Skip to content
2000
Volume 22, Issue 6
  • ISSN: 1570-1638
  • E-ISSN: 1875-6220

Abstract

Introduction

Cannabigerol (CBG), being one of the non-psychotropic phyto-cannabinoid, has been labelled and recognized to be antioxidant and neuroprotective; it may conceivably hold depression-relieving activity. Consequently, the objective of the present research procedure was to explore the depression-alleviating competence of cannabigerol in both stressed and unstressed mice using computational/ modelling, followed by analysis.

Methods

Target genes for Major Depressive Disorder (MDD) were identified using GeneCards and Swiss Target Prediction, with common targets screened Venny software. STRING database analysis established protein-protein interactions (PPI), identifying CNR2 (CB2 receptor) as a key target. Molecular docking of CBG with CB2 (PDB ID: 8GUR) showed strong binding, prompting evaluation. ADME profiling Schrödinger Maestro v10.5 confirmed CBG’s high oral absorption and favorable pharmacokinetics. Male Swiss albino mice underwent chronic unpredictable mild stress (CUMS) for three successive weeks, with CBG (10, 20, 40 mg/kg) and imipramine (15 mg/kg) administered and various behavioral and biochemical parameters being analyzed.

Results and Discussion

Cannabigerol demonstrated maximum oral absorption in ADME predictions using Schrödinger's Maestro (v10.5). Wayne diagram illustrated MDD-related targets, with CB2 (CNR2) rankings in top targets, based on SwissADME and Venny software analysis. Docking analysis revealed a high binding affinity (-10.53) for CB2, outperforming cannabidiol (-9.56) and comparable to Δ9-THC (-10.11). During evaluation, CBG (40 mg/kg) and Imipramine 15 mg/kg significantly reduced CUMS-induced exalted plasma corticosterone, nitrite quantities, and monoamine oxidase-A action in the brain of stressed mice. Additionally, both treatments substantially reversed the unpredictable chronic stress-induced decline in catalase action, demonstrating CBG’s possible potential in alleviating depression-like symptoms in mice.

Conclusion

Cannabigerol has shown significant depressive alleviating potential in mice exposed to chronic and unpredictable stress regimes, possibly interaction with cannabinoid receptors as indicated by modelling, which has been validated by our findings of the protocol.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cddt/10.2174/0115701638363093250324035540
2025-05-05
2025-10-19

