scholarly journals Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

2018 ◽  
Vol 48 (3) ◽  
pp. 971-982 ◽  
Author(s):  
Yang  Cheng ◽  
Tianyang Chen ◽  
Jian Ping ◽  
Jianjie Chen
Keyword(s):  
Treatment Group ◽  
Palmitic Acid ◽  
Inflammatory Cytokines ◽  
Kupffer Cells ◽  
Nonalcoholic Steatohepatitis ◽  
Lipid Accumulation ◽  
Hepatic Injury ◽  
High Dose ◽  
Therapeutic Effects ◽  
Dependent Manner

Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis.

scholarly journals Prevention and Reversal of Lipotoxicity-Induced Hepatic Insulin Resistance and Steatohepatitis in Mice by an Antioxidant Carotenoid, β-Cryptoxanthin

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 987-999 ◽  
Author(s):  
Yinhua Ni ◽  
Mayumi Nagashimada ◽  
Lili Zhan ◽  
Naoto Nagata ◽  
Masuko Kobori ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mrna Expression ◽  
Kupffer Cells ◽  
Lipid Accumulation ◽  
Hepatic Insulin Resistance ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
High Fat ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Abstract Excessive hepatic lipid accumulation promotes macrophages/Kupffer cells activation, resulting in exacerbation of insulin resistance and progression of nonalcoholic steatohepatitis (NASH). However, few promising treatment modalities target lipotoxicity-mediated hepatic activation/polarization of macrophages for NASH. Recent epidemiological surveys showed that serum β-cryptoxanthin, an antioxidant carotenoid, was inversely associated with the risks of insulin resistance and liver dysfunction. In the present study, we first showed that β-cryptoxanthin administration ameliorated hepatic steatosis in high-fat diet-induced obese mice. Next, we investigated the preventative and therapeutic effects of β-cryptoxanthin using a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat (CL) diet. After 12 weeks of CL diet feeding, β-cryptoxanthin administration attenuated insulin resistance and excessive hepatic lipid accumulation and peroxidation, with increases in M1-type macrophages/Kupffer cells and activated stellate cells, and fibrosis in CL diet-induced NASH. Comprehensive gene expression analysis showed that β-cryptoxanthin down-regulated macrophage activation signal-related genes significantly without affecting most lipid metabolism-related genes in the liver. Importantly, flow cytometry analysis revealed that, on a CL diet, β-cryptoxanthin caused a predominance of M2 over M1 macrophage populations, in addition to reducing total hepatic macrophage and T-cell contents. In parallel, β-cryptoxanthin decreased lipopolysaccharide-induced M1 marker mRNA expression in peritoneal macrophages, whereas it augmented IL-4-induced M2 marker mRNA expression, in a dose-dependent manner. Moreover, β-cryptoxanthin reversed steatosis, inflammation, and fibrosis progression in preexisting NASH in mice. In conclusion, β-cryptoxanthin prevents and reverses insulin resistance and steatohepatitis, at least in part, through an M2-dominant shift in macrophages/Kupffer cells in a lipotoxic model of NASH.

scholarly journals Guyanxiao formula antagonizes LPS-induced KOA chondrocyte injury by regulating the SDF-1 / CXCR4 signaling pathway1

2020 ◽  
Author(s):  
Qi Zhang ◽  
Zheng Shu-guang ◽  
Wang Bao-juan ◽  
Wang Lin ◽  
Li Tian-yang
Keyword(s):  
Treatment Group ◽  
Signaling Pathway ◽  
Toluidine Blue ◽  
Quantitative Polymerase Chain Reaction ◽  
Blue Staining ◽  
High Dose ◽  
Inflammatory Factor ◽  
Dependent Manner ◽  
Model Group ◽  
Cxcr4 Signaling

