TABLE 2.
Pharmacological activities, mechanism and therapeutic potential of JWH133 in the in vivo studies.
| Experimental model | JWH133 doses | Indication/Disease | Demonstrated actions and mechanisms | References |
|---|---|---|---|---|
| Compound 48/80-induced inflammation in BALB/cJBom mice | 20 and 20 µg/mouse i.p | Inflammation | Jonsson et al. (2006) | |
| Cecal ligation and puncture (CLP)-induced polymicrobial sepsis model in Sprague-Dawley rats | 0.0, 1, and 5 mg/kg, i.p | Inflammation | Inhibits the apoptosis and NF-κB signaling | Çakır et al. (2020) |
| C57Bl/6J mice injected with LPS-induced vascular inflammation | 10 mg/kg ip | Atherosclerosis | Attenuates the TNF-α- and/or endotoxin induced expression of ICAM-1 and VCAM-1 and vascular endothelium adhesion | Rajesh et al. (2007) |
| Shear stress-induced atherogenesis and plaque vulnerability in apoE−/− mice | 5 mg/kg, i.p. for 5 days/week | Atherosclerosis | Suppresses neutrophil production of MMP-9 via attenuation of ERK1/2 phosphorylation | Montecucco et al. (2012) |
| Balloon-induced neointima in WT, ApoE−/−, CB2−/− mice | 5 mg/kg, i.p. 1 h before surgery and for 28 days after | Atherosclerosis | Modulates neointima formation via decreasing of proliferation, macrophage infiltration, and smooth muscle cell content | Molica et al. (2012) |
| Monosodium iodoacetate-induced osteoarthritis pain in Sprague-Dawley rats | 1 mg/kg, s.c, for 28 days post-MIA injection | Osteoarthritis | Stimulation of CB2R diminished central sensitization process, leading to mitigation of pain behavior | Burston et al. (2013) |
| Subcutaneous xenografts mice and male PyMT transgenic mice | 5 mg/kg, i.p. for 4 weeks | Breast cancer | Modulates COX-2/prostaglandin E2 signaling pathways | Qamri et al. (2009) |
| ⁃Induces cell cycle arrest and apoptosis | ||||
| MMTV-neu mice, a model of ErbB2-driven metastatic breast cancer | 0.05 mg/animal/day, twice a week for 90 days | Breast cancer | Suppression of the pro-tumorigenic Akt pathway | Caffarel et al. (2010) |
| Rag-2_/_ mice, a mouse model of glioma | 50 μg for 8 days, intratumoral | Brain cancer | Induces apoptosis via ceramide synthesis and ERK1/2 activation | Sánchez et al. (2001) |
| Glioma and astrocytoma xenografts | 50 μg/d for 8 days or 25 days, intratumoral | Brain cancer | inhibition of vascular endothelial cell migration and survival as well as the decrease in expression of proangiogenic factors (VEGF and angiopoietin-2) and MMP-2 in the tumors | Blázquez et al. (2003) |
| Glioma xenografts mice | 50 μg/d for 8 days, peritumorally | Brain cancer | Downregulates MMP-2 via inhibiting sphingolipid ceramide synthesis | Blázquez et al. (2008) |
| Nude mice inoculated with glioma cells | 1.5 mg/kg, s.c | Brain cancer | Decreases efficiency of glioma stem cells and glioma formation due to reduced neurosphere formation and cell growth | Aguado et al. (2007) |
| SCID CB-17 mice inoculated with A549 cells | 1 mg/kg, peritumorally for 28 days | Lung cancer | Decreases tumor proliferation and neo-vascularization along with enhanced apoptotic death | Preet et al. (2011) |
| Nude mice inoculated with PDV.C57 epidermal tumor cells | 1,580 μg for 11 days locally infused at a rate of 0.52 μl/h | Skin cancer | Interferes with the tumor angiogenic switch together with the direct stimulation of apoptosis on tumor cells, which in turn inhibits tumor proliferation | Casanova et al. (2003) |
| Abolishes EGFR function | ||||
