231 - Mn- and Fe-porphyrin-based SOD mimics are powerful suppressors of itch in histamine-dependent and -independent mouse models

Abstract

Chronic itch or pruritis is a common syndrome associated with many skin and systemic diseases and significantly reduces the patients’ quality of life. Chronic itch causes constant scratching, increases risk of infection, disrupts sleep, and eventually reduces quality of life. Although antihistamines are the first choice for treating itch, most chronic itch conditions are resistant to this treatment. Major hurdle for development of novel effective anti-itch treatment is the lack of information about the etiology and neurobiology of itch. Oxidative stress has a role in acute and chronic itch: both H2O2 and tert-butylhydroperoxide (tBHP) injections into the nape of neck of mice induced a potent scratching response that lasts for at least 30 min. Several metalloporphyrin-based SOD mimics, that decrease oxidative stress in cellular and animal models of numerous diseases, were tested on their ability to reduce itch: MnTE-2-PyP5+(BMX-010, AEOL10113), MnTnBuOE-2-PyP5+(BMX-001), MnTnHex-2-PyP5+ and FeTnHex-2-PyP5+. BMX-001 and BMX-010 are now in 4 clinical trials. Itch was induced in mice with intradermal injections of either 100 µg of compound 48/80 or 200 µg of chloroquine (CQ). While compound 48/80 induces histamine release from mast cells, CQ causes histamine-independent itch. Given intraperitoneally 20 min before compound 48/80 and CQ, SOD mimics decreased itching defined by the number of scratching events. The higher the lipophilicity of the compound, the more potent was its efficacy in reducing the number of scratching events. Lipophilic MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+ were highly efficacious at 1 mg/kg single ip injection in reducing number of scratches by ~80% in a compound 48/80-induced itch model. Hydrophilic MnTE-2-PyP5+ was ~6-fold less efficacious than either of the lipophilic compounds in same model. At 50 mg/kg, curcumin produced smaller effect than one seen with 1 mg/kg of MnTnBuOE-2-PyP5+. Trolox (vitamin E analog) and N-acetylcysteine decreased scratching at 100 and 200 mg/kg, respectively.