Chronic, often "silent" inflammation is the new plague of the 21st century. This inflammation is triggered by ageing and a host of lifestyle factors, including obesity, insufficient exercise, a diet high in simple carbohydrates, and trans fatty acids as well as stress and sleep deprivation. Chronic inflammation plays a major role in a variety of diseases, including cancer, heart disease, Alzheimer's disease, diabetes, obesity, periodontal disease, allergies, asthma, depression and osteoporosis.1 Some herbal extracts and nutrients can effectively reduce various inflammatory mediators, including interleukin-6 (IL-6), IL-1 beta, TNF-alpha, prostaglandin E2 and leukotrienes.

ICC Research

Tetrandrine is a bis-benzylisoquinoline alkaloid, a compound extracted from the traditional Chinese herb Stephania tetrandra.

Calcium channel blocker: Tetrandrine functions as a calcium channel blocker, affecting blood pressure and heart function. 

Anti-hypertensive agent: It has been used clinically for its ability to lower blood pressure and reduce portal venous pressure in patients with hypertension. 

Anti-inflammatory agent: It is used to treat inflammatory conditions such as silicosis, hepatitis, and rheumatoid arthritis by targeting inflammation-related signalling pathways [1]. 

Tetrandrine may have both antidepressant-like and anxiolytic-like effects. Studies have shown it can reduce anxiety-like behaviour in animal models by regulating neurotransmitters like serotonin and norepinephrine, alleviating symptoms of drug withdrawal, and even treating post-traumatic stress disorder (PTSD)-like behaviours [2].

Regulates neurotransmitters: Tetrandrine appears to increase the levels of key neurotransmitters like serotonin (5-HT) and norepinephrine (NE) in the brain, which are often depleted in depression and anxiety.

Combats drug withdrawal anxiety: In animal models, tetrandrine has been shown to alleviate withdrawal symptoms, including anxiety, associated with certain drugs.

Treats PTSD-like symptoms: In animal models of PTSD, tetrandrine has been shown to reduce anxiety-related behaviours like fear and freezing.

Modulates brain function: It may also affect other aspects of brain function related to anxiety and depression, such as the expression of brain-derived neurotrophic factor (BDNF) [3]

1.     Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy. Oncotarget. 2016 Jun 28;7(26):40800-40815. doi: 10.18632/oncotarget.8315.

2.     Protective effects of tetrandrine on brain cells in phenobarbital-dependent and -withdrawn rats. Molecular Medicine Reports. 1939-1944 March-2015 Volume 11 Issue 3 https://doi.org/10.3892/mmr.2014.2997 

3.     Protective effects of tetrandrine on brain cells in phenobarbital-dependent and -withdrawn rats. Molecular Medicine Reports. November 25, 2014 https://doi.org/10.3892/mmr.2014.2997

Fangchinoline

Autophagy, an evolutionarily conserved cellular self-digestive process, is associated with different diseases and can be inhibited or induced by a series of agents. In this study, we reported that fangchinoline (FCL), an alkaloid from Stephania tetrandra S. Moore, increased the expression of LC3-II and the formation of GFP-LC3 puncta in non-small cell lung cancer (NSCLC) cells.

Fangchinoline, an active component of radix stephaniae tetrandrinea, has been shown to possess neuroprotective properties. It has been reported that excessive glutamate release has been proposed to

be involved in the pathogenesis of several neurological diseases. The primary purpose of the present study was to investigate the effect of fangchinoline on glutamate release in rat cerebral cortex nerve terminals and to explore the possible mechanism. 

Fangchinoline inhibits glutamate release from the rat cortical synaptosomes through the suppression of voltage-dependent Ca2+ channel activity and subsequent reduces Ca2+ entry into nerves appears to involve the suppression of PKC signal transduction pathway. This finding may explain the neuroprotective effects of fangchinoline against neurotoxicity

AKBA (acetyl-11-keto-boswellic acid), commonly known as frankincense shows promise in alleviating anxiety, primarily through its anti-inflammatory and neuroprotective effects. Studies suggest AKBA can reduce anxiety-like behaviours by modulating stress responses, reducing inflammation-related neurotoxicity, and restoring the balance of neurotransmitters like glutamate and GABA 

Anti-inflammatory effects: Anxiety is linked to inflammation, and AKBA can reduce inflammation by inhibiting key inflammatory enzymes and cytokines, such as IL-6 and TNF-α.

Neurotransmitter regulation: AKBA appears to help regulate neurotransmitter levels. It has been shown to decrease glutamate levels while increasing GABA levels, which could contribute to calming effects.

