Al-Harrasi A et al (2019). Distribution of the anti-inflammatory and anti-depressant compounds: Incensole and incensole acetate in genus Boswellia,161: 28-40, Phytochemistry.

Summary: Incensole acetate (IA) and its natural analogs, have been used in many pharmacopeias paving the road to understand its anti-depression like activity, are components of Boswellia resins. They are apparently safe as no side effects were reported, and they were very effective. Recent studies support this fact reporting IA of very low toxicity, and no signs of toxicity in animals were observed even when they were treated with high and multiple doses of IA.

Abstract: Incensole and its acetate have shown anti-inflammatory and anti-depression activities due to their ability to activate ion channels in the brain to alleviate anxiety or depression. The natural occurrence of these two structurally and medicinally fascinating 14-membered diterpenoids was reported mainly from the genus Boswellia. Incensole and incensole acetate were detected in and isolated from both essential oils and resins of frankincense. One total synthesis was reported for incensole. Both incensole and its acetate served as precursors for several synthetic transformations. Given the fact that no specific enzymes were isolated from Boswellia trees, the major sources for incensole and incensole acetate, the biosynthetic pathway of these two compounds was only speculated. Recent studies on incensole and incensole acetate including ours have revealed another secret of the ancient drug. Understanding their mode of action will open a door in modern neurobiology and provides new insights on the mysterious diseases of the nervous system. This review interpretatively discusses the natural existence of incensole and incensole acetate, the variation of their percentages in different Boswellia species and other sources, their synthetic modifications, their biosynthesis and their therapeutic potential..

Pollastro F et al (2016). Neuroactive and Anti-inflammatory Frankincense Cembranes: A Structure-Activity Study, 79: 1762-1768. J Nat Prod.

Summary: The cembrane skeleton of frankincense is a privileged structure for targeting TRPV3 and evaluating the pharmacological potential of its modulation. The in vivo evaluation of the neuroprotective activity of the phenolic monoterpene carvacrol demonstrate the druggability of TRPV3 by small molecules. Cembrane ligands such as incensol acetate (IA) and serratol qualify as better probes because of their higher potency and, at least for IA, and possibly for serratol, selectivity within the TRP ion channel family, should be seriously considered for in vivo investigations of the physiological role of TRPV3. Conversely, incensol seems an excellent candidate for neuroprotection, due to its pleiotropic mechanism of activity that includes, apart from the modulation of TRPV3, also the inhibition of the proinflammatory transcription factor STAT3.

Abstract: An expeditious isolation method for the cembrane diterpene alcohols incensol (1a) and serratol (2) has been developed from respectively African and Indian frankincense. The two native alcohols and a series of semisynthetic derivatives of incensol were evaluated for transient receptor potential vanilloid 3 (TRPV3) activation and the inhibition of NF-κB, the putative molecular targets underlying the psychotropic and anti-inflammatory activities of incensol acetate (IA, 1b). Serratol (2) was the most potent TRPV3 activator, outperforming by 2 orders of magnitude the reference agonist thymol and by 1 order of magnitude incensol acetate (1b). Acylation, epimerization, and oxidation did not significantly improve the affinity of incensol for TRPV3, while NF-κB inhibition, marginal for both natural alcohols, could be improved by esterification of incensol (1a) with lipophilic acids. Interestingly, incensol (1a) but not IA (1b) was a potent inhibitor of STAT3, raising the possibility that hydrolysis to incensol (1a) might be involved in the in vivo biological activity of IA (1b). Serratol was not amenable to chemical modification, but some marine cembranoids related to the frankincense diterpenoids showed a certain degree of TRPV3-activating properties, qualifying the aliphatic macrocyclic cembrane skeleton as a selective chemotype to explore the pharmacology of TRPV3, a thermo-TRP otherwise resistant to modulation by small molecules.

Moussaieff A et al (2012). Protective effects of incensole acetate on cerebral ischemic injury, 1443: 89-97. Brain Res.

Summary: The study showed that incensole (frankincense) protects mice from middle cerebral artery occlusion (ischemic stroke model) by functioning through inhibition of NF-kB. Incensole shows a dose-dependent and time-dependent protection suggesting a potential novel therapeutic to treat cerebral ischemia.

