Promoted inhibition of TLR4/miR-155/ NF k B p65 signaling by cannabinoid receptor 2 agonist (AM1241), aborts inflammation and progress of hepatic fibrosis induced by thioacetamide

The endocannabinoid system plays a pivotal role, whether it is promoting or dampening hepatic fibrosis. This study investigated the role of Cannabinoid receptor 2 (CB ) activation by the synthetic analog (AM1241) on revoking the progress of liver fibrosis. Thioacetamide (TAA) was used to induce live...

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Bibliographic Details
Published in:Chemico-biological interactions 2021-02, Vol.336, p.109398
Main Authors: Ali, Alaa M, El-Tawil, Osama S, Al-Mokaddem, Asmaa K, Abd El-Rahman, Sahar S
Format: Article
Language:English
Subjects:
Animals
Cannabinoids - pharmacology
Dose-Response Relationship, Drug
Inflammation - chemically induced
Inflammation - drug therapy
Inflammation - pathology
Liver Cirrhosis - chemically induced
Liver Cirrhosis - drug therapy
Liver Cirrhosis - pathology
Male
MicroRNAs - antagonists & inhibitors
MicroRNAs - metabolism
Rats
Rats, Wistar
Signal Transduction - drug effects
Structure-Activity Relationship
Thioacetamide - adverse effects
Toll-Like Receptor 4 - antagonists & inhibitors
Toll-Like Receptor 4 - metabolism
Transcription Factor RelA - antagonists & inhibitors
Transcription Factor RelA - metabolism
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Summary:The endocannabinoid system plays a pivotal role, whether it is promoting or dampening hepatic fibrosis. This study investigated the role of Cannabinoid receptor 2 (CB ) activation by the synthetic analog (AM1241) on revoking the progress of liver fibrosis. Thioacetamide (TAA) was used to induce liver fibrosis in rats for three weeks followed by its concurrent administration with AM1241 at two different doses for another three weeks. Markers for liver function and oxidative stress, hepatic TNF-α, IL-1β and IL-6, qRT-PCR expression of Toll like receptor 4 (TLR4), TGF-β1, α-SMA and microRNA-155 (miR-155) genes, Western blot for protein levels of Vimentin and E-cadherin, immunohistochemical expression of NFκB p65 and histopathology of liver tissue were all investigated. AM1241 administration significantly maintained liver function markers and decreased; malondialdehyde, Vimentin, TLR4, TGF-β1, α-SMA and miR-155 genes expression, NFκB p65 immune-expression and pro-inflammatory cytokines (TNF-α, IL-1β and IL-6). Additionally, AM1241 significantly increased E-Cadherin level, GSH and SOD content. Histologically, AM1241 limited fibroplasia extension, and broke the itinerary of bridging fibrosis. In conclusion, activation of the CB receptors by AM1241 promoted liver regeneration and overrun the progression of liver fibrosis through; inhibition of TLR4/miR-155/NFκB p65 pathway, suppression of pro-inflammatory IL-6, IL-1β and TNF-α, reducing TGF-β1, α-SMA, Vimentin and up-regulating E-Cadherin.
ISSN:1872-7786