The pleiotropic anti-inflammtory effects of boswellic acids can be discussed as follows:
- Inhibition of leukotrienes biosynthesis
- Inhibition of human leukocyte elastase (HLE)
- Higher terpenoids, including boswellic acids (25 – 35%)
- By cathespin G (catG) inhibition
- By anticholinesterase (AChE) inhibition
Inhibition of leukotrienes biosynthesis
Leukotrienes are fatty acids which are formed from arachidonic acid by an enzyme called 5-lipoxygenase (5-LO) (Majeed et al., 1996, Henderson, 1994; Ford-Hutchinson et al., 1993). The function of leukotrienes is to mediate inflammation and allergic reactions in several conditions such as arthritis, inflammatory bowel diseases, atopic dermatitis, psoriasis, urticaria, asthma, allergic rhinitis, etc (Mogana et al., 2013).
Boswellic acids are reported to possess non-redox, non-competitive inhibitory actions on 5-LO enzyme via allosteric regulation. It has been suggested that the pentacyclic triterpene ring system is crucial for binding to the highly selective effector site, whereas functional groups (especially the 11-keto function in addition to a hydrophilic group on C-4 of the ring A) are essential for 5-LO inhibitory activity.
- Interacting with the 5-lipoxygenase-activating protein (FLAP) (Safayhi et al., 1992)
Based on IC50 values, acetyl-11-keto-β-boswellic acid (AKBBA) provides the most potent inhibitory action due to its optimal structure (Safayhi et al., 1992, Sailer et al., 1996).
Inhibition of human leukocyte elastase (HLE)
The HLE is a serine protease enzyme found in neutrophil leukocytes. It is involved in the inflammatory tissue injuries (Lee and Downey, 2001). Its role has been implicated in inflammatory and hypersensitivity conditions such as pulmonary emphysema, cystic fibrosis, chronic bronchitis, acute respiratory distress syndrome, glomerulonephritis and rheumatic arthritis (Shah et al., 2009).
Boswellic acids, especially AKBBA showed HLE inhibition with an IC50 of 15 μM.
Inhibition of cathepsin G (catG)
CatG is also a serine protease enzyme found in the neutrophils. Its role has been implicated in various pathophysiological processes, though controversially discussed, viz digestion of extracellular matrix and damaging local connective tissues, chemoinvasion of T cells and leukocytes, and stimulation of platelet aggregation Tausch et al., 2019.
Boswellic acids directly bind, competitively interact and reversibly inhibit catG at submicromolar IC50 ranges. They suppressed the catG activity ex vivo after oral administration to human subjects (Tausch et al., 2019).
Inhibition of acetylcholinesterase (AChE)
AChE is a specific enzyme that is involved in the hydrolysis of cholinergic neurotransmitter acetylcholine (ACh) into choline and acetate (Ota abd Houghton, 2007). Inhibitors of AChE have been implicated to have anti-inflammatory effects, reduce the release of cytokines (Mogana et al., 2013).
Ota and Houghton, 2007, reported that boswellic acids viz 11α-hydroxy-βboswellic acid and 11-keto-β-boswellic acid inhibit AChE activity. Their AChE inhibitory activity was associated to the presence of either the free hydroxyl group or keto group at C-11 and free hydroxyl group at C-3 in the ursane skeleton.
Inhibition of leukotrienes formation
- Leukotrienes are fatty acids which are formed from arachidonic acid by an enzyme called 5-lipoxygenase(5-LO)2,3,4
- Function of leukotrienes is to sustain the inflammatory reactions in the body by acting as chemo attractants for leucocytes that are the reservoirs of pro-inflammatory cytokines like tumour necrosis factor alpha (TNFα)
- Boswellic acids are reported to be non-competitive inhibitors of 5-LO enzyme
It has been suggested that the boswellic acids inhibit 5-LO by one of two ways:
- Directly interacting with 5-LO or
- Interacting with the five-lipoxygenase-activating protein (FLAP)5
- Based on IC50 (effective inhibitory concentration of tested substance) values, acetyl-11-keto-β-boswellic acid (IV) alone provided the most potent inhibitory action due to its optimal structure5,6