Possible Mode of Action of Hp

The preceding discussion indicates that Hp extracts influence a variety of pro-inflammatory processes. More work is required to determine if these effects are due to actions on multiple targets by one or more of the constituents of Hp. Alternatively, acting via a single target may have multiple effects. There is some evidence outlined above that Hp extracts can inhibit key intracellular pathways that promote inflammation. Many of these pathways are common to different inflammatory cells and, when inhibited, may attenuate different inflammatory processes simultaneously.

The notion that Hp inhibits pro-inflammatory second-messenger pathways suggests that this traditional herbal drug can compete with modern drugs. Pro-inflammatory second-messenger pathways are currently the target of much effort and investment in the development of novel anti-inflammatory drugs. Such drugs are potentially more effective anti-inflammatory agents as they act up-stream in the inflammatory cascade and will exert pleiotropic effects. For example, NSAIDs target the production of just one pro-inflammatory effector, while inhibition of a key intracellular pathway will influence an array of effector molecules.

One key intracellular promoter of inflammation is NFkB, which activates several pro-inflammatory genes. As discussed above, there is some contradictory evidence concerning Hp and inhibition of this key promoter of inflammation. In mouse fibroblasts an Hp extract, but not harpagoside, inhibited the activated NFkB pathway [35], whereas in human macrophage cell lines, harpagoside was inhibitory [37]. It is possible differences between species or cell type determine these differences.

Further studies should, perhaps, focus on this pathway as a potential target for the anti-inflammatory effects of Hp.

Also relevant in this regard is the inhibitory effects of Hp on the NFkB pathway and the possible anti-oxidant effects of Hp extracts, for which there is some evidence. Antioxidants are potential inhibitors of NFkB, which is activated by reactive oxygen species generated during inflammation, and are recognised as key promoters of inflammation and inducers of pro-inflammatory genes. In vitro assessment of a water extract of Devil's Claw showed moderate antioxidant capacity (Trolox assay), which was not due to the content of iridoids, which exert minimal antioxidant activity [40]. However, the constituent acteoside has antioxidant properties, as has been shown in a number of studies.

Acteoside is rarely discussed with regard to the pharmacology of Hp. It is present in Hp extracts in amounts similar to that of harpagoside [10], which is the more characteristic and most often discussed constituent of Hp. Acteoside and acety-lated derivatives are present in many plants and have been identified as an active ingredient of, for example, Plantago lanceolata. In its isolated form, acteoside exhibits an anti-inflammatory property in vitro due to its antioxidant effects [41-44], which also include inhibition of eicanosoids production [45, 46]. Also in in vivo models of inflammation, it down-regulates expression of ICAM-1 [47, 48], which is involved in leucocyte recruitment within inflamed tissue and of iNOS expression [49]. More recently, it has been shown that parenteral acteoside exerts significant dose-dependent anti-inflammatory effects in a rodent model of inflammatory bowel disease (dextran sulphate sodium-induced colitis in mice) when administered after induction of chronic inflammation [50]. The study demonstrated that acteoside reduced the degree of inflammation, local lymph node cytokine production, and intestinal myeloperoxidase activity. The authors speculated that the anti-inflammatory effects were due to an antioxidant effect causing a reduced oxidative burst of local inflammatory cells.

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