Redox regulation of cellular stress response in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic foci of inflammatory demyelination in the brain, spinal cord, and optic nerves. Recent studies have demonstrated not only that axonal damage and neuronal loss are significant pathologic components of MS, but that this neuronal damage is thought to cause the permanent neurologic disability often seen in MS patients. Emerging finding suggests that altered redox homeostasis and increased oxidative stress, primarily implicated in the pathogenesis of MS, are a trigger for activation of a brain stress response. Relevant to maintenance of redox homeostasis, integrated mechanisms controlled by vitagenes operate in brain in preserving neuronal survival during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. In the present study we assess stress response mechanisms in the CSF, plasma and lymphocytes of control patients compared to MS patients. We found that the levels of vitagenes Hsp72, Hsc70, HO-1, as well as oxidative stress markers carbonyls and hydroxynonenals were significantly higher in the blood and CSF of MS patients than in control patients. In addition, an increased expression of Trx and sirtuin 1, together with a decrease in the expression of TrxR were observed. Our data strongly support a pivotal role for redox homeostasis disruption in the pathogenesis of MS and, consistently with the notion that new therapies that prevent neurodegeneration through nonimmunomodulatory mechanisms can have a tremendous potential to work synergistically with current MS therapies, unravel important targets for new cytoprotective strategies

Elevated Levels of Carbonyl Proteins in Cerebrospinal Fluid of Patients with Neurodegenerative Diseases

“…Whereas higher levels of CPs in the CSF are associated with inflammatory or degenerative diseases, this does not hold for levels in the EDTA blood. This is in contrast to the findings of Pennisi et al (2011) who presented significant differences in the plasma of MS patients when compared to controls. Whereas Pennisi et al (2011) investigated CPs only in RRMS patients, we assessed the levels in relapsing and progressive MS patients as well as in patients with neurodegenerative diseases.…”

“…Moreover, former studies showed that levels of CPs in the CSF of patients with RRMS were higher than in controls (Pennisi et al 2011), and elevated levels of CPs were detected in the plasma of patients with Alzheimer's disease when compared with controls without dementia (Greilberger et al 2010). Here we show for the first time that CPs are increased in the CSF of neurodegenerative diseases, such as ALS and progressive MS.…”

“…Carbonyl proteins (CPs) are the end product of metabolic processes (Greilberger et al 2010;Pennisi et al 2011) and recent trials suggested CPs as a marker for OS in the plasma of patients with degenerative diseases like Alzheimer's disease (Greilberger et al 2010).…”

“…Nitrit oxide metabolites were assessed in the CSF of MS patients by Rejdak et al (2008). Whereas CPs have recently been assessed in the CSF of relapsing MS patients (Pennisi et al 2011), the relevance in the CSF of patients with diseases characterized by neurodegeneration remains unexplored. The aim of this proof of concept trial is to explore CPs in the CSF of neurodegenerative diseases, and whether they may serve as a marker for OS in the CSF of patients with neurodegenerative diseases.…”

Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

“…As plasma levels of SIRT1 were found to be increased in MS patients when compared with non-neurological disease controls, it is also postulated that soluble/circulating SIRT1 is an adaptive response during MS and it may play an important role in disease pathogenesis [85]. Therefore, a more comprehensive understanding of the molecular mechanism governing axonal preservation achieved through the activity of SIRT1 must be achieved to classify it as a neuroprotective agent of therapeutic potential.…”