A solution against inflammaging
As we age the immune system becomes increasingly dysfunctional and our immune response becomes excessive leading to chronic inflammation and driving the diseases of aging(1). Chronic levels of inflammation from various sources impair and alter intercellular signalling and disrupt tissue repair and regeneration as a result. This chronic age-related inflammation is often called inflammaging by researchers.
Therefore compounds to reduce this inflammation are of immense interest to researchers.
PI3K/Akt pathway suppression using Honokiol
Honokiol has been shown to inhibit the inflammatory response in neutrophils, macrophages and lymphocytes which has important implications for its use as an anti-inflammatory therapy(2-3).
PI3K/Akt is an intracellular signaling pathway important in regulating the cell cycle meaning it is directly related to cellular quiescence, proliferation, cancer, and longevity.
A 2008 study showed that honokiol has a powerful inhibitory and was able to reduce inflammation(4). The researchers investigated the regulatory effects of honokiol on the inflammatory responses mediated by monocytes and macrophages. They discovered that the anti-inflammatory effects of honokiol appear to be mediated by disrupting the early activated intracellular signaling molecule phosphoinositide 3-kinase PI3K/Akt, but not Src, the extracellular signal-regulated kinase, and p38.
The PI3K/Akt pathway also interacts with another regulatory pathway that mediates inflammation, the NF-kB protein complex.
NF-kB and inflammation
NF-kB is a protein complex is a master regulator of many inflammatory genes helping to mediate the immune response to pathogens. Unfortunately when this regulation becomes dysfunctional, then the immune response and resulting inflammation becomes excessive and contributes to diseases.
According to a 2013 study honokiol inhibits the production of inflammatory factors in glial (a tissue resident macrophage) cells by blocking the activation of the NF-kB protein complex(5). This is important as the NF-kB protein complex controls the transcription of DNA, cytokine production and cell survival and is a key player in the chronic levels of inflammation caused by aging which leads to age-related diseases.
When macrophages are exposed to bacterial lipopolysaccharide (LPS), macrophages release a number of immunoregulatory molecules including TNF-α, IL-1, IL-6 and other signals that recruit and activate other immune cells in order to fight infection.
A 2010 research study showed that honokiol was able to inhibit the activation of NF-kB in LPS-stimulated macrophages thus reducing inflammation(6). This ability to modulate the immune response could prove valuable in reducing the impact of extreme immune responses in old age due to the NF-kB protein complex.
The same study also showed that honokiol was also able to reduce inflammation by inhibiting the Mitogen-activated protein kinases (MAPKs) and protein kinase C-α (PKCα) which also both play a significant role in chronic inflammation.
Inflammation leads to many diseases
Honokiol and osteoarthritis
In 2014 researchers investigated the potential of honokiol for the treatment of osteoarthritis(7). The inflammatory cytokine interleukin-1β (IL-1β) stimulates several mediators of cartilage degradation and plays an important role in the development of osteoarthritis. IL-1β activates the proinflammatory IKK/IκBα/NF-κB signalling pathway which leads to inflammation and reduces collagen II production leading to osteoarthritis.
The study data showed that IL-1β stimulated the expression of inducible nitric oxide synthase (iNOS) and collagen II, cyclooxygenase-2 (COX-2) and the production of Nitric oxide (NO), Prostaglandin (PGE2), and interleukin-6 (IL-6), which could be reversed by honokiol. honokiol was able to suppress the IL-1β-triggered activation of the IKK/IκBα/NF-κB signaling pathway. Moreover, honokiol significantly inhibited the IL-1β-induced MMP-13 production which prevents collagen II reduction.
These impressive results suggest that this chondroprotective effect may place honokiol as a potential therapeutic choice in the treatment of osteoarthritis patients in the future.
Inflammation of the central nervous system (CNS) is associated with a disruption of cerebral endothelial cell (EC) regulation and compromised brain blood barrier integrity, followed by activated leukocyte migration to the CNS. TNF-α, a proinflammatory factor, upregulates adhesion molecules in ECs leading to the leakage of leukocytes into the CNS.
NF-κB as mentioned previously is a key inflammatory transcription factor and also upregulates adhesion molecules. A study in 2016 showed that honokiol was able to reduce TNF-α induced adhesion between neutrophils and ECs by inhibiting the expression of VCAM-1 mRNA and preventing NF-κB activation and the resulting inflammatory response(8). This study strongly suggests the anti-inflammatory action of honokiol is of interest for potential therapeutic therapies.
Honokiol a solution against Alzheimer’s ?
Acetylcholine is a neurotransmitter which stimulates the release of the granulocyte macrophage colony stimulating factor (GM‐CSF also known as colony stimulating factor 2 CSF2) as shown in studies (9). GM-CSF is an important hematopoietic growth factor and an immune modulator which mediates a variety of cell types including T cells, macrophages, endothelial cells and fibroblasts upon receiving stimuli. Although produced in local tissues, it can also act in a paracrine manner in order to recruit circulating neutrophils, lymphocytes and monocytes to enhance their functions in the immune response.
