Application and Mechanism of Action of Crotamiton

Application of Crotamiton

Crotamiton is an anti-scabies medication,Scabies is a contagious skin disease caused by the microscopic mite Sarcoptes scabiei that causes intense itching. Studies have found that Crotamiton also also have an antipruritic effect on non-scabies mite itching, caused by pruritogens. It is usually sold in the form of a lotion or cream. In addition, it has shown anti-aging activity.

While screening our in-house 1,072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic and anti-aging effects, and could further lead to promising application prospects.

Mechanism of Action

Recently, Crotamiton was also found to inhibit non-scabies itching in mice, but the mechanism of action is still unclear, and the mechanism of action will be elucidated through relevant animal studies. Crotamiton strongly inhibited histamine-induced calcium influx in HEK293T cells, expressing both histamine receptor 1 (H1R) and transient receptor potential vanilloid 1 (TRPV1), as a model of histamine-induced itching. Similarly, it also blocked chloroquine-induced calcium influx in HEK293T cells, expressing both Mas-related G-protein-coupled receptor A3 (MRGPRA3) and transient receptor potential A1 (TRPA1), as a model of histamine-independent itching. Furthermore, crotamiton also suppressed both histamine- and chloroquine-induced calcium influx in primary cultures of mouse DRG. Additionally, crotamiton strongly suppressed histamine- and chloroquine-induced scratching in mice. Overall, it was found that crotamiton has an anti-pruritic effect against non-scabietic itching by histamine and chloroquine. Therefore, crotamiton may be used as a general anti-pruritic agent, irrespective of the presence of scabies.

References:

[1] DA-SOM CHOI. Crotamiton, an Anti-Scabies Agent, Suppresses Histamine- and Chloroquine-Induced Itch Pathways in Sensory Neurons and Alleviates Scratching in Mice.[J]. Biomolecules & Therapeutics, 2020. DOI:10.4062/biomolther.2020.063.

[2] KETING BAO. Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9[J]. eLife, 2021. DOI:10.1101/2021.09.19.460995.