Re-evaluation of the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria

Abstract

Ischemic heart disease, associated with high morbidity and mortality, represents a major challenge for the development of drug-based strategies to improve its prognosis. Results of pre-clinical studies suggest that agonists of cannabinoid CB₂ receptors and multitarget cannabidiol might be potential cardioprotective strategies against ischemia-reperfusion injury. The aim of our study was to re-evaluate the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria published recently by the European Union (EU) CARDIOPROTECTION COST ACTION. To meet the minimum criteria of those guidelines, experiments should be performed (i) on healthy small animals subjected to ischemia with reperfusion lasting for at least 2 hours and (ii) confirmed in small animals with comorbidities and co-medications and (iii) in large animals. Our analysis revealed that the publications regarding cardioprotective effects of CB₂ receptor agonists and cannabidiol did not meet all three strict steps of IMPACT. Thus, additional experiments are needed to confirm the cardioprotective activities of (endo)cannabinoids mainly on small animals with comorbidities and on large animals. Moreover, our publication underlines the significance of the IMPACT criteria for a proper planning of preclinical experiments regarding cardiac ischemia-reperfusion injury.

Keywords: Cannabidiol; Cannabinoid receptor; Cannabinoids; IMproving Preclinical assessment of Cardioprotective therapies (IMPACT); Myocardial infarction; Myocardial ischemia-reperfusion injury.

FIGURE 1

Potential beneficial and detrimental effects of the (endo)cannabinoids considered in this review and mediated via CB₁R (cannabinoid receptor type 1) and CB₂R activation (cannabinoid receptor type 2). Green circles with a plus sign describe (partial) agonism at the respective receptor; red circles with a minus sign describe antagonism, inverse agonism or inhibition at the respective mechanism (degradation or uptake). Synthetic, plant-derived compounds and endocannabinoids are written in blue, green, and black font, respectively. 2-AG, 2-arachidonoylglycerol; ACEA, arachidonyl-2′-chloroethylamide; ACPA, arachidonylcyclopropylamide; AEA, anandamide; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; MethAEA, methanandamide; PEA, N-palmitoylethanolamide; RIM, rimonabant; THC, Δ⁹-tetrahydrocannabinol. The scheme is based on figures shown by Pacher and Haskó 2008; Steffens and Pacher 2012; Tang et al., 2021; Weresa et al., 2022; Rorabaugh et al., 2023; Maccarrone et al., 2023.

FIGURE 2

A schematic representation of typical protocols for ischemia, hypoxia or acute myocardial infarction (AMI) that have been used to examine whether (endo)cannabinoids have cardioprotective effects during various preconditioning strategies (A, B) or when administered to assess their pharmacological effects (C). At the top of the image (left part), the time of application displays different approaches to administer (endo)cannabinoids. For results, see Tables 1-5. LAD, left anterior descending artery; LCx, left circumflex coronary artery; NO, nitric oxide; LPS, lipopolysaccharide.

FIGURE 3

Are the studies regarding the cardioprotective effects of cannabinoid CB₂ receptor (CB₂R) agonistic drugs and cannabidiol (CBD) against cardiac ischemia/reperfusion (I/R) in accordance with the minimum (min.) criteria of the IMPACT (IMproving Preclinical Assessment of Cardioprotective Therapies) three-step schedule proposed by the European Union (EU) CARDIOPROTECTION COST ACTION (Lecour et al., 2021)? Our literature review, which is the basis for this scheme, shows that only 9 (blue numbers) and 4 (green numbers) of the studies examining the effects of CB₂R activation and CBD, respectively, meet the minimum criteria of STEP 1. The minimum criteria of STEP 2 are partially met by two studies with CB₂R activation only. Studies in large animals (STEP 3) are still lacking. For clarification: to meet STEP 2, experiments should be performed on small animals with con-founders such as co-morbidities (e.g., diabetes mellitus) or medications (used during surgery or for treatment of diseases) since these factors may influence the observed results.