Andrographolide: Regulating the Master Regulator NF-κB

Abstract

Natural product based medicines are being used in India since 12th century BC and their efficacies are well established in Indian traditional medicine system. However, the mechanism of action as per the modern medicinal system was not well reported. Plant-derived natural compounds are very useful for inflammatory disorders and other diseases such as cancer. Various medicines like artemisinin, vincristine, vinblastine, taxol, and so forth, are invaluable contributions of nature to modern medicine. The role of transcription factor NF-κB was well delineated in inflammatory processes. Binding of NF-κB to the promoter site of several inflammatory genes activate them to secrete proinflammatory cytokines and chemokines. Plant derived natural compounds like andrographolide could be useful in inflammatory disorders as it directly inhibit the binding of NF-κB with DNA at promoter site. Transcription factor NF-κB is a master regulator of the proinflammatory gene expression program and since it was suppressed by andrographolide, hence andrographolide is rightly termed as regulator of master regulator.

Introduction

Natural products based medicine has saved millions of lives and represents significant contributions in global health market. Plant derived medicines such as Artemisinin for malaria; Vincristine, Taxol and Sulphoraphane for cancer treatment are being used in modern medicine system. After screening several plant products, Andrographis paniculata was found suitable for suppressing inflammatory responses. It is an annual and herbaceous plant belonging to the family Acanthaceae which grows throughout tropical and subtropical Asia, Southeast Asia, and India. An active constituent of plant Andrographis paniculata namely andrographolide was identified which is chemically a labdane diterpenoid with molecular formula C₂₀H₃₀O₅ and molecular weight 350.4 g/mol (Fig. 1).

Fig. 1.

Chemical structure of andrographolide

In our recent study conducted on soldiers deployed in extreme altitude areas such as Siachen, found that soldiers has higher base line level of proinflammatory chemokines [1]. Low oxygen availability at high altitude causes cellular stress leading to mucosal barrier injury, neuroinflammation and memory impairment [2, 3] We have identified Andrographolide an active ingredient of plant Andrographis paniculata which prevented neuroinflammation by suppressing the master regulator of proinflammatory cytokines, NF-κB and improved synaptic plasticity markers [4].

Furthermore, Inhibitory effects of andrographolide on activated macrophages and adjuvant-induced arthritis was also studied and found that andrographolide imparted anti-inflammatory effects by suppressing the NF-κB and two key inflammatory enzymes and a signaling pathway that mediates expression of pro-inflammatory cytokines in situ. It is plausible that andrographolide might be useful as a drug for the clinical treatment of various inflammatory diseases like rheumatoid arthritis or diseases associated with joint pain [7]. In our recent study it was found that andrographolide is very potent in eliminating chikungunya virus (CHIKV). The study has shown that andrographolide reduced the CHIKV RNA copy number and viral protein expression in vitro and in vivo. Further, it also reduces TNF-α the proinflammatory cytokine responsible for severe arthritic pain in chikungunya fever. Thus, andrographolide could be a potential therapeutic agent against chikungunya disease [5–7].

In all the cases described above the key master regulator was NF-κB a pleiotropic regulator of many genes which was suppressed by andrographolide leading to decreased proinflammatory cytokines, chemokines and enzymes such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase-2 (iNOS).

The NF-κB family has five cellular members: p105/p50 (NF-κB1), p100/p52 (NF-κB2), p65 (RelA), RelB, and c-Rel. Each member consists of ~ 300 amino acids domain and shares high homology. It mediates DNA binding and interaction with inhibitory IkB protein [8]. In an unstimulated cell, NF-κB complexes bind with I-kB and localized in the cytoplasm. When cell get stimulated, the phosphorylation of I-kB occurs by the enzymes I-κB kinases α and β (IKK α and −β) and degraded via ubiquitin proteasome machinery. This leads to translocation of p50/p65 heterodimer of NF-κB to the nucleus where it binds to the DNA for the transcription of multiple genes such as proinflammatory cytokines (IL-1, IL-2, IL-6, IL-8, and TNF-α), Cox-2, iNOS, cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1).

How Andrographolide Downregulates NF-κB Expression?

A study published by Xia et al. [9] reported that andrographolide make a covalent adduct with reduced cysteine (62) of p50, thus blocking the binding of NF-κB oligonucleotide to nuclear proteins. Andrographolide suppressed the activation of NF-κB in stimulated endothelial cells, while, it had no suppressive effect on IκBα degradation, p50 and p65 nuclear translocation thus revealed a unique pharmacological mechanism of andrographolide protective anti-inflammatory actions.

Conclusion

Natural products have been widely used as folk medicines in Indian subcontinent since the 12th Century BC. It is still quite popular even today. For example, the plant Andrographis paniculata has long been used as a folk remedy for alleviation of inflammatory disorders in China, India, Japan, and Korea. Plant derived natural compounds like andrographolide could be useful in most of inflammatory disorders as it directly inhibit the binding of NF-κB with DNA at promoter site. It has a huge market potential. Andrographolide is a prescribed medicine for treatment of rheumatoid arthritis in China. Since it suppressed the inflammation, Cox-2, iNOS and adhesion moleculesregulated by NF-κB, It could be termed as regulator of master regulator.

Compliance with Ethical Standards

Conflict of interest

Author report no conflict of interest.