Norepinephrine Induces β2-adrenergic Receptor-associated Oxidative Stress and Melanocyte Damage in Organ-cultured Human Scalp Hair Follicles: Implications for Vitiligo-associated Poliosis

Poliosis in vitiligo is closely linked to loss or dysfunction of melanocytes within hair follicles, but the contribution of adrenergic stress signalling remains poorly understood. We first compared β2-adrenergic receptor immunoreactivity in vitiligo-associated poliosis hair follicles and normally pigmented hair follicles. We then used cultured human scalp hair follicles to examine the temporal effects of 5 μmol/L norepinephrine, with or without the selective β2-adrenergic receptor antagonist ICI-118551, over 1-7 days. Acute norepinephrine exposure (1 day) increased malondialdehyde levels, reduced superoxide dismutase activity, depolarized the mitochondrial membrane, increased 8-hydroxy-2'-deoxyguanosine and reduced B-cell lymphoma 2 immunoreactivity. Longer exposure (5-7 days) increased gamma histone 2 AX and terminal deoxy-nucleotidyl transferase dUTP nick end labelling signals and produced progressive melanocyte ultrastructural injury. Norepinephrine also reduced tyrosinase-related protein 2 and glycoprotein 100 (premelanosome protein, gp100) immunoreactivity, shortened gp100-positive melanocyte dendrites and produced a biphasic change in Masson-Fontana-stained melanin, with an early increase followed by a decline. ICI-118551 attenuated these effects. These findings show that sustained norepinephrine exposure damages the pigmentation of healthy human scalp hair follicles through a pathway involving β2-adrenergic receptor, oxidative stress, DNA damage and apoptosis. Because functional experiments were not performed in vitiligo hair follicles, the relevance of this pathway to vitiligo-associated poliosis remains to be further researched.