Plant-Derived Antioxidant May Have Role in Blistering Skin Disorder

BALTIMORE, Aug. 22 -- An experimental model of epidermolysis bullosa simplex responded promptly to an antioxidant phytochemical found in broccoli and related plants, investigators here reported.

Injection of pregnant mice with sulforaphane followed by topical treatment of newborn pups led to 83% survival, whereas 93% of pups died soon after birth without treatment, Paul Talalay, M.D., of Johns Hopkins, and colleagues, reported online and in the Aug. 20-24 issue of Proceedings of the National Academy of Sciences.

Sulforaphane works by activating two different signaling pathways but also has "potent anti-inflammatory properties that are manifested in the skin of treated newborns," the authors stated. "This anti-inflammatory effect may help limit the extent of tissue damage and/or assist tissue repair."

Epidermolysis bullosa simplex is a rare inherited skin disorder. In affected individuals, fluid-filled blisters arise on the skin in response to trauma. Debilitating and sometimes lethal, there is no cure.

Most cases of epidermolysis bullosa simplex occur as a consequence of mutations in keratin 5 or 14, genes that code for cytoskeletal intermediate filaments in keratinocytes. The mutations result in tissue fragility and susceptibility to trauma.

Dr. Talalay and colleagues reported findings from studies of sulforaphane to activate two signaling pathways (hedgehog and Keap1/Nrf2/ARE) and subsequent induction of the transcription factor Nrf2.

Activation of the pathways led to elimination of blistering, correlating with "reprogramming of keratin synthesis in the epidermis."

Initially, K14-null newborn mouse pups were treated with topical sulforaphane, which reduced cutaneous blistering, but results were inconsistent.

The investigators then gave sulforaphane to female mice by intraperitoneal injection on the last day of pregnancy. The treatment resulted in substantial induction of K16 and K17 (genes associated with wound repair) in embryonic skin.

Finally, the investigators examined the effects of combining intraperitoneal injection of sulforaphane every other day during the last week of pregnancy, followed by topical application of sulforaphane to newborn pups on days 0, 1, and 3.

The combination regimen had a dramatic and consistent effect on the appearance and integrity of pups' skin.

Following the combined administration of sulforphane, the K14-null pups "could not longer be identified based on their physical appearance and behavior" on day 0.5.

"The available evidence suggests that Nrf2 inducers like sulforaphane would be therapeutically effective in patients [with epidermolysis bullosa simplex] harboring any type of mutation at the K14 locus," the authors stated.