Tachykinergic mechanisms in atopic dermatitis

Atopic dermatitis (AD) is an often severely itching, chronic, inflammatory skin disorder and may worsen due to stress and anxiety. Tachykinins have been suggested to influence the level of inflammation as well as being involved in pruritus, stress and anxiety.

The aim of the study was to investigate the role of tachykinins, including substance P and neurokinin (NK) A, in the pathogenesis of AD, pruritus and worsening during stress.

Initially an animal model was used to investigate innervation, substance P and the neurokinin (NK)-1 receptor (R) in relation to eczema and stress using an immunohistochemistry method. Chronic mild stress seemed to decrease innervation in eczematous skin lesions and we recorded a decrease in substance P positive fibres in stressed eczematous skin compared to in stressed control. In addition, a tendency of increased levels of NK-1R m-RNA in skin of stressed compared to non-stressed eczematous mice was apparent using PCR. A decrease of substance P immunoreactivity was detected in the medial hippocampus of the brain in stressed compared to in non-stressed eczematous mice.

Tachykinin expression was then examined in the skin of AD patients, and possible correlations to clinical and psychodemographic parameters were investigated. The numbers of substance P- and NKA positive nerve fibres and also of NKA positive dermal cells were increased in lesional compared to non-lesional skin. In addition, there was a correlation between the NK1-R positive cells, and the level of acanthosis and inflammation, in the lesional skin. There was also a correlation between the depression score and the number of the NK-1R positive cells in lesional as well as in non-lesional skin.

Finally, the effect of an NK-1R antagonist, aprepitant, was evaluated in adult patients with moderate-severe AD, compared to a standard topical treatment in an open randomized trial. In both the treatment group and the control group significant improvement was evident both regarding extent of disease and pruritus. However, there was not any significant additional improvement for any of these parameters in the aprepitant-treated patients compared to controls.

In conclusion, tachykinins seem to have a role in the pathogenesis and stressworsening of AD. However, this role seems to be complex and further investigations are needed to fully understand these connections.

List of scientific papers

I. Lönndahl L, Lonne-Rahm SB, Nordlind K, Theodorsson E, El-Nour H. Decreased innervation of eczematous skin in NC/Nga atopic mice during chronic mild stress. Immunopharmacol Immunotoxicol. 2010; 32:147- 152.
https://doi.org/10.3109/08923970903219633

II. Grip L, Lonne-Rahm SB, Holst M, Johansson B, Nordlind K, Theodorsson E, El-Nour H. Substance P alterations in skin and brain of chronically stressed atopic-like mice. J Eur Acad Dermatol Venereol. 2013; 2:199-205.
https://doi.org/10.1111/j.1468-3083.2011.04443.x

III. Lönndahl L, Rasul A, Lonne-Rahm SB, Holst M, Johansson B, El-Nour H, Radu-Djurfeldt D, Nordlind K. Tachykinergic markers in atopic dermatitis. [Submitted]

IV. Lönndahl L, Holst M, Bradley M, Killasli H, Heilborn J, Hall MA, Zou L, Nordlind K. The substance P antagonist aprepitant shows no additive effect compared to standardized topical treatment alone, in atopic dermatitis patients. [Manuscript]