Stress response modulation: AKBA can modulate the central stress axis and reduce elevated corticosterone levels, a key stress hormone, suggesting it may help mitigate the effects of chronic stress.

Antioxidant properties: AKBA can combat oxidative stress, which is implicated in the development of anxiety and other neurological disorders. [1]. 

AKBA can improve memory impairment induced by cerebral inflammation. AKBA improved memory performance in MWM and PA tests (P < 0.05 to P < 0.001). Pre-treatment by AKBA improved the levels of hippocampal IL-10 (P < 0.001), BDNF (P < 0.001), CAT (P < 0.05 and P < 0.001), SOD P < 0.001 and thiols (P < 0.01 and P < 0.001) while reduced IL-6 (P < 0.001), TNF-α (P < 0.001), NO (P < 0.05 and P < 0.001), GFAP (P < 0.001) and MDA (P < 0.001) levels. AKBA effectively ameliorated LPS-induced learning and memory impairments and improved BDNF in a neuroinflammation animal model. The effects seem to be due to setting a positive balance between pro-inflammatory to inflammatory cytokines and reinvigorate the antioxidant system [2]. 

1.     The effects of frankincense extract on depression and anxiety-like behaviours induced by lipopolysaccharide in rats, Learning and Motivation, Volume 73, 2021, https://doi.org/10.1016/j.lmot.2021.101708.

2.     The effects of acetyl-11-keto-β-boswellic acid on brain cytokines and memory impairment induced by lipopolysaccharide in rats, Cytokine, Volume 131, 2020, https://doi.org/10.1016/j.cyto.2020.155107.

Lipopolysaccharide (LPS) use resulted in depression and anxiety-like behaviours (increased immobility in the FST, decreased time in the central area in the OF, and reduced time in the open arms in the EPM, as well as increased markers of inflammation (IL-6 and TNF-α). Behaviours consistent with anxiety and depression, as well as increased markers of inflammation were reduced by frankincense extract treatment [1] 

Inflammation and oxidative stress are involved in the pathophysiology of anxiety and depression. [2]

1.     Lipopolysaccharide induced anxiety- and depressive-like behaviour in mice are prevented by chronic pre-treatment of esculetin, Neuroscience Letters, Volume 611, 2016, Pages 106-111, https://doi.org/10.1016/j.neulet.2015.11.031.

2.    Lipopolysaccharide induced anxiety- and depressive-like behaviour in mice are prevented by chronic pre-treatment of esculetin, Neuroscience Letters, Volume 611, 2016, Pages 106-111.https://doi.org/10.1016/j.neulet.2015.11.031. 

Urtica dioica Leaf

Urtica dioica (Stinging Nettle) is a herb that grows throughout the temperate zones of Europe andAmerica. It has been used as a medicine since ancient times and has been used to treat inflammatory conditions such as asthma, eczema and rheumatic conditions. In Germany, nettle leaf extract is approved as adjuvant therapy of rheumatic diseases.2 Nettle leaf extract (NLE) has been shown to reduce IL-2 and interferon-gamma release by monocytes, which “may inhibit the inflammatory cascade in autoimmune diseases like rheumatoid arthritis.”2 NLE was shown to reduce secretion of TNF-alpha by human dendritic cells, leading to reduced T cell-mediated inflammatory response.3 Mice suffering colitis treated with NLE exhibited fewer symptoms of colitis than untreated mice. Treated mice also have significantly lower levels of IL-1 beta and TNF-alpha than untreated mice.

Monocyte proliferation after LPS stimulation also occurred less in treated mice.4 When 20 healthy humans ingested NLE for 21 days, there was an 80 percent reduction in TNF-alpha and a 99 percent reduction in IL-1 beta when blood samples were stimulated with LPS ex vivo (outside the body).6 NLE has also been shown to inhibit NFkB activation.5 NLE thus exhibits multimodal anti-inflammatory activity.

Ocimum sanctum

Ocimum sanctum (Holy basil) is an East Indian herb highly esteemed in Ayurvedic medicine.7 Newmark and Schulick have reported holy basil leaf extract (HBE) to be an inhibitor of both cyclooxygenase-2 (COX-2) and 5-lipoxygenase.7 Kelm and colleagues found various compounds in holy basil leaves to be effective COX-2 inhibitors.35 A key constituent of HBE is ursolic acid.7 Ringbom and associates reported ursolic acid to be an effective COX-2 inhibitor.8 Godhwani and co-workers tested HBE in rats and found that it was about 60 percent as effective as sodiumsalicylate (an aspirin-related compound) in reducing inflammation in various tests.9 HBE has also been shown to reduce corticosterone release in response to noise stress in rats. This is a novel anti-inflammatory property of HBE, given that noise stress is ubiquitous in the modern world, that noise stress can increase cortisol release in humans, and that cortisol activates 5-lipoxygenase, producing inflammatory leukotrienes.11 As a COX-2 inhibitor (not as powerful, and thus safer, than the prescription COX-2 inhibitors that are currently prescribed), HBE represents an important herbal anti-inflammatory agent.

