Arecoline-induced skin inflammation: irritant or allergic dermatitis?

Abstract

A severe skin inflammatory reaction halted the development of a transdermal device to systemically deliver arecoline, a cholinergic agonist, for use in the management of a human neurological disorder. This report demonstrates that the skin reaction is most likely an allergic contact dermatitis (ACD) exacerbated by inflammation, as characterized by classical immunological tests employing inbred mice: abdominal skin sensitization followed by ear challenge and ear challenge of recipients of lymphoid tissues from previously sensitized donors. Chemical analysis of the parent compound in three vehicles was performed to determine the chemical stability of the prepared solutions and the antigen specificity of the murine ACD response. Arecoline was hydrolyzed to the pharmacologically inactive metabolite, arecaidine, to the greatest extent in aqueous vehicles. ACD reactions were greatest when mice were both topically sensitized and challenged with arecoline. In contrast, arecaidine, the hydrolyzed product, did not have immunological activity, but was capable of producing local inflammation in a dose-dependent manner upon subcutaneous injection. These data support the mechanistic hypothesis that upon absorption into skin, arecoline induces a local inflammatory response and a systemic ACD response. Influx of lymphocytes to an arecoline-treated skin site likely mediate ACD through the combined inflammation produced by arecoline and arecaidine and recognition of arecoline as an immunogen.