Abstract Background To determine whether Guyanxiao formula protects chondrocytes in a model of knee arthritis induced by lipopolysaccharide, and whether it can repair chondrocyte damage and suppress osteoarthritis cartilage degeneration by regulating SDF-1 / CXCR4 signaling pathway.Methods Lipopolysaccharide(LPS) induces chondrocytes in vitro to prepare knee osteoarthritis model. Toluidine blue (TBS) staining was used to observe the changes of proteoglycan content of rabbit chondrocytes in order to identify the source of cells. The biochemical detection method was used to determine the content of inflammatory factor nitric oxide (NO) in chondrocytes to identify whether the osteoarthritis chondrocytes were successfully modeled in vitro.The cell proliferation rate was measured by the cell viability test (CCK-8), the concentration with no obvious cytotoxicity was screened, and the low, medium and high dose groups of Guyanxiao formula were established.Immunofluorescence(IF) staining was used to observe the effect of Guyanxiao formula on the content of type Ⅱ collagen in chondrocytes of knee osteoarthritis.Enzyme-linked immunosorbent assay was carried out to determine the expression of inflammatory factors MMP-3, MMP-9 and MMP-13. The mRNA and protein expressions of SDF-1, CXCR4, Vascular endothelial growth factor(VEGF) were analyzed by reverse transcription quantitative polymerase chain reaction and Western blot analysis.Results The identify of chondrocytes was confirmed with toluidine blue staining. LPS treatment remarkably increased the NO content, indicating successful noodling of the KOA chondrocyte model. According to the CCK-8 experiment results, 0.36, 3.6, and 36 µg / mL were set as the low, medium, and high dose administration concentrations of ostitis.Immunofluorescence(IF) staining showed that the degree of type Ⅱ collagen damage in each treatment group was improved compared with the model group, and the high concentration group was the most obvious improvement in the Guyanxiao formula treatment group.The levels of MMP-3,MMP-9, MMP-13, and IL-1b were much lower in the Cell supernatant of the each treatment group than in that of model group.The levels of SDF-1, CXCR4, VEGF mRNA and protein were much lower in the Chondrocytes of the each treatment group than in that of model group. In addition, the therapeutic effect of Guyanxiao formula treatment group decreased in a concentration-dependent manner.Conclusion Guyanxiao formula antagonizes LPS-induced KOA chondrocyte injury by regulating the SDF-1 / CXCR4 signaling pathway.

scholarly journals Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models

2020 ◽  
Vol 8 (1) ◽  
pp. e000400 ◽  
Author(s):  
Taiki Kurino ◽  
Reiko Matsuda ◽  
Ayu Terui ◽  
Hiroyuki Suzuki ◽  
Tomomi Kokubo ◽  
...  
Keyword(s):  
Mouse Models ◽  
Pharmacological Activity ◽  
Tumor Model ◽  
High Dose ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Poor Outcome ◽  
Liver And Kidney ◽  
High Doses

BackgroundRecently, antiprogrammed cell death protein 1 (aPD-1) and antiprogrammed death-ligand 1 (aPD-L1) monoclonal antibodies (mAbs) have been approved. Even though aPD-1 and aPD-L1 mAbs target the same PD-1/PD-L1 axis, it is still unclear whether both mAbs exert equivalent pharmacological activity in patients who are sensitive to PD-1/PD-L1 blockade therapy, as there is no direct comparison of their pharmacokinetics (PK) and antitumor effects. Therefore, we evaluated the differences between both mAbs in PK and therapeutic effects in PD-1/PD-L1 blockade-sensitive mouse models.MethodsHerein, murine breast MM48 and colon MC38 xenografts were used to analyze the pharmacological activity of aPD-1 and aPD-L1 mAbs. The PK of the mAbs in the tumor-bearing mice was investigated at low and high doses using two radioisotopes (Indium-111 and Iodine-125) to evaluate the accumulation and degradation of the mAbs.ResultsaPD-1 mAb showed antitumor effect in a dose-dependent manner, indicating that the tumor model was sensitive to PD-1/PD-L1 blockade therapy, whereas aPD-L1 mAb failed to suppress tumor growth. The PK study showed that aPD-L1 mAb was accumulated largely in normal organs such as the spleen, liver, and kidney, resulting in low blood concentration and low distributions to tumors at a low dose, even though the tumors expressed PD-L1. Sufficient accumulation of aPD-L1 mAb in tumors was achieved by administration at a high dose owing to the saturation of target-mediated binding in healthy organs. However, degradation of aPD-L1 mAb in tumors was greater than that of aPD-1 mAb, which resulted in poor outcome presumably due to less inhibition of PD-L1 by aPD-L1 mAb than that of PD-1 by aPD-1 mAb.ConclusionAccording to the PK studies, aPD-1 mAb showed linear PK, whereas aPD-L1 mAb showed non-linear PK between low and high doses. Collectively, the poor PK characteristics of aPD-L1 mAb caused lower antitumor activity than of aPD-1 mAb. These results clearly indicated that aPD-L1 mAb required higher doses than aPD-1 mAb in clinical setting. Thus, targeting of PD-1 would be more advantageous than PD-L1 in terms of PK.

