Tuesday, 12 January 2016

Oxidative stress predicts progression

Genetic, Immune-Inflammatory, and Oxidative Stress Biomarkers as Predictors for Disability and Disease Progression in Multiple Sclerosis.

Kallaur AP, Reiche EM, Oliveira SR, Simão AN, Pereira WL, Alfieri DF, Flauzino T, Proença CM, Lozovoy MA, Kaimen-Maciel DR, Maes M.
Mol Neurobiol. 2016 Jan 5. [Epub ahead of print]

The aim of this study was to evaluate the TNFβ NcoI polymorphism (rs909253) and immune-inflammatory, oxidative, and nitrosative stress (IO&NS) biomarkers as predictors of disease progression in multiple sclerosis (MS). We included 212 MS patients (150 female, 62 male, mean (±standard deviation (SD)) age = 42.7 ± 13.8 years) and 249 healthy controls (177 female, 72 male, 36.8 ± 11 years). The disability was measured the Expanded Disability Status Scale (EDSS) in 2006 and 2011. We determined the TNFβ NcoI polymorphism and serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, IL-10, and IL-17, albumin, ferritin, and plasma levels of lipid hydroperoxides (CL-LOOH), carbonyl protein, advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). The mean EDSS (±SD) in 2006 was 1.62 ± 2.01 and in 2011 3.16 ± 2.29, and disease duration was 7.34 ± 7.0 years. IL-10, TNF-α, IFN-γ, AOPP, and NOx levels were significantly higher and IL-4 lower in MS patients with a higher 2011 EDSS scores (≥3) as compared with those with EDSS < 3. The actual increases in EDSS from 2006 to 2011 were positively associated with TNF-α and IFN-γ. Increased IFN-γ values were associated with higher pyramidal symptoms and increased IL-6 with sensitive symptoms. Increased carbonyl protein and IL-10 but lowered albumin levels predicted cerebellar symptoms. The TNFB1/B2 genotype decreased risk towards progression of pyramidal symptoms. Treatments with IFN-β and glatiramer acetate significantly reduced TNF-α but did not affect the other IO&NS biomarkers or disease progression. Taken together, IO&NS biomarkers and NcoI TNFβ genotypes predict high disability in MS and are associated with different aspects of disease progression. New drugs to treat MS should also target oxidative stress pathways.

Figure: Reactive oxygen and nitrogen species and their sources (endogenous and environmental). 

So oxidative and nitrosative stress pathways (i.e. reactive oxygen species (ROS) and reactive nitrogen species (RNS); see above for the ones examined), and TNFβ Ncol polymorphism of a single nucleotide region are predictive of disability progression over a 5 year period.

Generally, with mutations there is a change in the synthesis of the protein which may improve or lessen the activity of the said protein; and as TNFβ Ncol polymorphistm worsens disability it's possible that there is augmentation or facilitation of its action. ROS and RNS generally become a problem in neurological disorders when the levels produced exceed scavenging capacity (i.e. removal of the offending compound), which leads to cells undergoing either oxidative and/or nitrosative stresses and cell death. This process is not unique to MS but is frequently seen in stroke, as a result of ischaemia of the brain tissue, after head injury and other neurodegenerative diseases. As far as MS is concerned the understanding is that ROS and RNS are overproduced during the inflammatory activity, but lately it has also been demonstrated that mitochondrial of glial cells also generate these. None of these findings are novel on the whole.

But, why do neither IFN-β or glatiramer acetate have no effect on ROS/RNS species studied (I'm going to ignore the finding on treatment effect as the sample size and duration of the study is not long enough to demonstrate a benefit of 1st line therapy on disability)? For a biomarker study, on the other hand, 212 subjects is a moderate sample size and entirely viable to establish a trend if there is one... 

So the authors go on to conclude that treatments targeting oxidative stress pathways should be considered - a nebulous statement if there was one! It's not that neither therapies have an direct/indirect effect on the pathway; because as anti-inflammatory therapies I'd say this was a given. It may be because these are not targeting the process that is overproducing this to an excess in MS. The authors do not expand further on this, but I believe the answer may lie in the mitochondria themselves...

11 comments:

  1. What are you thoughts about MitoQ?

    Does this help elevate Tecfidera as a first-line treatment? Doesn't this drug increase antioxidant actvity (it appears to lower elevated CRP-levels in the blood too - as a systemic antinflammatory).

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    1. There are two avenues in this, deal with the free radical production and/or bolster the mitochondria. Thinking laterally maybe a combination trial of melatonin (receptor-independent free radical scavenger) and Coenzyme Q10 is long overdue???

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    2. Nrf2 when exposed to reactive oxygen species moves into the cell nucleus and binds to ARE (antioxidant response element), thereby activating the transcription of the antioxidant enzyme gene transcription. Since Biogen dumped the trial we'll never know!!!

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    3. At what levels do you think a combination of the two would be likely to be effective? I have doubts about the ability of many people to take higher levels of melatonin. Many folks that I've met (including myself, unfortunately) have trouble with higher doses due to sleep disturbance. I'm guessing CoQ10 is probably better tolerated.

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    4. MouseDoctor - I only meant "elevate" in the sense of become more often preferred to interferons or glatimer acetate at the initial treatment decision stage.

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    5. Thanks for your clarification I didn't mean to sound arrogant (as I am accused) however I believe the CRABS have had their day and time to move on (I know many of you including neuros, will disagree it is an opinion)

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    6. In reply to anon Jan 12, 2016 12 5:57pm, a clinical trial with a dose response has to be studied to test efficacy. Having said this it is well known that a drug formulated to be controlled release has a smoother side effect profile than immediate release. CoQ10 conversely well tolerated and high doses can be used. Maybe one of our many readers can pick up this as an investigator led trial design!

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  2. NDG so then will we see more clinical trials of Idebenone and/or Coenzyme Q10?
    I had asked in unrelated blogger coments this month about the formation of trimers superoxidatives by mutation um SOD-1 protein in ALS would have any implications for MS?! ...Chronic Fatigue Syndrome also causes stress superoxidative...

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    1. IPPoMS (Idebenone in PPMS -sponsored by NINDS) as far as I'm aware is still active. With regard to mutant SOD1 (commonly seen in familial ALS) in ALS it is known that it affects calcium handling by mitochondria and operation of their electron transport chain - the mitochondria are pretty much non-functional. As far as MS is concerned the mutation is non-significant and MS samples are often used as inflammatory controls in ALS SOD1 biomarker studies. However, there are increased levels of superoxide dismutases in active lesions because they bind superoxide and converts it to hydrogen peroxide which is more stable, but then has the potential to generate reactive hydroxyl radicles which are not good!

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    2. http://www.jbc.org/content/early/2015/12/17/jbc.M115.700385.long

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