Abstract: The resin of Boswellia species is a major anti-inflammatory agent that has been used for centuries to treat various conditions including injuries and inflammatory conditions. Incensole acetate (IA), a major constituent of this resin, has been shown to inhibit NF-κB activation and concomitant inflammation, as well as the neurological deficit following head trauma. Here, we show that IA protects against ischemic neuronal damage and reperfusion injury in mice, attenuating the inflammatory nature of ischemic damage. IA given post-ischemia, reduced infarct volumes and improved neurological activities in the mouse model of ischemic injury in a dose dependent fashion. The protection from damage was accompanied by inhibition of TNF-α, IL-1β and TGF-β expression, as well as NF-κB activation following injury. In addition, IA is shown to have a therapeutic window of treatment up to 6h after ischemic injury. Finally, the protective effects of IA were partially mediated by TRPV3 channels as determined by the TRPV3 deficient mice and channel blocker studies. This study suggests that the anti-inflammatory and neuroprotective activities of IA may serve as a novel therapeutic treatment for ischemic and reperfusion injury, and as a tool in the ongoing research of mechanisms for neurological damage.

Siddiqui MZ (2011). Boswellia Serrata, A Potential Anti-inflammatory Agent: An Overview, 73: 255-261. Indian J Pharm Sci.

Summary: This review examines a number of studies and reports show ingredients of frankincense are responsible for inhibition of pro-inflammatory enzymes.

Abstract: The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.

Moussaieff A et al (2008). Incensole acetate: a novel neuroprotective agent isolated from Boswellia carterii, 28: 1341-1352. J Cereb Blood Flow & Metab.

Summary: The study’s data indicate that a single postinjury dose of Incensole Acetate (IA), a novel anti-inflammatory agent, offers marked functional neuroprotection against TBI. As IA and its derivatives are major components of Boswellia resin, they appear to be safe as well as effective. From the authors in vivo work, they noted that IA is probably of very low toxicity, as they did not see any signs of toxicity in animals even when treated with high and multiple doses of IA. They propose IA and cembrene-type diterpenes as novel potential neuroprotective agents to be further explored for TBI as well as for neuroinflammatory and neurodegenerative diseases.

Abstract: Boswellia resin has been used as a major anti-inflammatory agent and for the healing of wounds for centuries. Incensole acetate (IA), isolated from this resin, was shown to inhibit the activation of nuclear factor-κB, a key transcription factor in the inflammatory response. We now show that IA inhibits the production of inflammatory mediators in an in vitro model system of C6 glioma and human peripheral monocytes. Given the involvement of postinjury inflammation in the pathophysiology and outcome of traumatic brain injury, we examined the effect of IA on the inflammatory process and on the recovery of neurobehavioral and cognitive functions in a mouse model of closed head injury (CHI). In the brains of post-CHI mice, IA reduced glial activation, inhibited the expression of interleukin-1b, and tumor necrosis factor-a mRNAs, and induced cell death in macrophages at the area of trauma. A mild hypothermic effect was also noted. Subsequently, IA inhibited hippocampal neurodegeneration and exerted a beneficial effect on functional outcome after CHI, indicated by reduced neurological severity scores and improved cognitive ability in an object recognition test. This study attributes the anti-inflammatory activity of Boswellia resin to IA and related cembranoid diterpenes and suggests that they may serve as novel neuroprotective agents

Moussaieff A et al (2007). Incensole acetate, a Novel Anti-Inflammatory Compound isolated from Boswellia Resin, Inhibits Nuclear Factor-κB Activation, 72: 1657-2664. Mol Pharmacol.

Summary: Incensole acetate (IA) found in frankincense demonstrates a robust anti-inflammatory effect in a mouse inflamed paw model. The identification of the NF-kB inhibitory effect of cembrenoid diterpenes, an important group of common natural products may open fields to the discovery of novel drugs for the treatment of diseases that pose unanswered challenges and affect a large segment of the population.

Abstract: Boswellia resin is a major anti-inflammatory agent in herbal medical tradition, as well as a common food supplement. Its anti-inflammatory activity has been attributed to boswellic acid and its derivatives. Here, we re-examined the anti-inflammatory effect of the resin, using inhibitor of nuclear factor-κBα (IκBα) degradation in tumor necrosis factor (TNF) α-stimulated HeLa cells for a bioassay-guided fractionation. We thus isolated two novel nuclear factor-κB (NF-κB) inhibitors from the resin, their structures elucidated as incensole acetate (IA) and its nonacetylated form, incensole (IN). IA inhibited TAK/TAB-mediated IκB kinase (IKK) activation loop phosphorylation, resulting in the inhibition of cytokine and lipopolysaccharide-mediated NF-κB activation. It had no effect on IKK activity in vitro, and it did not suppress IκBα phosphorylation in costimulated T-cells, indicating that the kinase inhibition is neither direct nor does it affect all NF-κB activation pathways. The inhibitory effect seems specific; IA did not interfere with TNFα-induced activation of c-Jun Nterminal kinase (JNK) and p38 mitogen-activated protein kinase. IA treatment had a robust anti-inflammatory effect in a mouse inflamed paw model. Cembrenoid diterpenoids, specifically IA and its derivatives, may thus constitute a potential novel group of NF-κB inhibitors, originating from an ancient anti-inflammatory herbal remedy.