  • From This Site

    /content/journals/cddt/10.2174/0115701638363093250324035540
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. WHO Fact sheet2023Available from: https://www.who.int/news-room/fact-sheets/detail/depression
  2. GlynL. Diagnostic and Statistical Manual of Mental Disorders.4th edWashington, DCAmerican Psychiatric Association19941610.1017/S0033291700035765
     [Google Scholar]
  3. YadavR. SharmaA. BhutaniR. Non-conventional pathophysiology targets for new treatment regimes of depression: A comprehensive review.Afr J Bio Sci20246935138110.33472/AFJBS.6.9.2024.351‑381
     [Google Scholar]
  4. SharmaA. KapoorG. KumarS. BhutaniR. SharmaD. ChettriS. Evaluation of medication/drug use rationale and impediments due to influencing perception of self-medication.J. Pharm. Negat. Results20221372329233610.47750/pnr.2022.13.S07.318
     [Google Scholar]
  5. ManjiH.K. DrevetsW.C. CharneyD.S. The cellular neurobiology of depression.Nat. Med.20017554154710.1038/8786511329053
     [Google Scholar]
  6. LeonardB. MaesM. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression.Neurosci. Biobehav. Rev.201236276478510.1016/j.neubiorev.2011.12.00522197082
     [Google Scholar]
  7. ParianteC.M. LightmanS.L. The HPA axis in major depression: Classical theories and new developments.Trends Neurosci.200831946446810.1016/j.tins.2008.06.00618675469
     [Google Scholar]
  8. DelgadoP. MorenoF. Antidepressants and the brain.Int. Clin. Psychopharmacol.199914Suppl.S9S1610.1097/00004850‑199905001‑0000310468323
     [Google Scholar]
  9. ChenY. JiangW. ChenY. Protective effect of betulinic acid for treating unpredictable chronic mild stress-induced depression in mice by inhibiting brain RIP 140 activation.Int. J. Clin. Exp. Med.201710121649216498
     [Google Scholar]
  10. ChangM. ZhangL. DaiH. SunL. Genistein acts as antidepressant agent against chronic mild stress‐induced depression model of rats through augmentation of brain‐derived neurotrophic factor.Brain Behav.2021118e230010.1002/brb3.230034333865
     [Google Scholar]
  11. ChenL. WangX. ZhangY. Daidzein alleviates hypothalamic-pituitary-adrenal axis hyperactivity, ameliorates depression-like behavior, and partly rectifies circulating cytokine imbalance in two rodent models of depression.Front. Behav. Neurosci.20211567186410.3389/fnbeh.2021.67186434733143
     [Google Scholar]
  12. JiangX. LiuJ. LinQ. Proanthocyanidin prevents lipopolysaccharide-induced depressive-like behavior in mice via neuroinflammatory pathway.Brain Res. Bull.2017135404610.1016/j.brainresbull.2017.09.01028941603
     [Google Scholar]
  13. PawarS. ShindeS. KhapareE. BacchavR. Evaluation of sinapic acid on STZ-induced depression in diabetic wistar rats.Ind J Pharma Educ Res20235741104111110.5530/ijper.57.4.133
     [Google Scholar]
  14. LeeS. KimH.B. HwangE.S. Antidepressant-like effects of p-coumaric acid on LPS-induced depressive and inflammatory changes in rats.Exp. Neurobiol.201827318919910.5607/en.2018.27.3.18930022870
     [Google Scholar]
  15. PiccinelliA.C. SantosJ.A. KonkiewitzE.C. Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model.Nutr. Neurosci.201518521722410.1179/1476830514Y.000000011924661285
     [Google Scholar]
  16. DhingraD. BansalS. Antidepressant-like activity of plumbagin in unstressed and stressed mice.Pharmacol. Rep.20156751024103210.1016/j.pharep.2015.03.00126398399
     [Google Scholar]
  17. ShenM. YangY. WuY. L‐theanine ameliorate depressive‐like behavior in a chronic unpredictable mild stress rat model via modulating the monoamine levels in limbic–cortical–striatal–pallidal–thalamic‐circuit related brain regions.Phytother. Res.201933241242110.1002/ptr.623730474152
     [Google Scholar]
  18. LiR. WangX. QinT. QuR. MaS. Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1β production and NLRP3 inflammasome activation in the rat brain.Behav. Brain Res.201629631832510.1016/j.bbr.2015.09.03126416673
     [Google Scholar]
