The antidepressant-like effect of NevGro® Forte in chronic unpredictable mild stress (CUMS) model of depression in rats


  • Zakirah Zainal Abidin Department of Diagnostic and Allied Health Science, Faculty of Health and Life Sciences, Management and Science University, 40100 Shah Alam, Selangor, Malaysia
  • Juwita Junit Department of Diagnostic and Allied Health Science, Faculty of Health and Life Sciences, Management and Science University, 40100 Shah Alam, Selangor, Malaysia
  • Muhammad Danial Che Ramli Department of Diagnostic and Allied Health Science, Faculty of Health and Life Sciences, Management and Science University, 40100 Shah Alam, Selangor, Malaysia
  • Syntyche Seow Ling Sing Ganofarm R&D Sdn Bhd, 01-01, Skypod Square, Persiaran Puchong Jaya Selatan, Bandar Puchong Jaya, 47100 Puchong, Selangor, Malaysia
  • Poh Guat Cheng Ganofarm R&D Sdn Bhd, 01-01, Skypod Square, Persiaran Puchong Jaya Selatan, Bandar Puchong Jaya, 47100 Puchong, Selangor, Malaysia
  • Zolkapli Eshak Department of Pharmacology and Chemistry, Faculty of Pharmacy, UiTM Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
  • Mohamad Anuar Ahad Centre for Drug Research, University Sains Malaysia, 11800 Gelugor Penang, Malaysia
  • Hussin Muhammad Toxicology and Pharmacology Unit, Herbal Medicine Research Centre, Institute of Medical Research, National Institutes of Health, 40170 Shah Alam, Selangor, Malaysia



Depression, NevGro® Forte , Antidepressant, Neurogenesis, Chronic Unpredictable Mild Stress (CUMS)


Depression is a leading cause of disability worldwide and it is a major contributor to the overall global burden of disease. Almost 320 million individuals globally are left untreated with depression and it has the highest prevalence. Although there are multiple conventional antidepressant types available, patients are still left untreated due to inadequate pharmacological effectiveness as well as the high rate of remissions, side effects, and patients’ non-compliance. Therefore, this study aims to determine the therapeutic effects of NevGro® Forte. The NevGro® Forte that contains a combination of three types of mushrooms, Lignosus rhinocerotis, Ganoderma lucidum and Hericium erinaceus, has been reported to have the therapeutic potential for alleviating depressive symptoms. Sixty Sprague Dawley rats induced to chronic unpredictable mild stress (CUMS) protocol were orally treated with NevGro® Forte daily for 4 weeks. Histological analysis was performed to probe the role of neurogenesis in mediating the therapeutic effect of NevGro® Forte. Fluoxetine (FLX) was orally administered to validate the neurogenesis-dependent mechanism of NevGro® Forte. The present study exhibited that 4 weeks of NevGro® Forte treatment ameliorated the depressive symptoms in CUMS rat model. There is a significant improvement in body weight, brain’s weight, and increased thickness of the pyramidal layer in the hippocampus following the treatment of NevGro® Forte. Scanning electron microscopy also revealed decreased degeneration characterised by flattened with less dense surface composition in the hippocampus. This research shows a positive outcome of using NevGro® Forte in ameliorating depressive symptoms.


Adebiyi, O., Adigun, K., Folarin, O., Olopade, J., & Olayemi, F. (2020). Administration of ethanolic extract of Erythrophleum ivorense (A Chev.) stem bark to male Wistar rats alters brain areas involved in motor coordination, behavior, and memory. Journal of Ethnopharmacology, 253, 112650.

Ahmad, M. F. (2018). Ganoderma lucidum: Persuasive biologically active constituents and their health endorsement. Biomedicine & Pharmacotherapy, 107, 507–519.

Alemi, F., Min, H., Yousefi, M., Becker, L. K., Hane, C. A., Nori, V. S., & Wojtusiak, J. (2021). Effectiveness of common antidepressants: a post market release study. EClinical Medicine, 41, 101171.

Ali, S., Abd El Wahab, M., Ayuob, N., & Suliaman, M. (2017). The antidepressant-like effect of Ocimum basilicum in an animal model of depression. Biotechnic & Histochemistry, 92(6), 390–401.

American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). American Psychiatric Publishing.

Ayuob, N. N., & Balgoon, M. J. (2018). Histological and molecular techniques utilized to investigate animal models of depression. An updated review. Microscopy Research and Technique, 81(10), 1143–1153.

Ba, D. M., Gao, X., Al-Shaar, L., Muscat, J. E., Chinchilli, V. M., Beelman, R. B., & Richie, J. P. (2021). Mushroom intake and depression: A population-based study using data from the US National Health and Nutrition Examination Survey (NHANES), 2005–2016. Journal of Affective Disorders, 294, 686–692.

Banasr, M., Dwyer, J. M., & Duman, R. S. (2011). Cell atrophy and loss in depression: reversal by antidepressant treatment. Current Opinion in Cell Biology, 23(6), 730–737.

Barch, D. M., Tillman, R., Kelly, D., Whalen, D., Gilbert, K., & Luby, J. L. (2019). Hippocampal volume and depression among young children. Psychiatry Research: Neuroimaging, 288, 21–28.