Camiella sinensis Polyphenols

Camiella sinensis (Green tea) is rich in flavonoids and epidemiological, in vitro, and animal-model studies have associated green tea consumption with health benefits, including decreased inflammation. Researchers have found both EGCG (the most important green tea polyphenol) and green tea extract (GTE) inhibited neutrophil-mediated angiogenesis in an in vivo inflammatory angiogenesis model.40 Inflammation-induced angiogenesis helps tumours create the massive blood supply they need for growth. Researchers also found that oral GTE enhanced resolution in a mouse lung inflammation model, significantly reducing subsequent fibrosis.12 Ahmed and associates found EGCG reduced expression and activity of COX-2 in human chondrocytes (cartilage-producing cells) from osteoarthritis cartilage.13 They also found GTE reduced inflammatory PGE2 production when the chondrocytes were stimulated by IL-1 beta.13 Kundu and co-workers found that mice pre-treated with oral GTE had reduced COX-2 expression when stimulated by a tumourpromoter.14 Wheeler and associates found that EGCG inhibited NFkB activation in human lung epithelial cells treated with IL-1 beta, which is a powerful activator of NFkB. They had also previously shown that EGCG inhibits TNF-alpha activation of super inflammatory NFkB.14

Aktas and colleagues found that EGCG reduced the severity of experimental autoimmune encephalomyelitis (inflammatory brain disease) when mice were orally pre-treated with EGCG. They also found that EGCG significantly reduced TNF-alpha production in the mice.15

Hussain and co-workers found that EGCG inhibited COX-2 without inhibiting COX-1 expression (COX-1 is important for intestinal and kidney health) in several different types of human prostate cancer cells.16 Varilek and associates found that GTE attenuated chronic inflammation in mice suffering inflammatory bowel disease, demonstrating lower interferon-gamma and TNF-alpha levels than control mice with colitis that were not given EGCG.46 Thus EGCG-rich green tea extract also qualifies as a broad-spectrum anti-inflammatory agent.17

Zingiberis officinalis

Zingiberis officinalis (Ginger) has been used throughout the world for thousands of years as a medicine. It is referred to as the “universal medicine” in East Indian Ayurvedic medicine. Ginger root contains a veritable cornucopia of natural anti-inflammatory compounds. The USDAPhytochemical Database reported as of 1999 that ginger has more 5-lipoxygenase inhibitors than any other botanical source.47 Dr. Srivastava reported excellent results with ginger root in 56 patients with various rheumatic complaints, with over 75 percent getting relief in pain and swelling. He suggested that ginger inhibits both inflammatory prostaglandin (COX-2) synthesis andleukotriene (5-lipoxygenase) synthesis.18

Newmark and Schulick note: “Ginger has multiple constituents that inhibit COX-2 and inhibit the 5-lipoxygenase metabolism of arachidonic acid…Ginger inhibits the creation of prostaglandin PGE2, which [gives ginger] strong anti-pyretic (or anti-heat) producing effects. It balances production of inflammatory prostaglandins PGE2 and PGI2, which also regulate the production of compounds that dilate the arteries. Ginger's constituents safely restore healthy platelet function by inhibiting the formation of thromboxanes. Ginger reduces the prostaglandins that sensitise pain receptors at nerve endings and has significant anti-ulcer effects (which indicates that ginger does not suppress intestine-essential COX-1 while suppressing COX-2).19

Jolad and colleagues reported that “Most of the [ginger root] fractions containing gingerols and/orgingerol derivatives showed excellent inhibition of LPS-induced PGE2 production.”20 Park and associates found that topical gingerol “suppressed TPA-induced skin inflammation in mice.50Given its balanced anti-COX-2 and anti-5-lipoxygenase activity, ginger root extract provides useful, yet safe anti-inflammatory activity.