In research studies honokiol has been shown to be an agonist of acetylcholine thus increasing levels of the neurotransmitter and stimulating the release of GM‐CSF (10-11). In a recent test, exposing old microglial (a tissue resident macrophage) cells to the conditioned media of young microglia or the addition of GM‐CSF was sufficient to induce microglial proliferation and reduce amyloid plaque size in Alzheimer’s (12).
A more recent study shows that honokiol was able to reduce inflammation and also mediate immune response via inhibition of TNF-α (Tumor necrosis factor) in rheumatoid arthritis (13). TNF-α is a cytokine involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction.
The study showed that in the case of rheumatoid arthritis honokiol had the opposite effect than in the brain and that it reduced TNF-α-induced IL-1β, GM-CSF and IL-8 production in peripheral blood mononuclear cells. This apparently paradoxical result compared to studies in the brain suggests honokiol has a tissue specific effect.
The results show that IL-1β, TNF-α, GM-CSF and IL-8 play an important role in the development of rheumatoid arthritis, and honokiol plays an anti-inflammatory role and could have beneficial effects in preventing and treating rheumatoid arthritis.
In closing these and the results of other research studies strongly suggest that honokiol is a potent anti-inflammatory and that it is of great interest as a potential therapy for a variety of inflammatory conditions and diseases. It may also be of interest as a dietary supplement as a preventative for inflammation and helping reduce the impact of the aging process.
(1) López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
(2) Liou, K. T., Shen, Y. C., Chen, C. F., Tsao, C. M., & Tsai, S. K. (2003). The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production. European journal of pharmacology, 475(1), 19-27.
(3) Liou, K. T., Shen, Y. C., Chen, C. F., Tsao, C. M., & Tsai, S. K. (2003). honokiol protects rat brain from focal cerebral ischemia–reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production. Brain research, 992(2), 159-166.
(4) Kim, B. H., & Cho, J. Y. (2008). Anti‐inflammatory effect of honokiol is mediated by PI3K/Akt pathway suppression1. Acta Pharmacologica Sinica, 29(1), 113-122.
(5) Zhang, P., Liu, X., Zhu, Y., Chen, S., Zhou, D., & Wang, Y. (2013). honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells. Neuroscience letters, 534, 123-127.
(6) Chao, L. K., Liao, P. C., Ho, C. L., Wang, E. I. C., Chuang, C. C., Chiu, H. W., … & Hua, K. F. (2010). Anti-inflammatory bioactivities of honokiol through inhibition of protein kinase C, mitogen-activated protein kinase, and the NF-κB pathway to reduce LPS-induced TNFα and NO expression. Journal of agricultural and food chemistry, 58(6), 3472-3478.
(7) Chen, Y. J., Tsai, K. S., Chan, D. C., Lan, K. C., Chen, C. F., Yang, R. S., & Liu, S. H. (2014). Honokiol, a low molecular weight natural product, prevents inflammatory response and cartilage matrix degradation in human osteoarthritis chondrocytes. Journal of Orthopaedic Research, 32(4), 573-580.
(8) Chen, P. J., Wang, Y. L., Kuo, L. M., Lin, C. F., Chen, C. Y., Tsai, Y. F., … & Hwang, T. L. (2016). honokiol suppresses TNF-α-induced neutrophil adhesion on cerebral endothelial cells by disrupting polyubiquitination and degradation of IκBα. Scientific reports, 6.
(9) Klapproth, H., Racké, K., & Wessler, I. (1998). Acetylcholine and nicotine stimulate the release of granulocyte-macrophage colony stimulating factor from cultured human bronchial epithelial cells. Naunyn-Schmiedeberg’s archives of pharmacology, 357(4), 472-475.
(10) Tsai, T. H., Westly, J., Lee, T. F., Chen, C. F., & Wang, L. C. H. (1995). Effects of honokiol and magnolol on acetylcholine release from rat hippocampal slices. Planta medica, 61(05), 477-479.
(11) Hou, Y. C., Chao, P. D. L., & Chen, S. Y. (2000). honokiol and magnolol increased hippocampal acetylcholine release in freely-moving rats. The American journal of Chinese medicine, 28(03n04), 379-384.
(12) Daria, A., Colombo, A., Llovera, G., Hampel, H., Willem, M., Liesz, A., … & Tahirovic, S. (2016). Young microglia restore amyloid plaque clearance of aged microglia. The EMBO Journal, e201694591.
(13) Wang, X. D., Wang, Y. L., & Gao, W. F. (2015). Honokiol possesses potential anti-inflammatory effects on rheumatoid arthritis and GM-CSF can be a target for its treatment. International journal of clinical and experimental pathology, 8(7), 7929.