Benkert, O., Szegedi, A., & Kohnen, R. (2000). Mirtazapine compared with paroxetine in major depression. The Journal of Clinical Psychiatry, 61(9), 656–663.

Beurel, E., Toups, M., & Nemeroff, C. B. (2020). The bidirectional relationship of depression and inflammation: double trouble. Neuron, 107(2), 234–256.

Bremner, J. D., Narayan, M., Anderson, E. R., Staib, L. H., Miller, H. L., & Charney, D. S. (2000). Hippocampal volume reduction in major depression. American Journal of Psychiatry, 157(1), 115–118.

Burstein, O., & Doron, R. (2018). The unpredictable chronic mild stress protocol for inducing anhedonia in mice. Journal of Visualized Experiments, 140, e58184.

Cherubini, E., & Miles, R. (2015). The CA3 region of the hippocampus: how is it? What is it for? How does it do it? Frontiers in Cellular Neuroscience, 9, 19.

Chong, P. S., Fung, M. L., Wong, K. H., & Lim, L. W. (2019). Therapeutic potential of hericium erinaceus for depressive disorder. International Journal of Molecular Sciences, 21(1), 163.

Chong, P. S., Poon, C. H., Roy, J., Tsui, K. C., Lew, S. Y., Phang, M. W. L., Tan, R. J. Y., Cheng, P. G., Fung, M. L., Wong, K. H., & Lim, L. W. (2021). Neurogenesis-dependent antidepressant-like activity of Hericium erinaceus in an animal model of depression. Chinese Medicine, 16(1), 132.

Dhikav, V., & Anand, K. (2012). Hippocampus in health and disease: An overview. Annals of Indian Academy of Neurology, 15(4), 239.

Dudek, K. A., Dion‐Albert, L., Kaufmann, F. N., Tuck, E., Lebel, M., & Menard, C. (2019). Neurobiology of resilience in depression: immune and vascular insights from human and animal studies. European Journal of Neuroscience, 53(1), 183–221.

Frisbee, J. C., Brooks, S. D., Stanley, S. C., & D’Audiffret, A. C. (2015). An unpredictable chronic mild stress protocol for instigating depressive symptoms, behavioral changes and negative health outcomes in rodents. Journal of Visualized Experiments, 106, e53109.

Jonas, P., & Lisman, J. (2014). Structure, function, and plasticity of hippocampal dentate gyrus microcircuits. Frontiers in Neural Circuits, 8, 107.

Kim, Y. K., & Park, S. C. (2021). An alternative approach to future diagnostic standards for major depressive disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 105, 110133.

Kittimongkolsuk, P., Pattarachotanant, N., Chuchawankul, S., Wink, M., & Tencomnao, T. (2021). Neuroprotective effects of extracts from tiger milk mushroom Lignosus rhinocerus against glutamate-induced toxicity in HT22 hippocampal neuronal cells and neurodegenerative diseases in Caenorhabditis elegans. Biology, 10(1), 30.

Konttinen, H., van Strien, T., Männistö, S., Jousilahti, P., & Haukkala, A. (2019). Depression, emotional eating and long-term weight changes: a population-based prospective study. International Journal of Behavioral Nutrition and Physical Activity, 16(1), 28.

Lew, S. Y., Teoh, S. L., Lim, S. H., Lim, L. W., & Wong, K. H. (2020). Discovering the potentials of medicinal mushrooms in combating depression – A review. Mini-Reviews in Medicinal Chemistry, 20(15), 1518–1531.

Liu, C., Gu, J. Y., Han, J. H., Yan, F. L., Li, Y., Lv, T. T., Zhao, L. Q., Shao, Q. J., Feng, Y. Y., Zhang, X. Y., & Wang, C. H. (2017). Enriched environment combined with fluoxetine ameliorates depression-like behaviors and hippocampal SYP expression in a rat CUS model. Brain Research Bulletin, 135, 33–39.

Meng, P., Zhu, Q., Yang, H., Liu, D., Lin, X., Liu, J., Fan, J., Liu, X., Su, W., Liu, L., Wang, Y., & Cai, X. (2019). Leonurine promotes neurite outgrowth and neurotrophic activity by modulating the GR/SGK1 signaling pathway in cultured PC12 cells. NeuroReport, 30(4), 247–254.

Micheli, L., Ceccarelli, M., D’Andrea, G., & Tirone, F. (2018). Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise. Brain Research Bulletin, 143, 181–193.

Niida, R., Yamagata, B., Matsuda, H., Niida, A., Uechi, A., Kito, S., & Mimura, M. (2018). Regional brain volume reductions in major depressive disorder and bipolar disorder: An analysis by voxel‐based morphometry. International Journal of Geriatric Psychiatry, 34(1), 186–192.

Nolan, M., Roman, E., Nasa, A., Levins, K. J., O’Hanlon, E., O’Keane, V., & Willian Roddy, D. (2020). Hippocampal and amygdalar volume changes in major depressive disorder: A targeted review and focus on stress. Chronic Stress, 4, 247054702094455.

