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. 2022;35(2):94-101.
doi: 10.1159/000519669. Epub 2021 Sep 16.

Influence of Janus Kinase Inhibitors on the Neuronal Activity as a Proof-of-Concept Model for Itch

Johannes Wohlrab  1   2 , David Stintzing  2 , Luise Schultz  3 , Konstantin Jügelt  3 , Olaf H-U Schroeder  3
Affiliations

Influence of Janus Kinase Inhibitors on the Neuronal Activity as a Proof-of-Concept Model for Itch

Johannes Wohlrab et al. Skin Pharmacol Physiol. 2022.

Abstract

Background: Itching is considered to be a subjective symptom of the activation of neurosensory structures by different signal molecules and trigger factors. The signaling cascades responsible for it are closely linked to inflammatory processes. This explains why itching also occurs in many inflammatory diseases. One of these signaling cascades is mediated by Janus kinases (JAKs). Recently, it could be shown on a molecular level that Janus kinase 1 (JAK1) directly activates frontal cortex neurons and thus can cause chronic itching.

Objectives: This study deals with the influence of different JAK inhibitors (JAKi) on the activity of chip-based neural networks of cultured frontal cortex neurons by investigating neurophysiological activity parameters. This in vitro model provides information on dose-dependent effects of model substances with different specificity regarding the inhibition of different JAKs.

Methods: Tofacitinib (pan-JAKi), baricitinib (JAK1/2i), and upadacitinib (JAK1i) in a concentration range from 10 nmol/L to 50 μmol/L were tested in a microelectrode array neurochip culture system.

Results: The results show that the inhibition of the neuronal activity of frontal cortex neurons increases with JAK1 selectivity and is dependent on concentration.

Conclusion: These observations are supported by data from clinical studies in atopic dermatitis and psoriasis. The clinical relevance of these results must be proven by further clinical studies with subjective and objective parameters for itching.

Keywords: Itch; Janus kinase; Janus kinase inhibitors; Neuronal activity.

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Conflict of interest statement

J.W. has received fees for lecturing and/or consulting and/or received funding for scientific projects and/or clinical studies from Abbvie, Leo, Lilly, Novartis, and Pfizer. D.S. declares no conflicts of interest. L.S., K.J., and O.S. are employees of NeuroProof GmbH.

Figures

Fig. 1
Fig. 1
Overview of the different receptor types of primary afferent sensory neurons, as well as cascades, during itching. IL-4R, interleukin-4 receptor subunit a; IL-31R, interleukin-31 receptor; NK-1R, neurokinine-1 receptor; TSLPR, thymic stromal lymphopoietin receptor; TRPV1, transient receptor potential cation channel subfamily V member 1.
Fig. 2
Fig. 2
Concentration-responses of DMSO (0.002–0.1%), tofacitinib, baricitinib, and upadacitinib (1–50 μM) on frontal cortex networks. Values are mean ± SEM with statistical significance (*/**/** for p ≤ 0.05/0.01/0.001). Values of rows 2–4 are scaled to a minimum of 50%. DMSO, dimethyl sulfoxide; SEM, standard error of mean.
See this image and copyright information in PMC

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