Treatment with CB₂Agonist JWH-133 Reduces Histological Features Associated with Erectile Dysfunction in Hypercholesterolemic Mice

Abstract

Hypercholesterolemia is one of the most important risk factors for erectile dysfunction, mostly due to the impairment of oxidative stress and endothelial function in the penis. The cannabinoid system might regulate peripheral mechanisms of sexual function; however, its role is still poorly understood. We investigated the effects of CB2 activation on oxidative stress and fibrosis within the corpus cavernosum of hypercholesterolemic mice. Apolipoprotein-E-knockout mice were fed with a western-type diet for 11 weeks and treated with JWH-133 (selective CB2 agonist) or vehicle during the last 3 weeks. CB2 receptor expression, total collagen content, and reactive oxygen species (ROS) production within the penis were assessed. In vitro corpus cavernosum strips preparation was performed to evaluate the nitric oxide (NO) bioavailability. CB2 protein expression was shown in cavernosal endothelial and smooth muscle cells of wild type and hypercholesterolemic mice. Treatment with JWH-133 reduced ROS production and NADPH-oxidase expression in hypercholesterolemic mice penis. Furthermore, JWH-133 increased endothelial NO synthase expression in the corpus cavernosum and augmented NO bioavailability. The decrease in oxidative stress levels was accompanied with a reduction in corpus cavernosum collagen content. In summary, CB2 activation decreased histological features, which were associated with erectile dysfunction in hypercholesterolemic mice.

The Combination of High-Fat Diet and Oral Marijuana Promotes the Development of Fibrosis in the Mouse Corpora Cavernosa

“…THC has been shown to slow the disease progression in rodents induced with rheumatoid arthritis, atherosclerotic plaques, and hepatic fibrosis. 37 , 49 , 50 , 51 , 52 , 53 In line with these studies, in this experiment, the corpora cavernosa of mice given a diet and THC extract did not demonstrate as a significant reduction in HO-1 expression as in those given a diet and MJ extract. This finding may explain the lack of architectural changes found in the corpora cavernosa of mice administered either NCD + THC or HFD + THC.…”

“… 15 , 47 , 48 While antagonism of CB 2 receptors found in immunomodulatory cells can dampen the recruitment of proinflammatory cytokines and myofibroblasts, agonism of CB 2 receptors in the corpora cavernosa may reduce reactive oxygen species. 15 , 47 , 48 , 49 , 50 The cascade of events brought on by CB 1 and CB 2 receptor modulation results in the plaque formation seen in vascular endothelium injury, remodeling, and eventual fibrosis. These mechanisms may also be at play in the fibrosis observed in the corpora cavernosa of mice fed HFD + MJ in this study.…”

Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

“…However their reputation as selective agonists, cemented by historical compound characterisation for CB 1 /CB 2 activity in transfected cell systems overexpressing either cannabinoid receptor, has meant that many studies do not employ stringent controls when using these ligands. A cursory search of the literature found multiple examples of JWH133 and HU308 being used in both primary cell assays and in vivo disease models without receptor antagonism or CB 2 deletion to confirm CB 2 dependence 48 49 50 51 52 53 54 55 56 57 . The off-target effects of JWH133 and HU308 may mean that results obtained in these studies have been erroneously attributed solely to the activation of CB 2 .…”

Diminazene Protects Corpus Cavernosum Against Hypercholesterolemia-Induced Injury

“…A well‐established animal model of hypercholesterolemia‐induced ED was used [25–27]. This ED model was chosen foremost because hypercholesterolemia is one of the most prevalent risk factors for the development of ED [28,29].…”

“…Sirius red staining was performed in penis cryosections as described previously [27,31]. Briefly, mouse penis cryosections (6 μm) were rinsed with water; nuclei were stained with Weigert's hematoxylin for 10 minutes, washed in tap water, and incubated with 0.1% Sirius red (Sigma Chemical Co, St Louis, MO, USA) in saturated picric acid for 60 minutes.…”