| Nude mice bearing B16 melanoma cells | 50 μg/day, daily for 8 days | Skin cancer | Rise in apoptosis and reduction of tumor vascularization, and vascular density | Blázquez et al. (2006) |
| Quetiapine-induced cardiotoxicity in Balb/C mice | 5 mg/kg, i.p. for 21 days | Cardiotoxicity | Modulates necroptosis process | Li et al. (2019b) |
| Ethanol-induced cardiotoxicity in C57BL/6J mice | 3 mg/kg, i.p. 1 h before ethanol administration for 30 or 45 days | Cardiotoxicity | Attenuates RIP1/RIP3/MLKL-mediated necroptosis | Liu et al. (2020b) |
| Clozapine-induced cardiotoxicity in C57BL/6J mice | 2 mg/kg, i.p. before clozapine administration for 14 days | Cardiotoxicity | Attenuates myocardial inflammation, fibrosis, and myocardial injury | Li et al. (2019a) |
| I/R injury of the C57Bl/6 mouse heart | 20 mg/kg, i.p. 5 min before reperfusion | Myocardial infarction | Inhibition of oxidative stress and neutrophil recruitment and activation of ERK 1/2 and STAT3 pathway | Montecucco et al. (2009) |
| I/R injury of the Sprague-Dawley rats heart | 20 mg/kg, I.V. 5 min before ischemia | Myocardial infarction | Prevents apoptotic cell death via suppressing the intrinsic mitochondrial apoptotic process and implication of the PI3K/Akt signaling pathway | Li et al. (2013a) |
| I/R injury of the C57Bl/6 WT and CB2−/− mice heart | 3 mg/kg, I.V. 5 min before reperfusion | Myocardial infarction | Prevention of oxidative stress-induced cardiac myocyte and fibroblast apoptosis and the suppression of myofibroblast activation | Defer et al. (2009) |
| I/R injury of the C57Bl/6 mouse heart | 1, 3, and 10 mg/kg, i.p. 5 min before ischemia | Myocardial infarction | Modulation of NLRP3 inflammasome pathway | Yu et al. (2019) |
| HFD-induced obese mice model (60% kcal fat content) for 10 weeks | 5, 10 mg/kg, i.p. for 21 days | Obesity | Attenuates pro-inflammatory M1 macrophage cytokines through the Nrf2/HO-1 mechanism | Wu et al. (2020) |
| db/db mice | 0.15, 0,5, 1 and 3 mg/kg, s.c | Diabetic neuropathy | ⁃Activation of antioxidant Nrf2/HO-1pathway potentiated the antiallodynic effects | McDonnell et al. (2017) |
| Seven-day-old swiss CD-1 mice | 1.5 mg/kg for 5 h (acute treatment) or for 5 consecutive days per week for 2 and 3 weeks (chronic treatment) | Spermatogenesis | Accelerates the spermatogenesis process and regulates transcription of the c-Kit and Stra8 genes at meiotic entry through specific alterations of histone modifications | Di Giacomo et al. (2016) |
| Trinitrobenzene sulfonic acid (TNBS)-induced colitis in wildtype and CB2−/− mice | 20 mg/kg, i.p. 30 min before the induction of colitis and then twice daily for 3 days | Colitis | Reduces intestinal inflammation via a decrease in colonic adhesions and myeloperoxidase activity | Storr et al. (2009) |
| Oil of mustard-induced model of colitis in CD-1 mice | 20 mg/kg, i.p. 30 min before the induction of colitis and then twice daily for 3 days | Colitis | Reductions in overt inflammatory damage and bowel dysmotility | Kimball et al. (2006) |
| Dextran sulfate sodium (DSS)- induced colitis in BALB/c mice | ||||
| IL-10−/− mice model of colitis | 1, 2.5, 5 mg/kg i.p. for 7 weeks | Colitis | Anti-inflammatory activities through inhibiting activated T cells, and inducting apoptosis in T cells | Singh et al. (2012) |
| Dextran sulfate sodium (DSS)- induced colitis in BL/6 mice | ||||
| Oil of mustard-induced model of colitis in CD-1 mice | 1 mg/kg s.c | Colitis | Modulation of GI motility attenuating the associated diarrhea | Kimball et al. (2010) |
