Acta Scientific Pharmacology

Research Article Volume 2 Issue 11

Evaluation of Anti-Inflammatory Effect of Combination Therapy of Silymarin Nanomicelles plus Berberine Nanomicelles in LPS-induced Depressive-like Behavior in Mice

Aysan Hasanitabar1, Marjan Fatholahi1, Ali Bitaraf2, Seyed Mahdi Rezayat1,3 and Seyyedeh Elaheh Mousavi1*

1Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
2School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
3Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

*Corresponding Author: Seyyedeh Elaheh Mousavi, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Received: July 08, 2021; Published: November 25, 2021


Depression is one of the most common mental illnesses globally, and unfortunately, current medications as a treatment, in this case, have a wide range of side effects. Therefore, finding new drugs is a valuable step in the treatment of depressive disorders. Berberine and Silymarin have many biological therapeutic properties like antioxidant, anti-inflammatory, and anti-cancer, while their bioavailability is not strong.

In order to increase the effectiveness and improve the bioavailability of drugs, new tools like nano micelles are suggested. Therefore, we aimed to investigate the effect of Berberine and Silymarin nanomicelles (NB+ NS) on the model of depression induced by Lipopolysaccharides (LPS) in mice.

LPS (1 mg/kg, i.p.) was injected to induce depression-like behavior, then, 24 h later, the treatment began, and behavioral tests like forced swimming test (FST), open field test (OFT), and tail suspension test (TST) were carried out. Also, the brain level of Tumor Necrosis Factor- α (TNF-α) and Interleukin-1 Beta (IL-1ß) were measured as well. In this study, the mice were divided into different groups including, control, LPS, Nanomicelle, Fluoxetine, Berberine, Silymarin, and NB 5+ NS 25.

All data were analyzed by Graph pad prism (version 5), and SPSS (P < 0.05 was considered significant).

This study showed that FST immobility time, TST immobilization time, brain levels of TNF-α and IL-1ß significantly decreased in NS 25+ NB 5 and fluoxetine groups compared to LPS and control groups (P < 0.05).

