Oxidative Stress, Redox Homeostasis and Cellular Stress Response in Ménière’s Disease: Role of Vitagenes

Abstract

Ménière's disease (MD) is characterized by the triad of fluctuating hearing loss, episodic vertigo and tinnitus, and by endolymphatic hydrops found on post-mortem examination. Increasing evidence suggests that oxidative stress is involved in the development of endolymphatic hydrops and that cellular damage and apoptotic cell death might contribute to the sensorineural hearing loss found in later stages of MD. While excess reactive oxygen species (ROS) are toxic, regulated ROS, however, play an important role in cellular signaling. The ability of a cell to counteract stressful conditions, known as cellular stress response, requires the activation of pro-survival pathways and the production of molecules with anti-oxidant, anti-apoptotic or pro-apoptotic activities. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include heat shock proteins (Hsps) as well as the thioredoxin/thioredoxin reductase system. In this study we tested the hypothesis that in MD patients measurable increases in markers of cellular stress response and oxidative stress in peripheral blood are present. This study also explores the hypothesis that changes in the redox status of glutathione, the major endogenous antioxidant, associated with abnormal expression and activity of carbonic anhydrase can contribute to increase oxidative stress and to disruption of systemic redox homeostasis which can be associated to possible alterations on vulnerable neurons such as spiral ganglion neurons and consequent cellular degeneration. We therefore evaluated systemic oxidative stress and cellular stress response in patients suffering from Meniere's disease (MD) and in age-matched healthy subjects. Systemic oxidative stress was estimated by measuring protein oxidation, such as protein carbonyls (PC) and 4-hydroxynonenal (HNE) in lymphocytes of MD patients, as well as ultraweak luminescence (UCL) as end-stable products of lipid oxidation in MD plasma and lymphocytes, as compared to age-matched controls, whereas heat shock proteins Hsp70 and thioredoxin (Trx) expression were measured in lymphocytes to evaluate the systemic cellular stress response. Increased levels of PC (P < 0.01) and HNE (P < 0.05) have been found in lymphocytes from MD patients with respect to control group. This was paralleled by a significant induction of Hsp70, and a decreased expression of Trx (P < 0.01), whereas a significant decrease in both plasma and lymphocyte ratio reduced glutathione GSH) vs. oxidized glutathione (GSSG) (P < 0.05) were also observed. In conclusion, patients affected by MD are under condition of systemic oxidative stress and the induction of vitagenes Hsp70 is a maintained response in counteracting the intracellular pro-oxidant status generated by decreased content of GSH as well as expression of Trx. The search for novel and more potent inducers of vitagenes will facilitate the development of pharmacological strategies to increase the intrinsic capacity of vulnerable ganglion cells to maximize antid...

Polymorphisms in Genes Involved in Oxidative Stress Response in Patients with Sudden Sensorineural Hearing Loss and Ménière's Disease in a Japanese Population

“…Furthermore, the serum concentration of reactive oxygen species (ROS; as measured using spectrophotometric methods) and a global oxidative stress index, which reflect oxidative and antioxidant counterparts, respectively, were significantly higher in patients with SSNHL than they were in controls (Capaccio et al, 2011). Increased levels of protein carbonyls and 4-hydroxynonenal, which are markers of protein oxidation, have been detected in the lymphocytes of patients with Ménière's disease compared with controls, with a significant decrease in the ratio of reduced glutathione versus oxidized glutathione both in the plasma and in lymphocytes (Calabrese et al, 2010). The results of these previous reports imply that the oxidative stress response is involved in the pathophysiology of both SSNHL and Ménière's disease.…”

Progress in the research of GSH in cells

“…Staroń et al [41] found that rheumatoid arthritis (RA) patients have higher ROS levels than healthy people, whereas the expression of the antioxidant enzymes catalase and GPx were not significant different, and that superoxide dismutase antioxidant activity and -SH levels were lower in RA patients than in the control group. The GSH:GSSG ratio was significantly (P < 0.05) decreased in the plasma and lymphocyte cells of patients with Ménière's disease [42].…”

Glutathione peroxidase and catalase enzyme gene polymorphisms in profound congenital hearing loss

“…[12] In Meniere's disease, the patient's plasma and lymphocyte oxide glutathione amounts were found to be higher than the reduced glutathione amount. [13] In the GPX1 codon 200 C/T polymorphism, the balance between oxidative stress and antioxidants failed, and this was thought to be the reason for many diseases, such as cancer, Alzheimer's etc. [14,15] In noise-induced hearing loss and idiopathic sudden hearing loss, investigating the effect of oxidative stress included studying various enzyme polymorphisms, and some relationships between the gene polymorphisms and the diseases were found.…”