scholarly journals Protective Effect of Genistein on Condylar Cartilage through Downregulating NF-κB Expression in Experimentally Created Osteoarthritis Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Jian Yuan ◽  
Wanghui Ding ◽  
Na Wu ◽  
Shijie Jiang ◽  
Wen Li
Keyword(s):  
Protective Effect ◽  
Temporomandibular Joint ◽  
Inflammatory Cytokines ◽  
Morphological Changes ◽  
High Dose ◽  
Therapeutic Effects ◽  
Condylar Cartilage ◽  
Positive Effects ◽  
Temporomandibular Joint Osteoarthritis ◽  
Genistein Treatment

Temporomandibular joint osteoarthrosis (TMJOA) is characterised by chronic inflammatory changes, with subsequent gradual loss of joint cartilage. NF-κB is a crucial transcription factor in the course of inflammatory and immune responses, which are involved in OA pathology activated by proinflammatory cytokines. Genistein is known to have anti-inflammation and modulation of metabolic pathways through repression of the NF-κB signaling pathway in inflammatory disease. But so far, studies on the effects of genistein on TMJOA are very limited. So, the purpose of this study is to investigate the protective effect of genistein against experimentally induced condylar cartilage degradation through downregulating NF-κB expression in created osteoarthritis rats in vivo. Male SD rats were created as temporomandibular joint osteoarthritis models and administered through oral gavage with low and high dosage genistein (30 mg/kg and 180 mg/kg, respectively) daily for 4 weeks. The morphological changes of the condylar cartilage were studied with HE and Masson staining. The expressions of p65 and inflammatory cytokines (IL-1β and TNFα) were detected using immunohistochemistry and real-time PCR. The results showed that experimentally created osteoarthritis reduced the condylar cartilage thickness of rats and increased the gene expression of cytokines (IL-1β and TNFα) and positive cells of p65. Genistein treatment had positive effects on the condylar cartilage renovation, while high dose genistein treatment had more significant effects on the reversing of OA changes and reduction of the expression of p65 and inflammatory cytokines (IL-1β and TNFα). The results indicated that high dose genistein treatment had obvious therapeutic effects on condyle cartilage damages of OA rats. The mechanism may be that genistein suppresses the NF-κB expression activated by inflammatory cytokines.

Clodronate-nintedanib-loaded exosome–liposome hybridization enhances the liver fibrosis therapy by inhibiting Kupffer cell activity

2022 ◽  
Author(s):  
Keqin Ji ◽  
Mingrui Fan ◽  
Dong Huang ◽  
Lingna Sun ◽  
Bingqin Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Inflammatory Cytokines ◽  
Kupffer Cell ◽  
Kupffer Cells ◽  
Cell Activity ◽  
Therapeutic Effects

CLD/NIN@LIEV decreases the nonspecific phagocytosis of nanoparticles and suppresses the inflammatory cytokines secreted by Kupffer cells, thus enhancing the therapeutic effects against liver fibrosis.

