Cannabidiol‐mediated RISK PI3K/AKT and MAPK/ERK pathways decreasing reperfusion myocardial damage

Abstract

Myocardial ischemia continues to be the first cause of morbimortality in the world; the definitive treatment is reperfusion; however, this action causes additional damage to ischemic myocardial tissue; this forces to seek therapies of cardioprotection to reduce this additional damage. There are many cardioprotective agents; within these, cannabinoids have shown to have beneficial effects, mainly cannabidiol (CBD). CBD is a non psychoactive cannabinoid. To evaluate the effect in experimental models of CBD in myocardial ischemia reperfusion in rats, twelve‐week‐old male rats have been used. The animals were divides in 3 groups: control(C), ischemia reperfusion (IR) and CBD pretreatment (1/day/5mg/kg /10days). Langendorff organ isolate studies were performed, and the area of infarction was assessed with triphenyl tetrazolium, in addition to molecular analysis of AT1 and AT2 receptors and Akt and Erk proteins and their phosphorylated forms related to RISK pathways. It was observed that there is an improvement with the use of CBD increasing inotropism and cardiac lusitropism, improving considerably the cardiovascular functionality. These could be related to the reduction of the area of infarction and activation of the AT2 receptor and the RISK pathway with absence of activation of the AT2 receptor (these could relate the reduction of the infarct area and the restoration of cardiovascular function with the activation of the AT2 receptor and the RISK pathway with the absence of activation of the AT2 receptor). The use of cannabinoids was shown to have beneficial effects when used as a treatment for myocardial reperfusion damage.

The molecular activity of cannabidiol in the regulation of Nrf2 system interacting with NF-κB pathway under oxidative stress

“…CBD-mediated reduction of JNK activation has been shown in CBD-treated diabetic mice (1, 10, or 20 mg/kg) [ 85 ]. However, the study in Wistar rats indicated CBD (5 mg/kg)-induced PI3K/AKT and MAPK/ERK pathways associated with reducing reperfusion myocardial damage [ 86 ]. Moreover, CBD (4 μM) has been shown to reduce the p38 level in keratinocytes in the skin of healthy and psoriatic people [ 87 ].…”

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

“…Thus, acute application of CB 1 R antagonists reduced AT 1 R levels in rodent VSMCs [ 41 ] and human podocytes [ 63 ], and their chronic administration diminished the AT 1 R expression in the aorta of ApoE −/− mice [ 41 ], mouse heart [ 43 ], and kidney [ 63 , 64 ] isolated from diabetic mice and/or rats ( Table 2 ; Figure 4 ). A decrease in AT 1 Rs was also observed in response to chronic treatment of rats with cannabidiol (heart [ 44 ]) and PEA (kidney, arteries [ 44 , 51 ]).…”

“…The studies by Mattace Raso et al [ 50 , 51 ] and Franco-Vadillo et al [ 44 ] document a beneficial and CB 1 R-independent influence of two cannabinoids on the harmful effects of Ang II (for details, see Table 1 ). A decrease in AT 1 R densities was found in the heart [ 44 ], carotid and mesenteric arteries [ 51 ], and kidney [ 50 ] in response to chronic administration of CBD for 10 days to rats [ 44 ] or PEA for 5 weeks to hypertensive SHR and their normotensive WKY counterparts [ 50 , 51 ]. CBD or PEA treatment also reduced detrimental changes in cardiac [ 44 ], vascular and renal [ 50 , 51 ] tissues, and BP in SHR [ 50 , 51 ].…”

“…A decrease in AT 1 R densities was found in the heart [ 44 ], carotid and mesenteric arteries [ 51 ], and kidney [ 50 ] in response to chronic administration of CBD for 10 days to rats [ 44 ] or PEA for 5 weeks to hypertensive SHR and their normotensive WKY counterparts [ 50 , 51 ]. CBD or PEA treatment also reduced detrimental changes in cardiac [ 44 ], vascular and renal [ 50 , 51 ] tissues, and BP in SHR [ 50 , 51 ]. CBD and PEA show an overlap in their biochemical effects [ 81 ].…”

The pharmacology and therapeutic role of cannabidiol in diabetes

“…[20] This prevents the disruption of endothelial barrier function and inhibits atherosclerosis formation, [20] which is independent of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) receptors. Moreover, CBD can exert a cardioprotective effect by relieving the infarcted myocardium in acute myocardial ischemia, [21][22][23][24] and ischemia reperfusioninduced ventricular arrhythmias through the activating of adenosine A1 receptors and the modulation of reperfusion injury salvage kinase (RISK)/phosphatidylinositol 3 kinases (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinases (ERK) pathways. [22,25] Diabetic cardiomyopathy is a unique prodrome that can lead to heart failure in diabetic patients, which is independent of the macrovascular complications of diabetes.…”