| LPS-stimulated transit in Sprague–Dawley rats | 1 mg/kg s.c | Colitis | Suppresses GI transit via inhibition of cyclooxygenase | Mathison et al. (2004) |
| Cerulein-induced acute pancreatitis in WT and MK2−/−mice | 5 μg/g, i.p. 30 min before the induction of acute pancreatitis | Acute pancreatitis | Suppression of JNK, stimulation of p38 and MK2-signaling pathway reducing the pancreatic injury | Michler et al. (2013) |
| GalN/LPS-induced acute liver injury in C57BL/6 mice | 20 mg/kg i.p, two doses administered 24 and 2 h before the GalN/LPS injection | Acute liver injury | Mediates an M1 to M2 transition in macrophages and modulates the expression of miR-145 to hamper the TLR4 signaling stimulation | Tomar et al. (2015) |
| Alcohol-fed WT and CB2_/_ mice induced fatty liver | 3 mg/kg, i.p. for 10 days | Alcoholic liver disease | Anti-inflammatory effects via upregulating of HO-1 in macrophages | Louvet et al. (2011) |
| Ethanol-fed WT and CB2Mye−/−, and ATG5Mye−/− mice | 3 mg/kg, i.p. for 10 days | Alcoholic liver disease | Stimulates autophagic process via upregulating of HO-1 in macrophage that mediates the anti-inflammatory and anti-steatogenic activities of CB2 receptors | Denaës et al. (2016) |
| CCl4-Induced liver cirrhosis in Wistar rats | 1 mg/kg, s.c. for 9 days | Liver cirrhosis | Mitigates hepatic fibrosis via decreasing collagen content, α-SMA, and increasing the proteolytic enzyme MMP-2 | Muñoz-Luque et al. (2008) |
| Bile duct ligation (BDL)-induced cirrhotic rats | 1 mg/kg, i.p. from days 35–42 days of BDL | Liver cirrhosis | Suppresses mesenteric blood flow leading to mitigation of liver fibrosis | Huang et al. (2012) |
| Thioacetamide or bile duct ligation-induced cirrhotic rats | 1 mg/kg, orally for 2 weeks | Liver cirrhosis | Improves phagocytosis of peritoneal macrophages through suppressing the TNFα signaling, pro-inflammatory cytokines secretion and oxidative stress | Yang et al. (2014) |
| CCl4-Induced liver cirrhosis in sprague–Dawley rats | 10 mg/kg, i.p. 2 h prior to the start of portal pressure measurements | Liver cirrhosis | Mediates HO-1 pathway which decreases vasoconstrictor production and portal hypertension related to PPARγ and CB2R | Steib et al. (2013) |
| CCl4-Induced liver injury in WT and CB2_/_ mice | 3 mg/kg, i.p. before CCl4 | Liver fibrosis | Mitigates hepatic injury and promotes hepatic regeneration through a paracrine mechanism including hepatic myofibroblasts and antifibrogenic effects | Teixeira-Clerc et al. (2010) |
| CCL4 plus clodronate- induced liver injury in C57BL/6 mice | 10 mg/kg, i.p. before CCl4 | Liver fibrosis | Transcriptional regulation of the CB2 receptor gene in hepatocytes by LXRα resulting in inhibition of USP4-stabilizing TβRI through miR-27b | Wu et al. (2019) |
| Hepatic ischemia/reperfusion in WT and CB2_/_ mice | i.p. 60 min prior to the occlusion of the hepatic artery and the portal vein | Hepatic ischemia/reperfusion | Attenuates oxidative stress and the infilteration of inflammatory cells | Bátkai et al. (2007) |
| Hepatic ischemia/reperfusion in C57BL/6 mice | 0.2 mg/kg, i.p. 24 h before the experiment | Hepatic ischemia/reperfusion | Selective depletion or deactivation of HSCs through CB2R activation reduces CD4+ T cell–dependent I/R injury | Reifart et al. (2015) |
| Collagen-induced arthritis (CIA) mice | 1, 4 mg/kg, i.p. from day 15 to day 35 | Rheumatoid arthritis | Inhibits production of pro-inflammatory cytokines, and prevents formation of bone-resorbing cells | Fukuda et al. (2014) |