scholarly journals Yellow loosestrife (Lysimachia vulgaris var. davurica) ameliorates liver fibrosis in db/db mice with methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang-Ju Son ◽  
Da Seul Jung ◽  
Ji Min Shin ◽  
Myungsuk Kim ◽  
Gyhye Yoo ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Nonalcoholic Steatohepatitis ◽  
Lipid Accumulation ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Alcoholic Extract ◽  
Hepatic Lipid ◽  
Smad Signaling ◽  
Hepatic Lipid Accumulation ◽  
Anti Inflammatory

Abstract Background Nonalcoholic steatohepatitis (NASH), a liver disease caused by a nonalcoholic fatty liver, is increasing in incidence worldwide. Owing to the complexity of its pathogenic mechanisms, there are no therapeutic agents for this disease yet. The ideal drug for NASH needs to concurrently decrease hepatic lipid accumulation and exert anti-inflammatory, antifibrotic, and antioxidative effects in the liver. Because of their multipurpose therapeutic effects, we considered that medicinal herbs are suitable for treating patients with NASH. Methods We determined the efficacy of the alcoholic extract of Lysimachia vulgaris var. davurica (LV), an edible medicinal herb, for NASH treatment. For inducing NASH, C57BLKS/J lar-Leprdb/Leprdb (db/db) male mice were fed with a methionine-choline deficient (MCD) diet ad libitum. After 3 weeks, the LV extract and a positive control (GFT505) were administered to mice by oral gavage for 3 weeks with a continued MCD diet as needed. Results In mice with diet-induced NASH, the LV extract could relieve the disease symptoms; that is, the extract ameliorated hepatic lipid accumulation and also showed antioxidative and anti-inflammatory effects. The LV extract also activated nuclear factor E2-related factor 2 (Nrf2) expression, leading to the upregulation of antioxidants and detoxification signaling. Moreover, the extract presented remarkable efficacy in alleviating liver fibrosis compared with GFT505. This difference was caused by significant LV extract-mediated reduction in the mRNA expression of fibrotic genes like the alpha-smooth muscle actin and collagen type 3 alpha 1. Reduction of fibrotic genes may thus relate with the downregulation of transforming growth factor beta (TGFβ)/Smad signaling by LV extract administration. Conclusions Lipid accumulation and inflammatory responses in the liver were alleviated by feeding LV extract to NASH-induced mice. Moreover, the LV extract strongly prevented liver fibrosis by blocking TGFβ/Smad signaling. Hence, LV showed sufficient potency for use as a therapeutic agent against NASH.

scholarly journals Ginsenoside panaxatriol reverses TNBC paclitaxel resistance by inhibiting the IRAK1/NF-κB and ERK pathways

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9281
Author(s):  
Panpan Wang ◽  
Dan Song ◽  
Danhong Wan ◽  
Lingyu Li ◽  
Wenhui Mei ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Viability ◽  
Inflammatory Cytokines ◽  
Cell Invasion ◽  
Combination Treatment ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Down Regulation ◽  
Tumor Sphere ◽  
Resistant Cells

Background Paclitaxel (PTX) resistance is a major obstacle in the treatment of triple-negative breast cancer (TNBC). Previously, we have reported that interleukin-1 receptor-associated kinase 1 (IRAK1) and its downstream pathways are associated with PTX resistance in TNBC cells. In this study, we sought to investigate the combination treatment of ginsenoside panaxatriol (GPT), one of the main active components in Panax ginseng, with PTX on viability and apoptosis of TNBC PTX resistant cells, and explore the role of IRAK1 mediated signaling pathways in the therapeutic effects. Methods CellTiter-Glo and colony formation assays were used to assess cell viability. Flow cytometry was used to analyze subG1 and apoptosis. Western blot was used to detect expressions of proteins involved in apoptosis and the IRAK1/NF-κB and ERK pathways. The mRNA expression of inflammatory cytokines, S100A7/8/9 and cancer stem cell (CSC)-related genes were examined by qPCR. Stem cells were identified by tumor sphere assay. Cell invasion ability was examined by transwell assay. Results We show that GPT inhibits MDA-MB-231 PTX resistant (MB231-PR) cell viability in a dose-dependent manner. When combined with PTX, GPT synergistically causes more cell death, induces subG1 accumulation and cell apoptosis. Besides, up-regulation of BAX/BCL-2 ratio, and down-regulation of MCL-1 are also observed. Moreover, this combination inhibits IRAK1, NF-κB and ERK1/2 activation, and leads to down-regulation of inflammatory cytokines (IL6, IL8, CXCL1, CCL2), S100A7/9 and CSC-related genes (OCT4, SOX2, NANOG, ALDH1, CD44) expression. In addition, the combination treatment suppresses MB231-PR cell invasion ability, and impairs tumor sphere growth both in MB231-PR and SUM159 PTX resistant (SUM159-PR) cells. Conclusion Our study demonstrates that GPT can resensitize TNBC PTX resistant cells to PTX by inhibiting the IRAK1/NF-κB and ERK pathways and reducing stem cell characteristics.

