Effects of high-affinity nerve growth factor receptor inhibitors on symptoms in the NC/Nga mouse atopic dermatitis model.
BACKGROUND
Nerve growth factor (NGF) is an important substance in the skin, where it modulates nerve maintenance and repair. However, the direct link between NGF and pruritic diseases such as atopic dermatitis is not yet fully understood. Our previous study showed that NGF plays an important role in the pathogenesis of atopic dermatitis-like skin lesions in NC/Nga mice. NGF mediates its effects by binding to two classes of transmembrane receptors, a high-affinity receptor (tropomyosin-related kinase A, TrkA) and a low-affinity receptor (p75).


OBJECTIVE
To determine the significance of NGF receptors in the pathogenesis of atopic dermatitis, the effects of TrkA inhibitors AG879 and K252a on the symptoms of NC/Nga mice were evaluated.


METHODS
Male NC/Nga mice with severe skin lesions were used. AG879 or K252a was applied to the rostral part of the back of mice five times a week. The dermatitis score for the rostral back was assessed once a week. The scratching behaviour was measured using an apparatus, MicroAct (Neuroscience, Tokyo, Japan). Immunofluorescence examinations were made in the rostral back skin for nerve fibres, NGF and TrkA receptor.


RESULTS
Repeated applications of AG879 or K252a significantly improved the established dermatitis and scratching behaviour, and decreased nerve fibres in the epidermis. NGF was observed more weakly in keratinocytes, and a lower expression of TrkA was observed in stratum germinativum of the epidermis of mice treated with AG879 or K252a compared with those treated with vehicle.


CONCLUSIONS
We suggest that NGF plays an important role in the pathogenesis of atopic dermatitis-like skin lesions via the high-affinity NGF receptor. These findings provide a new potential therapeutic approach for the amelioration of symptoms of atopic dermatitis.
Takano
N
N
Pharmacological Evaluation Laboratory, Self Medication Laboratories, Medicinal Development Research Laboratories, Taisho Pharmaceutical Co Ltd, Saitama City, Saitama, Japan. n.takano@po.rd.taisho.co.jp
Sakurai
T
T
Ohashi
Y
Y
Kurachi
M
M
D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use*; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D026121:Indole Alkaloids / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011537:Pruritus / Q000209:etiology; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D016896:Treatment Outcome; D020032:Tyrphostins / Q000627:therapeutic use*
C081020:AG-879; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D017475:Receptors, Nerve Growth Factor; D020032:Tyrphostins; C049985:staurosporine aglycone