The non-neuronal and nonmuscular effects of botulinum toxin: an opportunity for a deadly molecule to treat disease in the skin and beyond

Abstract

There is growing evidence that botulinum neurotoxins (BoNTs) exhibit biological effects on various human cell types with a host of associated clinical implications. This review aims to provide an update on the non-neuronal and nonmuscular effects of botulinum toxin. We critically analysed recent reports on the structure and function of cellular signalling systems subserving biological effects of BoNTs. The BoNT receptors and intracellular targets are not unique for neurotransmission. They have been found in both neuronal and non-neuronal cells, but there are differences in how BoNT binds to, and acts on, neuronal vs. non-neuronal cells. The non-neuronal cells that express one or more BoNT/A-binding proteins, and/or cleavage target synaptosomal-associated protein 25, include: epidermal keratinocytes; mesenchymal stem cells from subcutaneous adipose; nasal mucosal cells; urothelial cells; intestinal, prostate and alveolar epithelial cells; breast cell lines; neutrophils; and macrophages. Serotype BoNT/A can also elicit specific biological effects in dermal fibroblasts, sebocytes and vascular endothelial cells. Nontraditional applications of BoNT have been reported for the treatment of the following dermatological conditions: hyperhidrosis, Hailey-Hailey disease, Darier disease, inversed psoriasis, aquagenic palmoplantar keratoderma, pachyonychia congenita, multiple eccrine hydrocystomas, eccrine angiomatous hamartoma, eccrine sweat gland naevi, congenital eccrine naevus, Raynaud phenomenon and cutaneous leiomyomas. Experimental studies have demonstrated the ability of BoNT/A to protect skin flaps, facilitate wound healing, decrease thickness of hypertrophic scars, produce an anti-ageing effect, improve a mouse model of psoriasiform dermatitis, and have also revealed extracutaneous effects of BoNT arising from its anti-inflammatory and anticancer properties. BoNTs have a much wider range of applications than originally understood, and the individual cellular responses to the cholinergic impacts of BoNTs could provide fertile ground for future studies.

Botulinum toxin type A in chronic non‐dyshidrotic palmar eczema: A side‐by‐side comparative study

“…BTX‐A can suppress the release of several pro‐inflammatory neuropeptides as substance p, glutamate and calcitonin gene‐related peptide from postsynaptic nerve endings 4 . Acting on its receptors on the keratinocytes and lymphocytes, 23 it was demonstrated to reduce the acanthosis and the lymphocytic infiltration in a mouse model of psoriasiform dermatitis, 24 an action that is relevant in cases of chronic hand eczema.…”

The Safety and efficacy of botulinum toxin type A injection for postoperative scar prevention: A systematic review and meta‐analysis

“…The mechanical signals generated by tension on both sides of the wound can affect the movement and contraction of fibroblasts, the expression of Type I collagen, and the transformation from fibroblasts to myofibroblasts . However, the N‐terminal of BTXA light chain has the activity of zinc metalloproteinase, which can cut the synaptosomal‐associated protein of 25 kDa (SNAP‐25) and prevent the release of acetylcholine into the synaptic cleft, thus causing “chemo‐denervation,” reducing the tension on both sides of the wound and affecting the scar morphology . In addition, some evidences suggest that BTXA may affect scar formation by reducing fibroblast proliferation, reducing TGF‐β expression, and altering collagen deposition and remodeling processes .…”

“…3 and prevent the release of acetylcholine into the synaptic cleft, thus causing "chemo-denervation," reducing the tension on both sides of the wound and affecting the scar morphology. 25,26 In addition, some evidences suggest that BTXA may affect scar formation by reducing fibroblast proliferation, reducing TGF-β expression, and altering collagen deposition and remodeling processes. 27 further reduce the content of TGF-β1 28 and its downstream regulator connective tissue growth factor (CTGF).…”

“…The mechanical signals generated by tension on both sides of the wound can affect the movement and contraction of fibroblasts, the expression of Type I collagen, and the transformation from fibroblasts to myofibroblasts 24. However, the N-terminal of BTXA light chain has the activity of zinc metalloproteinase, which can cut the synaptosomal-associated protein of 25 kDa (SNAP-25)…”

Botulinum toxin type A for wrinkles: the least interesting use of this versatile protein

“…Grando and Zachary deserve thanks for their interesting and important work regarding the nonneuronal and nonmuscular effects of botulinum toxins, published in this issue of the British Journal of Dermatology . It is relevant to dermatologists and nondermatologists alike, both for education on these specific new applications and to give importance to investigating potential alternative molecular pathways and the off‐label potential of all pharmaceuticals.…”