A chemical and pharmacological study of a commercial Andrographis paniculata extract and andrographolide, to determine their anti-inflammatory drug potential

Abstract

There is increasing evidence that chronic inflammation is a contributing factor to many prevalent ageing-related diseases, such as acute and chronic neurodegenerative diseases, degenerative musculoskeletal diseases, cardiovascular diseases, diabetes, and cancer. To date, pharmacotherapy of inflammatory conditions is based mainly on the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, the prolonged use of NSAIDs can cause serious side effects. There is a need to develop novel and safe anti-inflammatory medicines. Andrographis paniculata (Acanthaceae), has been used as an herbal medicine in both traditional Indian and Chinese medicine for inflammation related ailments. A. paniculata anti-inflammatory activity is commonly attributed to the ent-labdane diterpenoid andrographolide, A. paniculata's characteristic and main secondary metabolite. This compound may be suitable as an alternative treatment for inflammation, with alternate pharmacological targets to that of NSAIDs with reduced side effects. The commercial A. paniculata extract was fractionated based on polarity (by chloroform-aqueous partitioning), and characterised by HPLC-PDA to quantify the andrographolide. A sulphonation metabolite of andrographolide was synthesised, purified by preparative HPLC and characterised by MS and 1HNMR. The commercial A. paniculata extract, andrographolide, sulphonation metabolite and NSAIDs (Diclofenac, Ibuprofen, Aspirin, Paracetamol) were tested in a number of anti-inflammatory in vitro cell based assays, nitric oxide (Griess reagent) , TNF-a and PGE2 (ELISA), 27 simultaneous cytokines (bead based ELISA) and NF-?B activation (flow cytometry). The andrographolide content accounted for the in vitro anti-inflammatory activity of A. paniculata. Andrographolide is a potent inhibitor of many mediators of inflammation. NSAIDs were not effective inhibitors of any of the mediators tested except PGE2. Andrographolide showed comparable inhibition of PGE2 release to that of the weak NSAIDs aspirin and paracetamol. Andrographolide's IC50 for most mediators was below the highest reported Cmax's in rats, but above those achieve in humans. The sulphonation metabolite of andrographolide had comparable activity to andrographolide against most inflammatory mediators and has greater activity against TNF-a and IL-6. The sulphonation metabolite's IC50 for the majority of mediators was well below (47 times) which had the only reported Cmax in rats. The sulphonation metabolite shows promise as a treatment for inflammation as it inhibited a wide range of inflammatory mediators below the reported in vivo levels. Pharmacokinetics studies in humans are needed to determine its pharmacokinetics. Further animal studies should be conducted to assess its safety.

Date of Award	2015
Original language	English