Park, L. T., & Zarate, C. A. (2019). Depression in the primary care setting. New England Journal of Medicine, 380(6), 559–568.

Patsalos, O., Keeler, J., Schmidt, U., Penninx, B. W. J. H., Young, A. H., & Himmerich, H. (2021). Diet, obesity, and depression: A systematic review. Journal of Personalized Medicine, 11(3), 176.

Planchez, B., Surget, A., & Belzung, C. (2019). Animal models of major depression: drawbacks and challenges. Journal of Neural Transmission, 126(11), 1383–1408.

Polesza k, E., Wośko, S., Sławińska, K., Wyska, E., Szopa, A., ŚWiąder, K., Wróbel, A., Szponar, J., Doboszewska, U., Wlaź, P., Wlaź, A., & Serefko, A. (2020). Influence of the endocannabinoid system on the antidepressant activity of bupropion and moclobemide in the behavioural tests in mice. Pharmacological Reports, 72(6), 1562–1572.

Qiao, H., An, S. C., Ren, W., & Ma, X. M. (2014). Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression. Behavioural Brain Research, 275, 191–200.

Rădulescu, I., Drăgoi, A., Trifu, S., & Cristea, M. (2021). Neuroplasticity and depression: Rewiring the brain’s networks through pharmacological therapy (Review). Experimental and Therapeutic Medicine, 22(4).

Ryu, S., Kim, H. G., Kim, J. Y., Kim, S. Y., & Cho, K. O. (2018). Hericium erinaceus extract reduces anxiety and depressive behaviors by promoting hippocampal neurogenesis in the adult mouse brain. Journal of Medicinal Food, 21(2), 174–180.

Santomauro, D. F., Mantilla Herrera, A. M., Shadid, J., Zheng, P., Ashbaugh, C., Pigott, D. M., Abbafati, C., Adolph, C., Amlag, J. O., Aravkin, A. Y., Bang-Jensen, B. L., Bertolacci, G. J., Bloom, S. S., Castellano, R., Castro, E., Chakrabarti, S., Chattopadhyay, J., Cogen, R. M., Collins, J. K., . . . Ferrari, A. J. (2021). Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. The Lancet, 398(10312), 1700–1712.

Scheggi, S., De Montis, M. G., & Gambarana, C. (2018). Making sense of rodent models of anhedonia. International Journal of Neuropsychopharmacology, 21(11), 1049–1065.

Tang, M., Huang, H., Li, S., Zhou, M., Liu, Z., Huang, R., Liao, W., Xie, P., & Zhou, J. (2019). Hippocampal proteomic changes of susceptibility and resilience to depression or anxiety in a rat model of chronic mild stress. Translational Psychiatry, 9(1), 260.

Umschweif, G., Greengard, P., & Sagi, Y. (2019). The dentate gyrus in depression. European Journal of Neuroscience, 53(1), 39–64.

Van Dijk, M. T., Cha, J., Semanek, D., Aw, N., Gameroff, M. J., Abraham, E., Wickramaratne, P. J., Weissman, M. M., Posner, J., & Talati, A. (2021). Altered dentate gyrus microstructure in individuals at high familial risk for depression predicts future symptoms. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 6(1), 50–58.

Vrany, E. A., Hawkins, M. A., Wu, W., & Stewart, J. C. (2018). Depressive symptoms and weight loss behaviors in U.S. adults. Eating Behaviors, 29, 107–113.

Vos, T., Lim, S. S., Abbafati, C., Abbas, K. M., Abbasi, M., Abbasifard, M., Abbasi-Kangevari, M., Abbastabar, H., Abd-Allah, F., Abdelalim, A., Abdollahi, M., Abdollahpour, I., Abolhassani, H., Aboyans, V., Abrams, E. M., Abreu, L. G., Abrigo, M. R. M., Abu-Raddad, L. J., Abushouk, A. I., . . . Murray, C. J. L. (2020). Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet, 396(10258), 1204–1222.

WHO. (2019). Depression. Retrieved October 21, 2023, from

WHO. (2022, March 2). COVID-19 pandemic triggers 25% increase in prevalence of anxiety and depression worldwide. Retrieved October 21, 2023, from

Wyska, E. (2019). Pharmacokinetic considerations for current state-of-the-art antidepressants. Expert Opinion on Drug Metabolism & Toxicology, 15(10), 831–847.

Zheng, R., Zhang, Y., Yang, Z., Han, S., & Cheng, J. (2021). Reduced brain gray matter volume in patients with first-episode major depressive disorder: A quantitative meta-analysis. Frontiers in Psychiatry, 12, 671348.




How to Cite

Zainal Abidin, Z., Junit, J., Che Ramli, M. D., Seow, S. L. S., Cheng, P. G., Eshak, Z., Ahad, M. A. and Muhammad, H. (2023) “The antidepressant-like effect of NevGro® Forte in chronic unpredictable mild stress (CUMS) model of depression in rats”, Neuroscience Research Notes, 6(4), pp. 261.1–261.16. doi: 10.31117/neuroscirn.v6i4.261.