［依頼総説］カンナビノイド作動薬, バニロイド作動薬によるダリエー病治療薬の開発

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  • Cannabinoid and vanilloid agonists as novel therapeutics for Darier's disease

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Darier's disease is an autosomal dominant inherited keratoderma and is caused by a haplo-insufficiency of the ATP2A2 gene product, SERCA2 Ca channel. Due to the decrease in the active SERCA2 protein, the affected keratinocytes cannot conduct normal Ca metabolism and result in the individual dyskeratosis and acantholysis. Based on this pathogenesis, we had screened several hundreds of bioactive reagents to identify potential agents that could activate the transcription of ATP2A2 and thus might be a candidate therapeutics for Darier's disease. Consequently, we found that drugs belonging to the classes of cannabinoid and vanilloid agonists significantly increase the ATP2A2/SERCA2 expression at both mRNA and protein levels in cultured normal keratinocytes as well as in Darier's affected ones. Skin grafted on nude mice and the threedimensional reconstituted model using patients' keratinocytes were used to confirm the effects of these therapeutics on phenotypic expression of Darier's disease. Following the application of selected agonists, the normal keratinizing process was restored without producing dyskeratotic cells and blisters, while the dyskeratotic cells and acantholytic lacunae still remained in the control treated with DMSO. The use of selective agonists confirmed that these pharmacological effects are produced through the activation of CB2, a cannabinoid receptor, and TRPV 3/4, a kind of thermal receptor sensing midrange temperatures. We also noted that human body temperature tends to be somewhat higher at the seborrheic lesional skin areas compared with the nearby areas when measured by the thermograph. Based on these findings, we can expect to identify novel therapeutics for Darier's disease and, moreover, we can understand why Darier's disease worsens at seborrheic areas during summer season. The temperature of lesions appears to be slightly higher than the sensing range of the TRPV receptor in order to trigger the induction of Serca2 mRNA transcription. Thus, Darier's patients might suffer from severe skin lesions at the seborrheic area in the summer season.

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