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

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.