MCAO/r | Pre-treatment | 30 min before injury | Substantial reduction compared to control | Day 1 | Longa’s neurological deficit score |
| Bai et al. [15] | 2017 | China | ACEA | CB1 agonist | Sprague-Dawley rats | MCAO/r | Post-treatment | 1 h after MCAO | Significant decrease compared to control | Day 3 | Garcia JH 18-point neurological deficit score |
| Caltana et al. [16] | 2015 | Argentina | ACEA | CB1 agonist | C57Bl/6 mice | MCAO | Post-treatment | 3, 24, and 48 h after injury | Significant decrease compared to control | Day 28 | Neurological score |
| Sun et al. [17] | 2013 | China | WIN55,212-2 | CB1 agonist | Sprague-Dawley rats | MCAO | Post-treatment | 2 h after injury | Significant decrease compared to vehicle treated | Day 1 | Neurological score |
| Yokubaitis et al. [18] | 2021 | USA | BCP | CB2 agonist | C57Bl/6 mice | Photo thrombosis | Pre-/post-treatment | 1 h prior to injury and 24 h post-injury | Significant decrease compared to vehicle treated | Day 3 | Grip strength test |
| Yang et al. [19] | 2017 | China | BCP | CB2 agonist | C57BL/6 mice | MCAO/r | Pre-/post-treatment | 3 days before injury and 2 h post-injury | Significant decrease compared to control | Day 2 | Longa’s neurological deficit score |
| Pottier et al. [20] | 2017 | France | JWH-133 | CB2 agonist | Sprague-Dawley rats | MCAO/r | Post-treatment | Daily from 1 h after MCAO to day 7 | Significant improvement compared to non-treated samples | Day 7 | N/A |
| Ronca et al. [21] | 2015 | USA | O-1966 | CB2 agonist | C57B/6 mice | Photo thrombosis | Pre-/post-treatment | 1 h prior to injury and 2.5 days following or 1 h prior to injury and 2 days following | Significant decrease compared to control | Day 1, 3, and 7 | Novel object recognition task, food-motivated operant task |
| Yu et al. [22] | 2015 | USA | AM1241 | CB2 agonist | Sprague-Dawley rats | MCAO/r | Pre-/post-treatment | 5 min before injury or from day 2–5 following | Significant decrease compared to vehicle-treated (pre-treatment), non-significant improvement (post-treatment) | Day 2 and 6 | Bederson’s score |
| Choi et al. [23] | 2013 | South Korea | TC | CB2 agonist | Sprague-Dawley rats | MCAO/r | Post-treatment | 3 h after injury | Significant decrease compared to control | Day 1 | N/A |
| Zarruk et al. [24] | 2012 | Spain | JWH-133 | CB2 agonist | Swiss mice | MCAO | Post-treatment | 10 min or 3 h post-injury | Significant decrease compared to vehicle treated in both groups of treatment | Day 2 | mNSS |
| Shirazi et al. [25] | 2021 | New Zealand | Novel N-acylethanolamine derivatives | CB1/CB2 agonist | C57BL/6J mice | Photo thrombosis | Post-treatment | 1 h post-injury | Significant decrease compared to vehicle treated (NAE-18:4n-6, NAE-18:5n-3); non-significant improvement compared to vehicle treated (NAE-22:5n-6, NAE-22:6n-3, NAE-20:5n-3, NAE-20:4n-6) | Day 7 | NAE-18:4n-6, NAE-18:5n-3 |
| Murakami et al. [26] | 2013 | Japan | TAK-937 | CB1/CB2 agonist | Sprague-Dawley rats | Photo thrombosis | Post-treatment | Continuous administration from 3 h, 5 h, or 8 h–24 h | Significant decrease compared to vehicle treated (3–24 h and 5–24 h); no improvement (8–24 h) | Day 2 | N/A |
| Suzuki et al. [27] | 2012 | Japan | TAK-937 | CB1/CB2 agonist | Sprague-Dawley rats or cynomolgus monkeys | MCAO/r or Thromboembolic MCAO | Post-treatment | Continuous infusion for 22 h following perfusion (rats), continuous infusion for 23.5 h following clot injection (monkeys) | Significant decrease compared to vehicle-treated (rats), non-significant improvement compared to vehicle treated (monkeys) | Day 1 | Foot-fault test, Bederson’s score |
| Schmidt et al. [28] | 2012 | Germany | KN38-72717 | CB1/CB2 agonists | Sprague-Dawley rats | mMCAO | Pre-/post-treatment | 2 h before injury, during eMCAO, 30 min, 4 h, 3 days, 6 days after injury | Significant decrease compared to vehicle treated in multiple timepoints | Day 7 and 21 | Ladder-rung walking test |
