BoNT-A amelliorates itch sensitization in atopic dermatitis mice by inhibiting histamine release.

In this study, we thoroughly investigated the potential mechanisms underlying the therapeutic effects of Botulinum Toxin Type A (BoNT-A) on ameliorating pruritic behavior and allodynia in a murine model of atopic dermatitis (AD). Recognizing the pivotal role of mast cells in AD pathogenesis, we hypothesized that BoNT-A inhibits mast cell degranulation via the cleavage of SNAP-25. Using P815 cells and primary mast cells, we confirmed the expression of SNAP-25 and SV2, and through siRNA-mediated knockdown, we validated that SNAP-25 is a pivotal mediator of mast cell degranulation and the specific target required for BoNT-A' s inhibitory action. In our in vivo experiments utilizing MC903-induced AD mice, we observed that BoNT-A administration significantly reduced scratching bouts and alleviated pruritus allodynia while decreasing mast cell recruitment in both epidermal and dermal layers. Furthermore, to elucidate the involvement of the central nervous system, we constructed a BoNT-A/FITC complex and demonstrated that the toxin undergoes retrograde transport from peripheral nerves to the spinal cord dorsal horn. Therefore, it appears to exert an antipruritic effect by downregulating the expression of pruritus-related ion channels and neuropeptides, specifically TRPV1 and CGRP. Consequently, our findings establish that BoNT-A exerts its therapeutic effects through a dual mechanism: peripherally by inhibiting mast cell degranulation via the SNAP-25/SV2 pathway, and centrally by modulating neurogenic inflammation within the spinal cord, thus providing a novel perspective for the treatment of allergic diseases.