Keywords: Nanomicelles; Silymarin; Berberin; LPS; Depression


  1. Nestler EJ., et al. “Neurobiology of Depression”. Neuron 1 (2002): 13-25.
  2. Millan MJ. “Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application”. Pharmacology and Therapeutics2 (2006): 135-370.
  3. Malhi GS and Mann JJ. “Depression”. The Lancet10161 (2018): 2299-2312.
  4. Widner B., et al. “Neopterin production, tryptophan degradation, and mental depression—What is the link?” Brain, Behavior, and Immunity5 (2002): 590-595.
  5. Cipriani A., et al. “Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis”. The Lancet10128 (2018): 1357-1366.
  6. Takikawa O., et al. “Interferon-Gamma-Dependent/Independent Expression of Indoleamine 2,3-Dioxygenase”. In: Huether G, Kochen W, Simat TJ, Steinhart H, editors. Tryptophan, Serotonin, and Melatonin: Basic Aspects and Applications. Boston, MA: Springer US; (1999): 553-557.
  7. Fujigaki H., et al. “The signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3-dioxygenase by lipopolysaccharide: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways, and synergistic effect of several proinflammatory cytokines”. Journal of Biochemistry4 (2006): 655-662.
  8. Baghai TC., et al. “Drug treatment of depression in the 2000s: an overview of achievements in the last 10 years and future possibilities”. The World Journal of Biological Psychiatry4 (2006): 198-222.
  9. Kumar A., et al. “Current knowledge and pharmacological profile of berberine: An update”. European Journal of Pharmacology 761 (2015): 288-297.
  10. Kulkarni SK and Dhir A. “On the mechanism of antidepressant-like action of berberine chloride”. European Journal of Pharmacology1 (2008): 163-172.
  11. Chatuphonprasert W., et al. “Suppression of beta-naphthoflavone induced CYP1A expression and lipid-peroxidation by berberine”. Fitoterapia6 (2011): 889-895.
  12. Cai Z., et al. “Role of berberine in Alzheimer's disease”. Neuropsychiatric Disease and Treatment 12 (2016): 2509-2520.
  13. Zhang Z., et al. “Solid dispersion of berberine–phospholipid complex/TPGS 1000/SiO2: preparation, characterization and in vivo studies”. International Journal of Pharmaceutics1 (2014): 306-316.
  14. Wen-zhuan Ma., et al. “Preparation characterization and antitumor activity in vitro of berberine hydrochloride polymeric micelles”. China Journal of Chinese Materia Medica 40 (2015): 1001-5302.
  15. Zahmatkeshan M., et al. “Improved drug delivery and therapeutic efficacy of PEgylated liposomal doxorubicin by targeting anti-HER2 peptide in murine breast tumor model”. European Journal of Pharmaceutical Sciences 86 (2016): 125-135.
  16. Wang T., et al. “Preparation of an anhydrous reverse micelle delivery system to enhance oral bioavailability and anti-diabetic efficacy of berberine”. European Journal of Pharmaceutical Sciences1 (2011): 127-135.
  17. Wang M-J., et al. “Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation”. European Journal of Neuroscience11 (2002): 2103-2112.
  18. Dixit N., et al. “Silymarin: A review of pharmacological aspects and bioavailability enhancement approaches”. Indian Journal of Pharmacology4 (2007): 172-179.
  19. Thakare VN., et al. “Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice”. Journal of Psychopharmacology2 (2017): 223-235.
  20. Neha Jaggi AS and Singh N. “Silymarin and Its Role in Chronic Diseases”. In: Gupta SC, Prasad S, Aggarwal BB, editors. Drug Discovery from Mother Nature. Cham: Springer International Publishing (2016): 25-44.
  21. Priya LB., et al. “Chapter 21 - Phytonanoconjugates in oral medicine”. In: Andronescu E, Grumezescu AM, editors. Nanostructures for Oral Medicine: Elsevier (2017): 639-668.
  22. Cai CX., et al. “Chapter 29 - Nutritional and Dietary Interventions for Nonalcoholic Fatty Liver Disease”. In: Watson RR, Preedy VR, editors. Dietary Interventions in Liver Disease: Academic Press (2019): 357-72.
  23. Bijak M. “Flavonolignans - compounds not only for liver treatment”. Polskiego Towarzystwa Lekarskiego 42 (2017): 34-37.
  24. El-Elimat T., et al. “Silymarin Prevents Memory Impairments, Anxiety, and Depressive-Like Symptoms in a Rat Model of Post-Traumatic Stress Disorder”. Planta Medica1 (2019): 32-40.
  25. Junghanns JU and Müller RH. “Nanocrystal technology, drug delivery and clinical applications”. International Journal of Nanomedicine3 (2008): 295-309.
  26. Kakran M. “Fabrication of Nanoparticles of Silymarin, Hesperetin and Glibenclamide by Evaporative Precipitation of Nanosuspension for Fast Dissolution”. Pharmaceutica Analytica Acta 06 (2014).
  27. Ahmad U., et al. “Silymarin nanoemulsion against human hepatocellular carcinoma: development and optimization”. Artificial Cells, Nanomedicine, and Biotechnology2 (2018): 231-241.
  28. Yousefdoost S., et al. “Evaluation of Nano and Microcapsules of Silymarin in Simulated Gastrointestinal Conditions for Animal Target Delivery”. Iranian Journal of Applied Animal Science2 (2019): 247-255.
  29. Kosari-Nasab M., et al. “Anxiolytic- and antidepressant-like effects of Silymarin compared to diazepam and fluoxetine in a mouse model of mild traumatic brain injury”. Toxicology and Applied Pharmacology 338 (2018): 159-173.
  30. Del Grande da Silva G., et al. “Pro-inflammatory cytokines and psychotherapy in depression: Results from a randomized clinical trial”. Journal of Psychiatric Research 75 (2016): 57-64.
  31. Miller AH and Raison CL. “The role of inflammation in depression: from evolutionary imperative to modern treatment target”. Nature Reviews Immunology1 (2016): 22-34.
  32. Amitai M., et al. “The Relationship Between Plasma Cytokine Levels and Response to Selective Serotonin Reuptake Inhibitor Treatment in Children and Adolescents with Depression and/or Anxiety Disorders”. Journal of Child and Adolescent Psychopharmacology 8 (2016): 727-732.
  33. Al-Drees A and Khalil MS. “Histological and immunohistochemical effects of L-arginine and silymarin on TNBS-induced inflammatory bowel disease in rats”. Histology and Histopathology11 (2016): 1699-5848.
  34. Khoshnoodi M., et al. “Possible involvement of nitric oxide in antidepressant-like effect of silymarin in male mice”. Pharmaceutical Biology5 (2015): 739-745.
  35. Thakare VN., et al. “Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus”. Pharmacological Reports5 (2016): 1020-1027.
  36. Peng W-H., et al. “Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice”. Life Sciences11 (2007): 933-938.
  37. Bryant Sg., et al. “Current concepts in clinical therapeutics: major affective disorders, Part 1”. (1986): 0278-2677.
  38. Javed S., et al. “Reassessing bioavailability of silymarin”. Alternative Medicine Review (2011): 1089-5159.
  39. Shi J., et al. “Nanotechnology in Drug Delivery and Tissue Engineering: From Discovery to Applications”. Nano Letters9 (2010): 3223-3230.
  40. Simões SMN., et al. “Polymeric micelles for oral drug administration enabling locoregional and systemic treatments”. Expert Opinion on Drug Delivery 2 (2015): 297-318.
  41. Azadi R., et al. “Anti-inflammatory Efficacy of Berberine Nanomicelle for Improvement of Cerebral Ischemia: Formulation, Characterization and Evaluation in Bilateral Common Carotid Artery Occlusion Rat Model”. BMC Pharmacology and Toxicology (2020).
  42. Posternak MA., et al. “Is there a delay in the antidepressant effect? A meta-analysis”. The Journal of Clinical Psychiatry (2005): 0160-6689.
  43. Mousavi SE., et al. “Licofelone Attenuates LPS-induced Depressive-like Behavior in Mice: A Possible Role for Nitric Oxide”. Journal of Pharmacy and Pharmaceutical Sciences 1 (2018): 184-194.
  44. Pishva SP., et al. “The effect of berberine nanomicelles on hepatic cirrhosis in bile duct-ligated rats”. Nanomedicine Journal4 (2018): 199-209.


Citation: Seyyedeh Elaheh Mousavi., et al. “Evaluation of Anti-Inflammatory Effect of Combination Therapy of Silymarin Nanomicelles plus Berberine Nanomicelles in LPS-induced Depressive-like Behavior in Mice".Acta Scientific Pharmacology 2.12 (2021): 03-13.


Copyright: © 2020 Seyyedeh Elaheh Mousavi., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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