| Reichenbach et al. [29] | 2016 | USA | SR141716A | CB1 antagonist | C57Bl/6 mice | Photo thrombosis | Pre-/post-treatment | 1 h before or after injury | Significant decrease compared to vehicle treated (pre-treatment); non-significant improvement (post-treatment) | Day 1 | Hata et al. five point neurological score |
| Jalin et al. [30] | 2015 | Spain | Hinokiresinols | CB1/CB2 antagonist | Sprague-Dawley rats | MCAO/r | Post-treatment | 2 h and 7 h after injury | Significant decrease compared to vehicle treated | Day 1 | N/A |
| Bravo-Ferrer et al. [31] | 2016 | Spain | JWH-133 or SR144528 | CB2 agonist or CB2R antagonist (respectively) | C57BL/6 mice | MCAO | Post-treatment | 2 days following injury till day 6 | No improvement compared to vehicle treated (both drugs) | Day 14 and 28 | NR |
| Zhang et al. [32] | 2012 | USA | O-1966, SR141716A, both, or SR144528 | CB2 agonist, CB1 antagonist, CB1 antagonist/CB2 agonist, or CB2 antagonist (respectively) | C57BL/6 mice | MCAO/r | Pre-treatment | 1 h before injury | O-1966: significant decrease compared to control; SR141716A: significant decrease compared to control; O-1966 and SR141716A: significant decrease compared to control; SR144528: no improvement | Day 1 | N/A |
| Zhang et al. [33] | 2009 | USA | O-1966 | CB2 agonist | C57BL/6 mice | MCAO/r | Pre-/post-treatment | 1 h before injury | Significant decrease with 5 mg dose only compared to vehicle treated | Day 1 | Significant improvement compared with vehicle group |
| Zhang et al. [34] | 2007 | USA | O-3853, O-1966 | CB2 agonist | C57BL/6 mice | MCAO/r | Pre-/post-treatment | 1 h before and after the injury | Significant decrease in size with both pre- and post-treatment | Day 1 | Significant improvement with both pre- and post-treatment group |
| Zhang et al. [33] | 2009 | USA | O-1966, SR141716A, SR144528 | CB1 and CB2 antagonist | C57BL/6 mice | MCAO/r | Pre-treatment | 1 h before injury | CB2 receptor activation and CB1 receptor inhibition were neuroprotective, with the greatest protection achieved by combining a CB2 agonist and CB1 antagonist | Day 1 | CB2 receptor activation and CB1 receptor inhibition were neuroprotective, with the greatest protection achieved by combining a CB2 agonist and CB1 antagonist |
| Hu et al. [36] | 2010 | China | WIN 55,212-2, U0126 | CB agonist, CB antagonist | Sprague-Dawley rats | MCAO/r | Pre-treatment | 1 day before the injury | CB agonist has neuroprotective function while the antagonist proves the opposite effect | Day 1, 3, 6 | Pretreatment with CB agonist has protective function |
| Berger et al. [37] | 2004 | Germany | SR141716A | CB1 antagonist | Wistar rats | MCAO/r | Post-treatment | 30 min after injury | CB1 antagonist reduces infarct size significantly | Day 1 | NR |
| Muthian et al. [38] | 2004 | USA | WIN 55212-2, SR141716, LY320135 | CB1 antagonist | Wistar rats | MCAO/r | Pre-treatment | 5 min pre-onset | CB1 antagonist reduces infarct size significantly, while no effect with CB1 agonist | Day 1 | Significantly improved neurological function with CB1 receptor antagonist |
| Hayakawa et al. [39] | 2007 | Japan | Delta(9)-THC, SR141716 | CB agonist, CB antagonist | ddY mice | MCAO/r | Pre-treatment | Pre-onset | Delta 9 THC significantly decreased the infarct volume | Day 1 | NR |
| Leker et al. [40] | 2003 | Jerusalem | HU-210 | CB antagonist | Sprague-Dawley rats | pMCAO | Post-treatment | 1, 2, 4, or 6 h | Motor disability and infarct volumes were significantly reduced in animals treated with HU-210 | Day 3 | Motor disability and infarct volumes were significantly reduced in animals treated with HU-210 |
Pre-treatment, treatment administered before inducing stroke; post-treatment, treatment administered after inducing stroke; CB, cannabinoid; CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor type 2; MCAO/r, middle cerebral artery occlusion with reperfusion; MCAO, middle cerebral artery occlusion; NR, not reported; N/A, not applicable; STAIR, Stroke Therapy Academic Industry Roundtable; h, hours; min, minutes.