  19. VieiraG. CavalliJ. GonçalvesE.C.D. Antidepressant-like effect of terpineol in an inflammatory model of depression: Involvement of the cannabinoid system and d2 dopamine receptor.Biomolecules202010579210.3390/biom1005079232443870
     [Google Scholar]
  20. SharmaA. DhingraD. DuttR. Syringic acid reversed depression-resembling behavior induced by chronic unpredictable mild stress paradigm in mice.Int. J. Pharm. Sci. Drug Res.202113665166010.25004/IJPSDR.2021.130608
     [Google Scholar]
  21. FilhoC.B. JesseC.R. DonatoF. Chronic unpredictable mild stress decreases BDNF and NGF levels and Na+,K+-ATPase activity in the hippocampus and prefrontal cortex of mice: Antidepressant effect of chrysin.Neuroscience201528936738010.1016/j.neuroscience.2014.12.04825592430
     [Google Scholar]
  22. SharmaA. DhingraD. BhutaniR. NayakA. GargA. Depression-reminiscent behavior induced by chronic unpredictable mild stress paradigm in mice substantially abrogated by diosmin.Curr. Psychiatry Res. Rev.202420325126910.2174/0126660822261988231127072951
     [Google Scholar]
  23. CalapaiF. CardiaL. EspositoE. Pharmacological aspects and biological effects of cannabigerol and its synthetic derivatives.Evid. Based Complement. Alternat. Med.2022202211410.1155/2022/333651636397993
     [Google Scholar]
  24. de MeijerE.P.M. BagattaM. CarboniA. The inheritance of chemical phenotype in Cannabis sativa L.Genetics2003163133534610.1093/genetics/163.1.33512586720
     [Google Scholar]
  25. PollastroF. De PetrocellisL. Schiano-MorielloA. Amorfrutin-type phytocannabinoids from Helichrysum umbraculigerum.Fitoterapia2017123131710.1016/j.fitote.2017.09.01028941742
     [Google Scholar]
  26. AnokwuruC.P. MakoloF.L. SandasiM. Cannabigerol: A bibliometric overview and review of research on an important phytocannabinoid.Phytochem. Rev.20222151523154710.1007/s11101‑021‑09794‑w
     [Google Scholar]
  27. ChaudharyS Garima1K KumarCV Integrating network pharmacology and molecular docking techniques to uncover the repurposing mechanism of budipine for hypertensive disease treatment.Asi J Pharma Res Heal Care2024161505710.4103/ajprhc.ajprhc_135_23
     [Google Scholar]
  28. MuthuramalingamP. JeyasriR. ValliammaiA. Global multi-omics and systems pharmacological strategy unravel the multi-targeted therapeutic potential of natural bioactive molecules against COVID-19: An in silico approach.Genomics202011264486450410.1016/j.ygeno.2020.08.00332771622
     [Google Scholar]
  29. ZhaoL. ZhangH. LiN. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula.J. Ethnopharmacol.2023309116306610.1016/j.jep.2023.11630636858276
     [Google Scholar]
  30. LiX. ChangH. BoumaJ. Structural basis of selective cannabinoid CB2 receptor activation.Nat. Commun.2023141144710.1038/s41467‑023‑37112‑936922494
     [Google Scholar]
  31. VennyJ.C.O. An interactive tool for comparing lists with Venn’s diagrams.2007Available from: [https://bioinfogp.cnb.csic.es/tools/venny/index.html
    [Google Scholar]
  32. SzklarczykD. GableA.L. LyonD. STRING v11: Protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets.Nucleic Acids Res.201947D1D607D61310.1093/nar/gky113130476243
     [Google Scholar]
  33. PanneerselvamT. SivakumarV. ArumugamS. SelvarajK. IndhumathyM. Design, Network analysis and in silico modeling of biologically significant 4-(substituted benzyl)-2-amino-6-hydroxypyrimidine-5-carboxamide nanoparticles.Drug Res. (Stuttg.)201767528930110.1055/s‑0042‑12451528268236
     [Google Scholar]
  34. BhutaniR. PathakD.P. KapoorG. HusainA. IqbalM.A. Novel hybrids of benzothiazole-1,3,4-oxadiazole-4-thiazolidinone: Synthesis, in silico ADME study, molecular docking and in vivo anti-diabetic assessment.Bioorg. Chem.20198361910.1016/j.bioorg.2018.10.02530339863
     [Google Scholar]
  35. BhutaniR. PathakD.P. KapoorG. HusainA. KantR. IqbalM.A. Synthesis, molecular modelling studies and ADME prediction of benzothiazole clubbed oxadiazole-Mannich bases, and evaluation of their anti-diabetic activity through in vivo model.Bioorg. Chem.20187761510.1016/j.bioorg.2017.12.03729316509
