title: Direct effects of radon exposure on the neural system - a possible target for pain relief
Creators: name: Joswig, Juliane
Publisher: name: UNSPECIFIED
Year: 2022

description: About 1 % of the worldwide population suffers from rheumatoid arthritis, which causes systemic inflammation and leaves patients suffering from chronic pain even after resolution of clinical signs. Patients often decide to undergo radon therapy to relief their pain despite the fact that radon has been declared the second most common cause of developing lung cancer. Although radon therapy has been used for over 100 years in some countries, the molecular mechanism underlying its pain relieving effect is still unknown. However, the identification of the molecular working mechanism of radon therapy is of high interest so that alternative therapies can be developed to achieve comparable pain alleviation without patients having to endure risking the development of lung cancer. Although the experience of pain in general is an important warning device to invoke reflex withdrawal, pain can also take on a disease character. This phenomenon is defined as chronic pain, which presents with pain lasting several weeks or longer and serves no obvious beneficial function. Traditionally, the spinal dorsal horn and periphery were the main targets for pain therapy. However, it has been suggested that when central changes occur in the brain following chronic pain, it may be too late to interfere at the periphery and the brain becomes an essential target to alleviate pain. In case of RA patients, synaptic changes in the brain could present a point of action for radon therapy. In order to identify a potential molecular working mechanism of radon exposure, this thesis started to investigate the effect radon inhalation exhibits on the neurosensory system. Firstly, due to radon‟s similar physical characteristics to xenon, the hypothesis arose that radon, like xenon, may bind to N-Methyl-D-aspartate-receptors (NMDARs) thereby inhibiting pathological pain transmission. Molecular dynamic simulations showed that radon indeed hijacks four of the same binding sites as xenon on NMDARs with some binding energies even exceeding those of xenon. Additionally, an in vitro radon binding assay showed an increased amount of DNA double strand breaks (DSBs) in cells expressing NMDARs compared to cells lacking NMDARs. Interpolating from a linear regression correlation between DNA DSB induction and deposited radiation dose, it was calculated that cells expressing NMDARs obtain a 47 % higher dosage from radon exposure. This led to the assumption that especially NMDAR-rich environments could present a target for radon therapy. Therefore, it was validated that radon reaches the brain, which represents a NMDAR-rich environment. Immunofluorescent staining of radon induced DNA DSBs showed that radon damages brain tissue to the same degree as other tissues such as heart or liver. A linear regression from the correlation of DNA DSBs to deposited radiation dose yielded an estimated radiation dose of 2.3 mGy per cell. Lastly, the effect of radon inhalation on K/BxN 2 serum transfer mice brain indicates a dual function of radon in pain alleviation. While the maintenance of long-term potentiation (LTP) could be impaired after radon exposure caused by a significant reduction of NMDAR GluN2B phosphorylation of Y1472, there is evidence for a restored long-term depression (LTD) expression through significant increase in active protein kinase C-α (PKC-α). All in all, the results presented in this work postulate a novel molecular working mechanism for radon therapy by directly affecting the neurosensory system.