scholarly journals Hyaluronic acid optimizes therapeutic effects of Hydrogen peroxide-induced oxidative stress on breast cancer

2020 ◽  
Author(s):  
Ardeshir Abbasi ◽  
Nafiseh Pakravan ◽  
Zuhair Hassan
Keyword(s):  
Oxidative Stress ◽  
Hyaluronic Acid ◽  
Cancer Cells ◽  
Mononuclear Cells ◽  
Phase Cell ◽  
High Dose ◽  
Therapeutic Effects ◽  
Mrna Levels ◽  
Dependent Manner

Abstract Background and Purpose: Distinguishing the multiple effects of reactive oxygen species (ROS) on cancer cells is important to understand their role in tumour biology. Conversely, elevated levels of ROS-induced oxidative stress can induce cancer cell death. However, some anti-oxidative or ROS-mediated oxidative therapies have also yielded beneficial effects.Experimental approach: To better define the effects of oxidative stress, in vitro experiments were conducted on 4T1 and splenic mononuclear cells (MNCs) under hypoxic and normoxic conditions. Furthermore, H2O2 [10-1000μM], was used as a ROS source alone or in combination with hyaluronic acid (HA), which is frequently used as drug delivery vehicle.Key Results: Our results indicate that treatment of cancer cells with H2O2+HA was significantly more effective than H2O2 alone. In addition, treatment with H2O2+HA led to increased apoptosis, decreased proliferation, and multi-phase cell cycle arrest in 4T1 cells in a dose-dependent manner under normoxic or hypoxic conditions. Also, migratory tendency and the mRNA levels of VEGF, and MMP-2,9 were significantly decreased. Of note, HA treatment combined with 100-1000μM H2O2+ caused more damage to MNCs as compared to treatment with lower concentrations [10-50μM]. Based on these results we propose to administer high dose H2O2+HA [100-1000μM] for intra-tumoral injection and low doses for systemic administration.Conclusions & Implications: Intra-tumoral route could have toxic and inhibitory effects not only on the tumour but also on residential myeloid cells defending it, whereas systemic treatment could stimulate peripheral immune responses against the tumour. More in vivo research is required to confirm this hypothesis.

scholarly journals Combination of lyophilized adipose-derived stem cell concentrated conditioned medium and polysaccharide hydrogel in the inhibition of hypertrophic scarring

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chaoyu Zhang ◽  
Ting Wang ◽  
Li Zhang ◽  
Penghong Chen ◽  
Shijie Tang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conditioned Medium ◽  
Dose Group ◽  
High Dose ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Hypertrophic Scarring ◽  
Rabbit Ear ◽  
Adipose Derived Stem Cell ◽  
Polysaccharide Hydrogel

