Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitro
Due to the structural diversity and rapid prevalence of synthetic cannabinoids (SCs) in the market, the information linking the chemical structure of SCs to their toxicity remains scant, despite emerging in the 1970s. In the present study, we aimed to investigate the toxicity and underlying mechanis...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Ecotoxicology and Environmental Safety |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651324015768 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832590987108548608 |
|---|---|
| author | Fenghua Zhou Yan Shi Sujun Tan Xiaoli Wang Weicheng Yuan Shuqi Tao Ping Xiang Bin Cong Chunling Ma Di Wen |
| author_facet | Fenghua Zhou Yan Shi Sujun Tan Xiaoli Wang Weicheng Yuan Shuqi Tao Ping Xiang Bin Cong Chunling Ma Di Wen |
| author_sort | Fenghua Zhou |
| collection | DOAJ |
| description | Due to the structural diversity and rapid prevalence of synthetic cannabinoids (SCs) in the market, the information linking the chemical structure of SCs to their toxicity remains scant, despite emerging in the 1970s. In the present study, we aimed to investigate the toxicity and underlying mechanisms of indole SCs JWH-018 and JWH-019 in mice (C57BL/6, male, 6–8 weeks old), zebrafish (AB strain, male, 4–5 months old) and modified human embryonic kidney (HEK) 293 T cells, using behavioral, pharmacokinetic, pharmacological approaches, and molecular docking. JWH-018 induced time- and dose-dependent cannabinoid-like effects in mice (administration dosages: 0.02, 0.1, and 0.5 mg/kg, i.p.), and yielded dose-dependent anxiogenic effects and lower aggression behavior in zebrafish (administration dosages: 0.01, 0.05, and 0.25 µg/g, i.p.), unlike JWH-019. These effects were blocked by the selective cannabinoid receptor 1 (CB1R) antagonist AM251. JWH-018, but not JWH-019, activated the CB1R-dependent extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway in vivo and in vitro. Molecular docking identified essential residues PHE268, PHE170, and TRP279 within CB1R as pivotal contributors to enhancing receptor-ligand associations. While both drugs had a similar binding pattern with shared linker binding pockets in CB1R, there were still differences in their spatial conformation. These findings shed light on the molecular pharmacology and activation mechanism of SCs for CB1R and should guide further research into the mechanisms underlying their deleterious effects in humans. |
| format | Article |
| id | doaj-art-c31c45597e6c4f768ca3d7ddd1d8dbcc |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-c31c45597e6c4f768ca3d7ddd1d8dbcc2025-01-23T05:25:47ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01289117500Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitroFenghua Zhou0Yan Shi1Sujun Tan2Xiaoli Wang3Weicheng Yuan4Shuqi Tao5Ping Xiang6Bin Cong7Chunling Ma8Di Wen9College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR China; Clinical Pathology Department, Shandong Second Medical University, Shandong Province, Weifang, Shandong Province 261042, PR ChinaShanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Science Platform, Key Laboratory of Judicial Expertise, Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai 200063, PR ChinaCollege of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR ChinaCollege of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR ChinaCollege of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR ChinaClinical Pathology Department, Shandong Second Medical University, Shandong Province, Weifang, Shandong Province 261042, PR ChinaShanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Science Platform, Key Laboratory of Judicial Expertise, Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai 200063, PR ChinaCollege of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR ChinaCollege of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR China; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province 050017, PR China; Corresponding authors at: College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR China.College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR China; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province 050017, PR China; Corresponding authors at: College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR China.Due to the structural diversity and rapid prevalence of synthetic cannabinoids (SCs) in the market, the information linking the chemical structure of SCs to their toxicity remains scant, despite emerging in the 1970s. In the present study, we aimed to investigate the toxicity and underlying mechanisms of indole SCs JWH-018 and JWH-019 in mice (C57BL/6, male, 6–8 weeks old), zebrafish (AB strain, male, 4–5 months old) and modified human embryonic kidney (HEK) 293 T cells, using behavioral, pharmacokinetic, pharmacological approaches, and molecular docking. JWH-018 induced time- and dose-dependent cannabinoid-like effects in mice (administration dosages: 0.02, 0.1, and 0.5 mg/kg, i.p.), and yielded dose-dependent anxiogenic effects and lower aggression behavior in zebrafish (administration dosages: 0.01, 0.05, and 0.25 µg/g, i.p.), unlike JWH-019. These effects were blocked by the selective cannabinoid receptor 1 (CB1R) antagonist AM251. JWH-018, but not JWH-019, activated the CB1R-dependent extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway in vivo and in vitro. Molecular docking identified essential residues PHE268, PHE170, and TRP279 within CB1R as pivotal contributors to enhancing receptor-ligand associations. While both drugs had a similar binding pattern with shared linker binding pockets in CB1R, there were still differences in their spatial conformation. These findings shed light on the molecular pharmacology and activation mechanism of SCs for CB1R and should guide further research into the mechanisms underlying their deleterious effects in humans.http://www.sciencedirect.com/science/article/pii/S0147651324015768Synthetic cannabinoidsToxicityCannabinoids receptor 1ERK1/2Molecular docking |
| spellingShingle | Fenghua Zhou Yan Shi Sujun Tan Xiaoli Wang Weicheng Yuan Shuqi Tao Ping Xiang Bin Cong Chunling Ma Di Wen Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitro Ecotoxicology and Environmental Safety Synthetic cannabinoids Toxicity Cannabinoids receptor 1 ERK1/2 Molecular docking |
| title | Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitro |
| title_full | Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitro |
| title_fullStr | Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitro |
| title_full_unstemmed | Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitro |
| title_short | Unveiling the toxicity of JWH-018 and JWH-019: Insights from behavioral and molecular studies in vivo and vitro |
| title_sort | unveiling the toxicity of jwh 018 and jwh 019 insights from behavioral and molecular studies in vivo and vitro |
| topic | Synthetic cannabinoids Toxicity Cannabinoids receptor 1 ERK1/2 Molecular docking |
| url | http://www.sciencedirect.com/science/article/pii/S0147651324015768 |
| work_keys_str_mv | AT fenghuazhou unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT yanshi unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT sujuntan unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT xiaoliwang unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT weichengyuan unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT shuqitao unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT pingxiang unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT bincong unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT chunlingma unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro AT diwen unveilingthetoxicityofjwh018andjwh019insightsfrombehavioralandmolecularstudiesinvivoandvitro |