Scientists in the U.S. have developed compounds derived from solenopsin, the toxic constituent of fire ant venom, which helped to reduce skin thickening and inflammation in a mouse model of psoriasis, and which they suggest could be evaluated as potential new treatments for psoriasis in humans.
Psoriasis is an autoimmune chronic inflammatory skin condition that affects an estimated 2.5–6 million patients in the U.S., or about 1–2% of the population. Topical treatments—primarily corticosteroids—have been the mainstay of managing mild to moderate psoriasis for 50 years. Systemic drugs including methotrexate, vitamin A derivatives, and cyclosporine, and biologic treatments including drugs that target tumor necrosis factor alpha (TNF-alpha), interleukin (L)-23, and IL-17, are used to treat more generalized and severe disease.
Biologic therapies aren’t suitable for most patients with mild to moderate disease. They are expensive, and can also result in systemic immunosuppression. Unfortunately, long-term use of topical steroids can also lead to resistance, and may cause cutaneous atrophy. Some thicker lesions are also refractory to topical steroid therapy, report Jack L. Arbiser, M.D., Ph.D., professor of dermatology at Emory University School of Medicine, his colleagues at Emory, and colleagues at the Veterans Affairs Medical Center (Decatur, GA), Case Western Research University (Cleveland, OH), the University of Alabama (Birmingham, AL), and Universität München (Germany). Alternative topical treatments, including vitamin D analogs, retinoids, and calcineurin inhibitors, have been developed, but these haven’t really impacted topical steroid use, the researchers suggest.
Ceramides are a family of lipids that play a key role in maintaining skin-barrier function, and loss of this barrier function leads to increased expression of vascular endothelial growth factor (VEGF), which is a major mediator of angiogenesis and inflammation. The use of emollients that restore the skin barrier can help to resolve psoriasis, but they also can’t cure the disease. Unfortunately, ceramides can also act as what the researchers call a “double-edged sword.” While in their natural state they promote skin homeostasis, ceramides can be metabolized to sphingosine-1-phosphate (S1P), which is linked with cellular growth, inflammation, and tumorigenesis.
Dr. Arbiser’s laboratory had previously shown that the fire ant venom compound solenopsin inhibits blood vessel growth and offers potential as an anticancer agent. In their latest work, reported in Scientific Reports (“Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis,”) the researchers describe the development of two solenopsin-derived analogs that remain in their beneficial form, and can’t be metabolised to S1P.
The team formulated the compounds into a skin cream, which they then applied topically to a well-validated mouse model of psoriasis (KC-Tie2 mice), for 28 days. The results showed that the solenopsin analog treatment reduced two key features of psoriasis, acanthosis and hyperkeratosis, in treated animals. Skin thickness in the treated mice decreased by about 30%, and the animals also demonstrated about 50% less skin infiltration by immune cells. Solenopsin analog therapy also reduced the expression of genes that are upregulated by existing psoriasis treatments, including steroids and ultraviolet light. “This may be compensatory and a mechanism of resistance to anti-psoriasis therapy, and it suggests that the solenopsin compounds could be used in combination with existing approaches,” Arbiser says.
When tested on immune cells in culture, the two compounds also reduced production of the inflammatory signal IL-22, and increased production of anti-inflammatory IL-12. “Emollients can soothe the skin in psoriasis, but they are not sufficient for restoration of the barrier,” Dr. Arbiser commented. “We believe that solenopsin analogs are contributing to full restoration of the barrier function in the skin.”
The researchers conclude that “further studies of these analogs as anti-psoriatic drugs are warranted in humans.”