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Andrographolide: Potential Treatment for Ulcerative Colitis & Other Inflammatory Diseases

The Dextran Sulfate Sodium (DSS)-Induced Colitis Model is a common animal model used to study ulcerative colitis (UC) that can recapitulate many aspects of the disease: weight loss, diarrhea, gastric bleeding, intestinal inflammation, and increased permeability of the intestinal barrier. Feeding mice 40-50 kDa sized DSS damages the epithelial layer of the intestines (specifically the colon) and downregulates the expression of tight junction proteins ZO-1, as well as various claudins, making the mucosal barrier of the intestines more permeable (1). This damage to the epithelial layer allows for increased translocation of bacteria and bacterial toxins from the lumen of the intestines to the bloodstream, stimulating a severe inflammatory response and inducing colitis. Despite increased intestinal permeability being a driving factor of UC, most treatment options do not help resolve this key feature of the disease.

Treatment of UC has typically involved managing flare-ups of the disease through changes in diet to avoid inflammatory triggers and administration of immunosuppressant drugs to subdue inflammatory responses. In severe cases, surgery to remove damaged segments of the intestines may be necessary. However, in 2018 a new treatment that can improve the “leaky gut” characteristic of UC was approved by the FDA. Tofacitinib (Xeljanz), a Janus kinase (JAK) inhibitor originally used to treat rheumatoid arthritis, can inhibit JAK activation and prevent INF-γ mediated changes to intestinal epithelial cell permeability and preserve the intestinal barrier integrity (1). Identifying other drugs and compounds with healing effects on the intestinal mucosal barrier could not only help reduce the severity of UC flare-ups, but could also help lower the number of flare-ups patients experience.

One such compound is andrographolide, an active compound from the plant Andrographis paniculata that has been extensively used in traditional herbal medicine in China, Thailand, India, and other Asian countries for the treatment of several inflammatory diseases, including inflammatory bowel diseases (IBD). Previous studies of andrographolide show that it can reduce inflammation is models of UC by inhibiting activation of the IL-23/IL-17 axis (2) and down regulate levels of TNF-α and GM-CSF in bronchoalveolar fluid of mice in the OVA-Induced Asthma Model (3). Additionally, andrographolide treatment has a therapeutic effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (4). Given these findings, andrographolide (and its derivatives) could be a viable treatment option for a variety of inflammatory diseases.

Recently, researchers at Jinan University College of Pharmacy sought to study the effect of an andrographolide derivative conjugated with lipoic acid (antioxidant), termed AL-1, on the DSS colitis model (5). In this study, C57BL/6 mice were given water containing 2.5% DSS ad libitum for seven days. During these 7 days, mice either received no treatment (disease group) or AL-1 treatment (treatment group).

Mice receiving the AL-1 treatment showed significantly reduced disease activity (reduced weight loss, more normal stool consistency, and reduced fecal blood) compared to the disease group. Additionally, AL-1 treatment reduced serum levels of inflammatory cytokines such as IL-6, TNFα, and IL-1β. AL-1 could inhibit disease progression and improve the inflammatory profile of DSS-fed mice, but the underlying mechanism was not apparent. 

To evaluate the intestinal permeability of DSS-colitis mice, the mice were fed a 4-kDa, FITC-labelled dextran. Measuring the serum levels of the fluorescent molecule 3 hours after feeding can be used as a marker for paracellular permeability of the intestinal epithelial layer. The treatment group showed reduced levels of FITC-Dextran in serum compared to the disease group, indicating that AL-1 treatment helped preserve the normal permeability of the intestinal barrier. Serum levels of endotoxin, another measure of intestinal permeability, confirmed the ability of AL-1 to improve intestinal permeability in the DSS-colitis model. To better understand these protective effects of AL-1, the researchers performed a series of immunohistochemistry (IHC) studies to elucidate the morphological changes induced by andrographolide.

First, immunohistological analysis of intestinal tissue showed that AL-1 prevented the loss of goblet cells seen in the disease group. AL-1 also preserved the expression of mucin-2, a vital component of intestinal mucus, which was downregulated in the disease group. Furthermore, IHC staining showed that the disease group had significant down regulation of tight junction proteins ZO-1, claudin-1, claudin-3, and JAM-A. AL-1 treatment was able to preserve the expression of these tight junction proteins. Therefore, AL-1 improved the function intestinal barrier function not only by preserving mucus production in the intestines, but also by maintaining the expression of tight junction proteins in the epithelial cells of the intestines.

By preventing loss of intestinal mucosal barrier function in the DSS-Induced Colitis Model, AL-1 treatment could significantly reduce disease severity. The reduced levels of endotoxin in serum from AL-1 treated mice indicate that the preserved intestinal barrier function could prevent the translocation of bacterial antigens from the intestinal lumen, which could be a key factor in preventing or mitigating US flare-ups. Identifying other compounds that can improve intestinal barrier function in UC patients could drastically improve the lives of UC patients. Chondrex, Inc.’s DSS-Induced Colitis Model and Intestinal Permeability Evaluation products are therefore essential tools for studying the therapeutic capacity of compounds intended to improve UC treatment. 


References

  1. A. Sayoc-Becerra et al., The JAK-inhibitor tofacitinib rescues human intestinal epithelial cells and colonoids from cytokine-induced barrier dysfunction. Inflamm Bowel Dis. 26, 407-422 (2019).
  2. Q. Zhu et al., Andrographolide presents therapeutic effect on ulcerative colitis through the inhibition of IL-23/IL-17 axis. Am J Transl Res. 10, 465-473 (2018).
  3. A. Abu-Ghefreh, H. Canatan, C. Ezeamuzie, In vitro and in vivo anti-inflammatory effects of andrographolide. International Immunopharmacology 9, 313-318 (2009).
  4. J. Tichauer et al., Andrographolide suppresses chronic and relapsing-remitting experimental autoimmune encephalomyelitis. Conference Abstract: 15th International Congress of Immunology (ICI), 2013.
  5. N. Jiang et al., Andrographolide derivative AL-1 reduces intestinal permeability in dextran sulfate sodium (DSS)-induced mice colitis model. Life Sciences 241, (2020).