SRS27,a semisynthetic diterpenoid lactone,inhibits airway inflammation and hyper-responsiveness via NF-κB pathway in an allergic mouse asthma model

Andrographis paniculata contains two main diterpenoid constituents,andrographolide(AGP)and 14-deoxy-11,12-didehydroandrographolide(DDAG),which were found to exhibit antiasthma effects in a mouse asthma model.However,due to inadequacies of both compounds in terms of drug-likeness,DDAG analogues were semisynthesised to tackle these shortcomings.The objective of the study was to investigate the potential of DDAG analogues as new antiasthma agents.Among the analogues,(SRS27)was proven to inhibit cysteinyl leukotrienes(CysLT)and nitric oxide(NO)synthesis in mouse macrophages,like AGP.DDAG,on the other hand,failed to exhibit such activities.SRS27 is less cytotoxic than AGP,suggests that a simple chemical modification of DDAG produces a compound with CysLT and NO inhibitory activites similar to AGP while maintaining toxicity profile similar to DDAG.It is interesting to note that other analogues such as SRS28,SRS49,SRS76 and SRS83 with chemical modifications on the same carbon numbers 3 and 19 of DDAG were unable to show inhibition of CysLT and NO synthesis.Consequently,the potential anti-inflammatory effect of SRS27 was investigated in ovalbumin(OVA)-induced mouse asthma model.The compound was administered in a prophylactic manner and showed a substantial decrease in mouse asthma model parameters.SRS27 at 3mg·kg-1 significantly reduced OVA-induced total cell such as macrophages,eosinophils,lymphocytes and neutrophils,as well as inflammatory cytokines such as IL-4,IL-5,IL-13 and eotaxin in bronchoalveolar lavage BAL fluid.The compound also suppressed serum IgE production.In addition,SRS27 suppressed mucus hyper-secretion and expression of inflammatory mediators such as TNF-α,MCP-1,Muc5 ac,RANTES,IL-33 and iNOS.SRS27 is the first known DDAG derivative tested positive in mouse asthma model and as such SRS27 could serve as a prototype prophylactic agent.