Boswellia serrata

Boswellic acids (BAs) are pentacyclic triterpenes with strong anti-inflammatory activity. Their most important source is the extract of the gum resin of Boawella Serrata, a tropical tree that grows in India and Africa. In a randomized, double-blind, split-face, comparative study, the efficacy, tolerability, and safety of a base cream containing 0.5 % BAs were assessed, as compared to the same cream without these active ingredients in the treatment of clinical manifestations ofphotoaging of facial skin. A significant improvement of tactile roughness and fine lines in the half side of the face treated with BAs; noninvasive instrumental diagnostic investigations showed an improvement of elasticity, a decrease of sebum excretion, and a change of echographicparameters suggesting a reshaping of dermal tissue. The treatment was always well tolerated without adverse effects. These findings seem to indicate that the topical application of BAs may represent a suitable treatment option for selected features of skin photoaging.21

Traditionally Boswellia serrata extract is used in the Indian Ayurvedic medicine for the treatment of inflammatory diseases. In 2002 the EMEA designated Boswellia an orphan drug status for the treatment of peritumoral oedema. Pharmacokinetic studies yielded low plasma concentrations of the active ingredients 11-keto-beta-boswellic acid (KBA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA). In continuation of the tests investigating the factors limiting bioavailability of boswellicacids, a study was carried out to examine the permeability of KBA and AKBA in human Caco-2 cell lines. In addition, the interaction of KBA and AKBA with the organic anion transporter OATP1B3 and the multi drug resistant proteins P-glycoprotein and MRP2 was evaluated using partly fluorescent-based assays. The permeability studies revealed poor permeability of AKBA and moderate absorption of KBA. Most of KBA and AKBA were found to be retained by the Caco-2 monolayer. Neither KBA nor AKBA could be identified as substrates of P-glycoprotein; however, both KBA and AKBA modulated the activity of OATP1B3 and MRP2, indicating that therapeutic relevant interactions with other anionic drugs may be expected. The results of this study provide the first explanation for the pharmacokinetic properties of KBA and AKBA.22

References

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3. Broer J, Behnke B. Immunosuppressant effect of IDS30, a stinging nettle leaf extract, on myeloid dendritic cells in vitro. J Rheumatol 2002, 29:659-66.

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7. Newmark T, Schulick P. Beyond Aspirin. Hohm Press, Prescott AZ 2000, Ch. 9.

8. Ringbom T et al. Ursolicacid from Plantago major, a selective inhibitor of cyclooxygenase-2 catalyzed prostaglandin biosynthesis. J Nat Prod 1998, 61:1212-15.

9. Godshani S et al. Ocimum sanctum: an experimental study evaluating its anti-inflammatory, analgesic and antipyretic activity in animals. J Ethnopharmacol 1987, 21:153-63.

10. Manev H et al. Putative role of neuronal 5-lipoxygenase in an aging brain. FASEB J 2000, 14:1464-69.

11. Dona M et al. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. J Immunol 2003, 170:4335-41.

12. Ahmed S et al. Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes. Free Rad Biol Med 2002, 33:1097-1105.

13. Kundu J et al. Inhibition of phorbol ester-induced COX-2 expression by epigallocatechingallate in mouse skin and cultured human mammary epithelial cells. J Nutr 2003, 133:3805S-10S.

14. Wheeler D et al. Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 [beta]-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr2004, 134:1039-44.

15. Aktas O et al. Green tea epigallocatechin-3-gallate mediates T cellular NF-kB inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 2004, 173:5794-5800.

16. Hussain T et al. Green tea constituent epigallocatechin-3-gallate inhibits COX-2 without affecting COX-1 expression in human prostate carcinoma cells. Int J Cancer 2005, 113:660-69.

17. Varilet G et al. Green tea polyphenol extract attenuates inflammation in interleukin-2-deficient mice, a model of autoimmunity. J Nutr 2001, 131:2034-39.

18. Srivastava K, Mustafa T. Ginger (Zingiberofficinale) and rheumatic disorders. Med Hypoth1989, 29:25-28.

19. Newmark T, Schulick P. Beyond Aspirin. Hohm Press, Prescott AZ 2000, Ch. 9.

20. Jolad S et al. Fresh organically grown ginger (Zingiberofficinale): composition and effects on LPS-induced PGE2 production. Phytochem 2004, 65:1937-54.

21. Pedretti A, Capezzera R, Zane C, Facchinetti E,Calzavara-Pinton P. (2009) Topical Boswellic acids for treatment of photoaged skin.PlantaMedica.

22. Krüger P, Kanzer J, Hummel J, Fricker G, Schubert-Zsilavecz M, Abdel-Tawab M. (2009). Permeation of Boswellia extract in the Caco-2 model and possible interactions of its constituents KBA and AKBA with OATP1B3 and MRP2. Eur J Pharm Sc