| Collagen-induced arthritis (CIA) in mice | 10 mg/kg, i.p. from day 22 to day 45 | Rheumatoid arthritis | Inhibits osteoclastogenesis and inflammation-mediated bone destruction via inhibiting NF-kB signaling pathway | Zhu et al. (2019) |
| Experimental autoimmune uveoretinitis in B10.RIII mice and BALB/c mice | 0.015–1.5 mg/kg, i.p | Autoimmune uveoretinitis | Anti-inflammatory activity through suppressing the stimulation and function of autoreactive T cells and averting leukocyte trafficking into the inflamed retina | Xu et al. (2007) |
| Hypochlorite-induced systemic sclerosis in BALB/c, C57BL/6 CB2−/− mice | 1,1.5, 2, 2.5, 3, and 4 mg/kg, i.p. for 6 weeks | Systemic sclerosis | Inhibits systemic fibrosis, skin fibroblast proliferation and autoimmune reaction | Servettaz et al. (2010) |
| I/R Injury of albino NMRI mice kidney | 0.2, 1 and 5 mg/kg, i.p. 30 min prior initiation of reperfusion-induced ischemia | Renal ischemia reperfusion | Suppression of inflammatory cytokines secretion by NF-κB and mitigates apoptosis | Feizi et al. (2008) |
| Cyclophosphamide-induced cystitis in C57BL/6J mice | 1 mg/kg, i.p. 30 min before cyclophosphamide | Cystitis | Activates autophagy via AMPK-mTOR pathway mitigating bladder inflammatory responses and severity of cystitis | Liu et al. (2020a) |
| Bleomycin-induced dermal fibrosis in WT and CB2−/− mice | 2.5 mg/kg, i.p. for 4 weeks | Dermal fibrosis | ⁃Antifibrotic effects by preventing the infiltration of leukocytes into skin lesion | Akhmetshina et al. (2009) |
| Paraquat-induced lung injury in Sprague-Dawley rats | 5 and 20 mg/kg, i.p. before paraquat administration | Lung injury | Mitigates lund injury via suppressing the stimulation of MAPKs and NF-kB signaling | Liu et al. (2014) |
| Bleomycin-induced pulmonary fibrosis in C57BL/6 mice | 2.5 mg/kg, i.p. for 21 days | Pulmonary fibrosis | Anti-fibrotic activity via repressing TGF-β1/Smad2 signaling pathway | Fu et al. (2017) |
| Nicotine-induced lung fibrosis in swiss mice | 1 mg/kg, i.p. before nicotine administration | Pulmonary fibrosis | Anti-fibrotic activity via downregulating the expression of connective tissue growth factor, and α-SMA | Wawryk-Gawda et al. (2018) |
| Lung ischemia/reperfusion Injury in C57BL/6 mice | 5 mg/kg, i.p. 5 min before occlusion | Lung ischemic reperfusion injury | Attenuates the inflammation and oxidative stress relies on activation of PI3K/Akt signaling | Zeng et al. (2019) |
| Lung ischemia/reperfusion Injury in C57BL/6 mice | 5 mg/kg, i.p. 5 min before occlusion | Lung ischemic reperfusion injury | Inhibits oxidative stress via downregulation of NOX2 | Huang et al. (2020) |
| Respiratory syncytial virus challenged Balb/c mice | i.p. for 5 days | Acute respiratory tract infections | Anti-inflammatory activity via reducing the influx of BAL cells, leukocyte migration into the lungs, and cytokines/chemokines | Tahamtan et al. (2018) |
| Skeletal muscle contusion model in Sprague-Dawley rat | 10 mg/kg, i.p. injected 30 min after contusion and once a day for 13 days | Skeletal muscle contusion | Inhibits fibrosis and improves muscle regeneration via reducing TGF-β1, fibronectin-EIIIA and α-SMA, decreases production of myofibroblasts, and concurrently upregulation of MMP-1/2 | Yu et al. (2015) |
| Incised skin wound model in BALB/c mice | 3 mg/kg, i.p. for 1–9 days | Skin wound healing | Inhibition of inflammatory process by attenuating infiltrated M1 macrophage cells and enhancing M2 macrophage phenotype | Du et al. (2018) |