     [Google Scholar]
  36. LiW. LiQ.J. AnS.C. Preventive effect of estrogen on depression-like behavior induced by chronic restraint stress.Neurosci. Bull.201026214014610.1007/s12264‑010‑0609‑920332819
     [Google Scholar]
  37. Estrada-CamarenaE. Fernández-GuastiA. López-RubalcavaC. Antidepressant-like effect of different estrogenic compounds in the forced swimming test.Neuropsychopharmacology200328583083810.1038/sj.npp.130009712637949
     [Google Scholar]
  38. BrierleyD.I. SamuelsJ. DuncanM. WhalleyB.J. WilliamsC.M. Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats.Psychopharmacology (Berl.)201623319-203603361310.1007/s00213‑016‑4397‑427503475
     [Google Scholar]
  39. El-AlfyA.T. IveyK. RobinsonK. Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L.Pharmacol. Biochem. Behav.201095443444210.1016/j.pbb.2010.03.00420332000
     [Google Scholar]
  40. MaoQ.Q. IpS.P. KoK.M. TsaiS.H. CheC.T. Peony glycosides produce antidepressant-like action in mice exposed to chronic unpredictable mild stress: Effects on hypothalamic-pituitary-adrenal function and brain-derived neurotrophic factor.Prog. Neuropsychopharmacol. Biol. Psychiatry20093371211121610.1016/j.pnpbp.2009.07.00219596036
     [Google Scholar]
  41. AntoniukS. BijataM. PonimaskinE. WlodarczykJ. Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability.Neurosci. Biobehav. Rev.20199910111610.1016/j.neubiorev.2018.12.00230529362
     [Google Scholar]
  42. SteruL. ChermatR. ThierryB. SimonP. The tail suspension test: A new method for screening antidepressants in mice.Psychopharmacology (Berl.)198585336737010.1007/BF004282033923523
     [Google Scholar]
  43. BartosJ. PesezM. Colorimetric and fluorimetric analysis of steroids. london.Academic Press197616
     [Google Scholar]
  44. GreenL.C. WagnerD.A. GlogowskiJ. SkipperP.L. WishnokJ.S. TannenbaumS.R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids.Anal. Biochem.1982126113113810.1016/0003‑2697(82)90118‑X7181105
     [Google Scholar]
  45. SchurrA. LivneA. Differential inhibition of mitochondrial monoamine oxidase from brain by hashish components.Biochem. Pharmacol.197625101201120310.1016/0006‑2952(76)90369‑5938542
     [Google Scholar]
  46. CharlesM. McEwanJ. MAO activity in rabbit serum.In: Tabor H, Tabor CW, Eds. Methods in enzymology. New York, London: Academic Press1977176928
     [Google Scholar]
  47. HenryRJDC WinkelmanJW Clinical chemistry principles and techniques.New York, London: Harper and Row19742968
     [Google Scholar]
  48. AebiH. Catalase in vitro .Methods Enzymol1984105121610.1016/S0076‑6879(84)05016‑36727660
     [Google Scholar]
  49. WillnerP. Animal models as simulations of depression.Trends Pharmacol. Sci.199112413113610.1016/0165‑6147(91)90529‑22063478
     [Google Scholar]
  50. WillnerP. Validity, reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation.Psychopharmacology (Berl.)1997134431932910.1007/s0021300504569452163
     [Google Scholar]
  51. SousaN. CerqueiraJ.J. AlmeidaO.F.X. Corticosteroid receptors and neuroplasticity.Brain Res. Brain Res. Rev.200857256157010.1016/j.brainresrev.2007.06.00717692926
     [Google Scholar]
  52. MasonB.L. ParianteC.M. The effects of antidepressants on the hypothalamic-pituitary-adrenal axis.Drug News Perspect.2006191060360810.1358/dnp.2006.19.10.106800717299602
     [Google Scholar]
  53. RéusG.Z. StringariR.B. de SouzaB. Harmine and imipramine promote antioxidant activities in prefrontal cortex and hippocampus.Oxid. Med. Cell. Longev.20103532533110.4161/oxim.3.5.1310921150338
     [Google Scholar]
  54. MaesM. GaleckiP. ChangY.S. BerkM. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.Prog. Neuropsychopharmacol. Biol. Psychiatry201135367669210.1016/j.pnpbp.2010.05.00420471444
     [Google Scholar]
  55. SiloteG.P. SartimA. SalesA. Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms.J. Chem. Neuroanat.20199810411610.1016/j.jchemneu.2019.04.00631039391
     [Google Scholar]
