Multiple sclerosis (MS) is by far one of the most commonly occurring demyelinating neuroinflammatory diseases of young adults that is characterized by degradation of the myelin sheath of axons resulting eventually in permanent neurological deficits. Several mediators of the kallikrein-kinin system (KKS) have been identified to be critical contributors to MS pathogenesis and potent direct modulators of neurological functions. In this context, high levels of plasma prekallikrein (PK) were found in active central nervous system (CNS) lesions of MS patients. Recently, Kv7 channels that generate the M-current were found to be altered following demyelination thereby representing potential new molecular players. The aim of our study was to investigate the effect of mediators of the KKS in MS and their modulation of Kv7 channels.In our study, we performed gene expression analysis following cuprizone-induced myelin loss showing decreased levels of Kallikrein 6 in the auditory cortex (Au1) mice. To study the electrophysiological properties of the Kv7.2 and Kv7.3 channels under the influence of kallikrein, channel subtypes were expressed individually and in combination in Xenopus laevis oocytes. Characteristic M-currents showed a significant kallikrein-induced increase when Kv7.3 channel were expressed alone or together with Kv7.2. Furthermore, we investigated the influence of kininogen on myelination in an organotypic slice culture model.In conclusion, we found that components of the KKS are involved in MS and a better understanding of the KKS may help to realize novel therapeutic approaches in MS injury treatment.