Abstract Background Mesenchymal stem cell-based acellular therapies have been widely exploited in managing hypertrophic scars. However, low maintenance dose and transitory therapeutic effects during topical medication remain a thorny issue. Herein, this study aimed to optimize the curative effect of adipose-derived stem cell conditioned medium (ADSC-CM) in the prevention of hypertrophic scarring. Methods In the present study, ADSC-CM was concentrated via the freeze-drying procedure. The efficacy of different dose groups (CM, CM5, CM10) was conducted on the proliferation, apoptosis, and α-smooth muscle actin (α-SMA) expression of human keloid fibroblasts (HKFs) in vitro. Incorporation of adipose-derived stem cell concentrated conditioned medium (ADSCC-CM) into polysaccharide hydrogel was investigated in rabbit ear, in vivo. Haematoxylin-eosin (H&E) and Masson’s trichrome staining were performed for the evaluation of scar hyperplasia. Results We noted that ADSCC-CM could downregulate the α-SMA expression of HKFs in a dose-dependent manner. In the rabbit ear model, the scar hyperplasia in the medium-dose group (CM5) and high-dose group (CM10) was inhibited with reduced scar elevation index (SEI) under 4 months of observation. It is noteworthy that the union of CM5 and polysaccharide hydrogel (CM5+H) yielded the best preventive effect on scar hyperplasia. Briefly, melanin, height, vascularity, and pliability in the CM5+H group were better than those of the control group. Collagen was evenly distributed, and skin appendages could be regenerated. Conclusions Altogether, ADSCC-CM can downregulate the expression of α-SMA due to its anti-fibrosis effect and promote the rearrangement of collagen fibres, which is integral to scar precaution. The in situ cross bonding of ADSCC-CM and polysaccharide hydrogel could remarkably enhance the therapeutic outcomes in inhibiting scar proliferation. Hence, the alliance of ADSCC-CM and hydrogel may become a potential alternative in hypertrophic scar prophylaxis.

scholarly journals β-caryophyllene, an FDA-Approved Food Additive, Inhibits Methamphetamine-Taking and Methamphetamine-Seeking Behaviors Possibly via CB2 and Non-CB2 Receptor Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiang-Hu He ◽  
Ewa Galaj ◽  
Guo-Hua Bi ◽  
Yi He ◽  
Briana Hempel ◽  
...  
Keyword(s):  
Fixed Ratio ◽  
Incentive Motivation ◽  
Brain Stimulation Reward ◽  
High Dose ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Cb2 Receptor ◽  
Self Administration ◽  
Cb2 Receptors

Recent research indicates that brain cannabinoid CB2 receptors are involved in drug reward and addiction. However, it is unclear whether β-caryophyllene (BCP), a natural product with a CB2 receptor agonist profile, has therapeutic effects on methamphetamine (METH) abuse and dependence. In this study, we used animal models of self-administration, electrical brain-stimulation reward (BSR) and in vivo microdialysis to explore the effects of BCP on METH-taking and METH-seeking behavior. We found that systemic administration of BCP dose-dependently inhibited METH self-administration under both fixed-ratio and progressive-ratio reinforcement schedules in rats, indicating that BCP reduces METH reward, METH intake, and incentive motivation to seek and take METH. The attenuating effects of BCP were partially blocked by AM 630, a selective CB2 receptor antagonist. Genetic deletion of CB2 receptors in CB2-knockout (CB2-KO) mice also blocked low dose BCP-induced reduction in METH self-administration, suggesting possible involvement of a CB2 receptor mechanism. However, at high doses, BCP produced a reduction in METH self-administration in CB2-KO mice in a manner similar as in WT mice, suggesting that non-CB2 receptor mechanisms underlie high dose BCP-produced effects. In addition, BCP dose-dependently attenuated METH-enhanced electrical BSR and inhibited METH-primed and cue-induced reinstatement of drug-seeking in rats. In vivo microdialysis assays indicated that BCP alone did not produce a significant reduction in extracellular dopamine (DA) in the nucleus accumbens (NAc), while BCP pretreatment significantly reduced METH-induced increases in extracellular NAc DA in a dose-dependent manner, suggesting a DA-dependent mechanism involved in BCP action. Together, the present findings suggest that BCP might be a promising therapeutic candidate for the treatment of METH use disorder.

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