  56. Martinez NayaN. KellyJ. CornaG. GolinoM. AbbateA. ToldoS. Molecular and cellular mechanisms of action of cannabidiol.Molecules20232816598010.3390/molecules2816598037630232
     [Google Scholar]
  57. LaarisN. GoodC.H. LupicaC.R. Δ9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus.Neuropharmacology2010591-212112710.1016/j.neuropharm.2010.04.01320417220
     [Google Scholar]
  58. MendigurenA. AostriE. RodillaI. PujanaI. NoskovaE. PinedaJ. Cannabigerol modulates α2-adrenoceptor and 5-HT1A receptor-mediated electrophysiological effects on dorsal raphe nucleus and locus coeruleus neurons and anxiety behavior in rat.Front. Pharmacol.202314118301910.3389/fphar.2023.118301937305529
     [Google Scholar]
  59. ChouhanN.K. AnanthabhatS.K. VaidyaS. SrihariP. A scalable process for the synthesis of key intermediates novoldiamine & hydroxynovaldiamine and their utility in chloroquine, hydroxychloroquine and mepacrine synthesis.Synth. Commun.20225271004101110.1080/00397911.2022.2061358
     [Google Scholar]
  60. LiX. Madhukar KudkeA. Joseph NepveuxV.F. XuY. Network-based pharmacology study reveals protein targets for medical benefits and harms of cannabinoids in humans.Appl. Sci. (Basel)2022124220510.3390/app12042205
     [Google Scholar]
  61. CalapaiF. CardiaL. EspositoE. Pharmacological aspects and biological effects of cannabigerol and its synthetic derivatives.Evid. Based Comp. Alternat. Med.2022202211410.1155/2022/333651636397993
     [Google Scholar]
  62. NavarroG. VaraniK. Reyes-ResinaI. Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1–CB2 heteroreceptor complexes.Front. Pharmacol.2018963210.3389/fphar.2018.0063229977202
     [Google Scholar]
  63. NavarroG. VaraniK. LilloA. Pharmacological data of cannabidiol- and cannabigerol-type phytocannabinoids acting on cannabinoid CB1, CB2 and CB1/CB2 heteromer receptors.Pharmacol. Res.202015910494010.1016/j.phrs.2020.10494032470563
     [Google Scholar]
  64. JastrząbA. Jarocka-KarpowiczI. SkrzydlewskaE. The origin and biomedical relevance of cannabigerol.Int. J. Mol. Sci.20222314792910.3390/ijms2314792935887277
     [Google Scholar]
  65. GugliandoloA. PollastroF. GrassiG. BramantiP. MazzonE. In vitro model of neuroinflammation: Efficacy of cannabigerol, a non-psychoactive cannabinoid.Int. J. Mol. Sci.2018197199210.3390/ijms1907199229986533
     [Google Scholar]
  66. WillnerP. TowellA. SampsonD. SophokleousS. MuscatR. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant.Psychopharmacology (Berl.)198793335836410.1007/BF001872573124165
     [Google Scholar]
  67. SalhaM. AdenusiH. DupuisJ.H. Bioactivity of the cannabigerol cannabinoid and its analogues – the role of 3-dimensional conformation.Org. Biomol. Chem.202321224683469310.1039/D3OB00383C37222259
     [Google Scholar]
  68. CuttlerC. StueberA. CooperZ.D. RussoE. Acute effects of cannabigerol on anxiety, stress, and mood: A double-blind, placebo-controlled, crossover, field trial.Sci. Rep.20241411616310.1038/s41598‑024‑66879‑039003387
     [Google Scholar]
  69. PerezE. FernandezJ.R. FitzgeraldC. RouzardK. TamuraM. SavileC. In vitro and clinical evaluation of cannabigerol (CBG) produced via yeast biosynthesis: A cannabinoid with a broad range of anti-inflammatory and skin health-boosting properties.Molecules202227249110.3390/molecules2702049135056807
     [Google Scholar]
/content/journals/cddt/10.2174/0115701638363093250324035540
Loading
Cannabigerol and Cannabinoid Receptors in Major Depressive Disorder: Network Pharmacology, Molecular Docking, and In-vivo Analysis
Current Drug Discovery Technologies 22, E15701638363093 (2025); https://doi.org/10.2174/0115701638363093250324035540
/content/journals/cddt/10.2174/0115701638363093250324035540
/content/journals/cddt/10.2174/0115701638363093250324035540
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): antidepressant; cannabigerol; Depression; molecular docking; network pharmacology; unpredictable stress

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test