Dyclonine Hydrochloride

Dyclonine hydrochloride protects Friedreich‘s ataxia (FA) patient cells from thiol oxidative stress and induces frataxin (FXN) protein expression. The mechanism involves activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2) transcription factor, which binds to antioxidant response elements (AREs) located in the FXN gene locus. Dyclonine dose-dependently increased ARE-luciferase reporter activity in cellular assays, confirming Nrf2 pathway activation. In FA patient lymphoblasts, dyclonine treatment elevated both FXN transcript and FXN protein levels. In FA-YG8 transgenic mice, oral or intraperitoneal administration of dyclonine increased FXN protein expression in cerebellum, heart and liver tissues, accompanied by elevated levels of Nrf2 target proteins including heme oxygenase-1 (HO-1), NQO1 and GPX4.
Dyclonine also inhibited histone methyltransferase G9a activity, which contributes to silencing of the FXN locus through H3K9 methylation. In a proof-of-concept clinical study, six of eight FA patients showed increased buccal cell FXN levels after one week of topical dyclonine rinse, with fold induction correlating with disease severity.

Fig. 1 Dyclonine drives an induction of Nrf2 through the AREs in FXN gene. (Sahdeo S.; et al. 2014)