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Flavonoids & Neuro-Inflammation

Chronic inflammation, a culprit in multiple human physical conditions, is also shown to be involved in the pathophysiology of mental ill-health (Song & Kim, 2021).

Depression is a mental health issue affecting an increasingly large number of the global population.  Depression has a multi-faceted aetiology and multi-faceted impacts on an individual’s life. Depression robs sufferers of their quality of life, their engagement with their potential in the present and the future, often extending to impact the lives of those around them. It is an increasingly prolific concern globally, with the World Health Organisation listing it as a leading cause of disability affecting over 300 million individuals.

Brief Overview of Flavonoids

Flavonoids are hydroxylated polyphenols, produced by all plants, and widely available through the consumption vegetables, fruits, legumes and medicinal plants. They are responsible for the vivid colors found in many fruits and vegetables, serving various functions, including UV protection, plant signaling, and defense against pathogens. Flavonoids as a group can be further broken down by classification as shown in Figure 1.

Their role in the human body is multi-faceted and not limited to the modulation of inflammation however their anti-inflammatory mechanism is the focus here, as it pertains to depression. Via the shikimate pathway, flavonoids form part of the plant’s immune system. With the use of agrochemicals in modern agriculture, plants do not need to produce their own defence against pests and fungus, resulting in flavonoid deficient crops and a flavonoid deficient food supply, impacting the human body which has evolved to utilise this chemistry for health and well-being. Not all of the 6000+ flavonoids are able to navigate the blood brain barrier as this would depend on the molecular weight of the entity for transportation into the brain to exert an effect (Youdim et al, 2003).

Depression and Inflammatory Biomarkers

Proinflammatory cytokines, including interleukin-6 (IL-6), interleukin-1ß (IL-1 ß), C-reactive protein (CRP) and tumour necrosis factor-alpha (TNF-α) have been shown to be significantly higher in a subgroup of individuals with major depressive disorder compared with healthy subjects, highlighting a bidirectional link between depression and inflammation across multiple studies (Kiecolt-Glaser et al, 2015).

Neuroprotection and Maintenance of Mental Health

Flavonoids consumed regulary through supplementation and a nutritious diet high in organic fruits, vegetables and legumes have the potential as a neuro-protectant against depression and/or maintenance of mental health, even in individuals more likely to develop depression, such as those with previous trauma or chronic stress. Tan et al (2021) conducted a longitudinal study using data collected from 6404 participants of the Adventist Health Study-2. This sample was filtered from a cohort of approximately 96,000 participants who had previously completed an additional 50-page dietary questionnaire between from 2002-2006. Tan’s group comprehensively studied the rates of subsequent adult depression in those who had incurred adverse childhood experiences (ACEs) alongside their dietary flavonoid content into adulthood. After controlling for factors such as gender, level of education, ethnicity, lifestyle factors and caloric consumption, they confirmed several hypotheses, firstly that ACEs were a statistically reliable predictor of depression in adulthood; secondly that higher ACEs were a predictor of perceived stress leading to worse depressive symptoms; thirdly that a diet with a higher flavonoid content was negatively correlated with levels of perceived stress and depressive symptoms.


Voluntastrols contain a specific blend of secondary plant metabolites, including flavonoids. The phyto-actives in Voluntastrols are shown to modulate neuro-inflammation offering a novel and effective approach to mental health, neuro-protection and neurovascular network health.


Kiecolt-Glaser, J.K., Derry, H. M., & Fagundes, C. P. (2015). Inflammation: Depression Fans the Flames and Feasts on the Heat. The American Journal of Psychiatry, 172(11), 1075–1091. https://doi.org/10.1176/appi.ajp.2015.15020152

Maes, M., Bosmans, E., De Jongh, R., Kenis, G., Vandoolaeghe, E., & Neels, H. (1997). Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine9(11), 853–858. https://doi.org/10.1006/cyto.1997.0238

Ortiz-Andrade, R., Araujo-León, J. A., Sánchez-Recillas, A., Navarrete-Vazquez, G., González-Sánchez, A. A., Hidalgo-Figueroa, S., Alonso-Castro, Á. J., Aranda-González, I., Hernández-Núñez, E., Coral-Martínez, T. I., Sánchez-Salgado, J. C., Yáñez-Pérez, V., & Lucio-Garcia, M. A. (2020). Toxicological Screening of Four Bioactive Citroflavonoids: In Vitro, In Vivo, and In Silico Approaches. Molecules, 25(24), 5959. https://doi.org/10.3390/molecules25245959

 Pan, M.-S., Lai, C.-S., & Ho, C.-T. (2010). Anti-inflammatory activity of natural dietary flavonoids. Food & Function1(1), 15–31. https://doi.org/10.1039/c0fo00103a

 Raison, C. L., Capuron, L., & Miller, A. H. (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology27(1), 24–31. https://doi.org/10.1016/j.it.2005.11.006

 Song, J., & Kim, Y. (2021). Animal models for the study of depressive disorder. CNS Neuroscience & Therapeutics, 27(6), 633–642. https://doi.org/10.1111/cns.13622

 Tan, A., Morton, K. R., Lee, J. W., Hartman, R., & Lee, G. (2020). Adverse childhood experiences and depressive symptoms: Protective effects of dietary flavonoids. Journal of Psychosomatic Research131, 109957–109957. https://doi.org/10.1016/j.jpsychores.2020.109957

 Tayab, M. A., Islam, M. N., Chowdhury, K. A. A., & Tasnim, F. M. (2022). Targeting neuroinflammation by polyphenols: A promising therapeutic approach against inflammation-associated depression. Biomedicine & Pharmacotherapy147, 112668.

 Youdim, K.A., Dobbie, M. S., Kuhnle, G., Proteggente, A. R., Abbott, N. J., & Rice‐Evans, C. (2003). Interaction between flavonoids and the blood–brain barrier: in vitro studies. Journal of Neurochemistry85(1), 180–192. https://doi.org/10.1046/j.1471-4159.2003.01652.x

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