Low-Dose Administration of Cannabigerol Attenuates Inflammation and Fibrosis Associated with Methionine/Choline Deficient Diet-Induced NASH Model via Modulation of Cannabinoid Receptor

Abstract

Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD). NASH is distinguished by severe hepatic fibrosis and inflammation. The plant-derived, non-psychotropic compound cannabigerol (CBG) has potential anti-inflammatory effects similar to other cannabinoids. However, the impact of CBG on NASH pathology is still unknown. This study demonstrated the therapeutic potential of CBG in reducing hepatic steatosis, fibrosis, and inflammation. Methods: 8-week-old C57BL/6 male mice were fed with methionine/choline deficient (MCD) diet or control (CTR) diets for five weeks. At the beginning of week 4, mice were divided into three sub-groups and injected with either a vehicle, a low or high dose of CBG for two weeks. Overall health of the mice, Hepatic steatosis, fibrosis, and inflammation were evaluated. Results: Increased liver-to-body weight ratio was observed in mice fed with MCD diet, while a low dose of CBG treatment rescued the liver-to-body weight ratio. Hepatic ballooning and leukocyte infiltration were decreased in MCD mice with a low dose of CBG treatment, whereas the CBG treatment did not change the hepatic steatosis. The high dose CBG administration increased inflammation and fibrosis. Similarly, the expression of cannabinoid receptor (CB)1 and CB2 showed decreased expression with the low CBG dose but not with the high CBG dose intervention in the MCD group and were co-localized with mast cells. Additionally, the decreased mast cells were accompanied by decreased expression of transforming growth factor (TGF)-β1. Conclusions: Collectively, the low dose of CBG alleviated hepatic fibrosis and inflammation in MCD-induced NASH, however, the high dose of CBG treatment showed enhanced liver damage when compared to MCD only group. These results will provide pre-clinical data to guide future intervention studies in humans addressing the potential uses of CBG for inflammatory liver pathologies, as well as open the door for further investigation into systemic inflammatory pathologies.

Concentration-Dependent Attenuation of Pro-Fibrotic Responses after Cannabigerol Exposure in Primary Rat Hepatocytes Cultured in Palmitate and Fructose Media

“…Again, high concentrations of CBG, 10 µM CBG, and 30 µM CBG amplified the PA-F-induced secretion of TGF-β1. A previous study conducted by Aljobaily et al reported that a high concentration of CBG accelerated the inflammation state and the deterioration of NASH induced by a methionine/choline-deficient diet, which was reflected by an increased macrophage proliferation and infiltration [ 10 ]. These facts indicate that only a low concentration of CBG can suppress the palmitate and fructose-induced TGF-β1 activation and regulate the homeostasis of ECM.…”

“…At present, the non-psychotropic component of medical marijuana ( Cannabis sativa L.), namely, cannabigerol (CBG), appears to be a potential therapeutic agent for treating a variety of medical conditions. Studies indicate that CBG reduces the formation of reactive oxygen species in the intestinal epithelial cells during irritable bowel syndrome and also has potential anti-inflammatory effects that are similar to other cannabinoids [ 9 , 10 ]. Importantly, CBG acting on various receptors in the endocannabinoidome (eCBome) has an impact on the regulation of inflammation as well as processes related to lipid metabolism and overall hepatic metabolic functioning [ 11 ].…”

Protective Effects of Gnetin C from Melinjo Seed Extract against High-Fat Diet-Induced Hepatic Steatosis and Liver Fibrosis in NAFLD Mice Model

“…Liver fibrosis represents a more progressive form of NAFLD that occurs if hepatic steatosis and inflammation persist for an extended period, leading to permanent damage to the liver [ 50 ]. If NAFLD progression remains untreated, permanent fibrotic damage can eventually promote hepatic cirrhosis and hepatocellular carcinoma.…”

The Anti-Inflammatory Action of Cannabigerol Accompanied by the Antioxidant Effect of 3-O-ethyl Ascorbic Acid in UVA-Irradiated Human Keratinocytes

“…CBG is one of the main phytocannabinoids that has pharmacological significance as it does not exhibit psychotropic effects, but rather anti-inflammatory effects based on its binding to cannabinoid receptors even at concentrations as low as 0.1-1 μM (Navarro et al, 2018). Moreover, low doses of CBG alleviate inflammation and hepatic fibrosis; however, high doses of CBG may lead to the worsening of liver damage under oxidative conditions (Aljobaily et al, 2023). As far as its medical use is concerned, CBG has been proposed in therapies of prostate cancer (De Petrocellis et al, 2013) and glioblastoma (Lah et al, 2021), neuroprotection (García et al, 2018;Gugliandolo et al, 2018), antidiabetic action (Anokwuru et al, 2022), and in dermatology (Calapai et al, 2022).…”