[FitEyes Discussion 17102] The Selenium Paradox in Glaucoma

David Wrote:

*One glaucoma mystery explained: why is selenium a risk factor?*

*A medical hypothesis*

In this paper I will present the selenium paradox and propose an
explanation. Furthermore, I will show that understanding the selenium
paradox helps us understand a number of other mysteries related to
glaucoma. And I propose a new way to understand the glaucoma pathology
through the lens of one carbon metabolism (what is also called the
methylation cycle).

Selenium is an essential trace mineral humans must obtain from their diet.
Humans require selenium for a number of selenium-dependent enzymes (which
are also called selenoproteins) [7].

Research has shown that higher levels of selenium in the blood, and to some
extent higher levels of selenium in the aqueous humor, increase the risk of
glaucoma. A 2009 article in the British Journal of Ophthalmology [1]
concluded, "our data, added to that of others, suggest that glaucoma is
selenium-related."

A 2006 article in Experimental Eye Research says, "Epidemiological evidence
indicates that *selenium supplementation may increase risk for glaucoma and
ocular hypertension* [8]."

So that's what the research says. The only problem is that it seems to be
*paradoxical*. First, in the general sense, it is paradoxical because
selenium is an antioxidant and glaucoma patients, who, as a class, have
elevated oxidative stress in eye tissues and aqueous humor, obviously need
more antioxidant support. Oxidative stress is composed of either/both
reduced functionality of antioxidants and elevated levels of oxidants
(reactive oxygen species, etc.).

Glaucoma, Inflammation and Oxidative Stress: An Attempt to Unify Recent
News | FitEyes.com
<http://www.fiteyes.com/Glaucoma-Inflammation-and-Oxidative-Stress>

Oxidative stress is a serious problem for glaucoma patients. "Oxidative
stress, occurring not only in the trabecular meshwork, but also in retinal
cells, appears to be involved in the neuronal cell death affecting the
optic nerve in open angle glaucoma [2]."

"Both endogenous [and] exogenous levels of oxidative DNA damage in primary
open angle glaucoma patients were found to be statistically higher than
controls. [15]."

A 2014 article in the journal Current Eye Research concludes, "These
results suggest that a significant increase in oxidative stress may play a
role in the pathogenesis of primary open angle glaucoma and primary angle
closure glaucoma [4]." The same can be said of other forms of glaucoma.

In fact, FitEyes, with the help of Robert Ritch, MD, has been emphasizing
the following unified understanding of glaucoma since August 2010:

*All glaucomas have a final common pathway of retinal ganglion cell death
involving low-grade inflammation, oxidative damage, mitochondrial
dysfunction, and glial hyperactivation.*

Even more specifically, studies have shown that glaucoma patients have
reduced levels of the antioxidant *glutathione*. One study showed that
glutathione levels were decreased at the earliest stages of glaucoma [3].

"After correction for age and gender influences on blood glutathione
levels, patients with glaucoma exhibited significantly lower levels of
reduced and total glutathione than did matched control subjects [12]."

Glutathione is one of the most important antioxidants in the human body.
Mark Hyman, MD, calls it the "mother of all antioxidants, the master
detoxifier and maestro of the immune system [5]."

"Glutathione plays important roles in antioxidant defense, nutrient
metabolism, and regulation of cellular events (including gene expression,
DNA and protein synthesis, cell proliferation and apoptosis, signal
transduction, cytokine production and immune response, and protein
glutathionylation). Glutathione deficiency contributes to oxidative stress,
which plays a key role in aging and the pathogenesis of many diseases
(including kwashiorkor, seizure, Alzheimer’s disease, Parkinson’s disease,
liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer,
heart attack, stroke, and diabetes) [11]." And *glaucoma*.

Glutathione peroxidase (GPx) is the general name of an enzyme family whose
main biological role is to protect the body from oxidative damage by making
use of glutathione. The molecule glutathione and the enzyme glutathione
peroxidase are a system -- an antioxidant system.

Knowing the important of glutathione and it's deficiency in glaucoma, here
is the deeper paradox: glutathione peroxidase depends on *selenium*. It is
built on (contains) selenium. Without selenium, there is no glutathione
peroxidase -- and little or no antioxidant activity from the "mother of all
antioxidants" in the human body.

Five selenium-containing glutathione peroxidases (GPx) have been
identified: GPx1, GPx2, GPx3, and GPx4 have been shown to be
selenium-containing enzymes in all mammals, while GPx6 is also a
selenoprotein in humans [6].

Although each glutathione peroxidase is a distinct selenoprotein, they are
all antioxidant enzymes. They all "reduce potentially damaging reactive
oxygen species (ROS), such as hydrogen peroxide and lipid hydroperoxides,
to harmless products like water and alcohols by coupling their reduction
with the [transient] oxidation of glutathione [7]." In this process,
glutathione disables to damaging oxidant (ROS).

Dietary selenium normally favorably affects plasma reduced glutathione
concentrations [10]. So selenium supplementation should be beneficial for
glaucoma. But it isn't. This is a paradox because it does not make sense
that something glaucoma patients need more of would be detrimental to them.

Now that we understand the paradox, let's attempt to resolve it. The basis
for this resolution is an understanding of the methylation cycle.

The methylation cycle is a term that is widely used today. But Dr. Amy
Yasko explains that it is actually a combination of four interrelated
biochemical cycles, including:

  - The methionine cycle
  - The folate cycle
  - The BH4 (biopterin) cycle
  - The urea cycle

Another name for the methylation cycle is "one-carbon metabolism". This is
an even better name because methylation happens outside the four pathways
listed above. It's almost ubiquitous. The name "one-carbon metabolism"
comes from the fact that a methyl chemical group is a fundamental
one-carbon unit in biological systems. It consists of one carbon atom,
three hydrogen atoms and a single available bond that can attach to other
molecules. When the methyl group (one carbon unit) is attached to a
molecule, that is a methylation reaction.

The methylation cycle is directly or indirectly involved in the synthesis
of biologically important compounds including:

  - glutathione
  - carnitine
  - coenzyme Q10
  - phosphatidylcholine and citicoline
  - melatonin
  - creatine
  - N-acetyl-cysteine
  - SAMe
  - and lots of other important substances for the body.

Several of these substances are typically found to be low in glaucoma,
leading some glaucoma specialists to recommend them as supplements.

The body makes insufficient quantities of these compounds because of a
partial block in the methylation cycle. This leads to a general connection
between glaucoma and the methylation cycle. There may be more specific
connections, especially for glaucoma patients with certain SNP's (genetic
polymorphisms). (Side note: cysteine is the rate-limiting factor in
cellular glutathione biosynthesis, since this amino acid is relatively rare
in foods.)

Furthermore, and of great interest in glaucoma, the methylation cycle (via
SAMe production) is required for the formation of *myelin* (the covering
for nerves). But that subject is outside the scope of this paper.

Therefore, the methylation cycle ("one-carbon metabolism") plays a role in
glaucoma. (It plays a role in almost everything happening in the human
body, but we see specific connections to glaucoma.)

My hypothesis in regard to the selenium paradox is that the pathological
role of selenium in glaucoma is due to abnormalities in one-carbon
metabolism that must be present in a large porportion of glaucoma patients
but that have so far not been characterized by researchers in this field.
The evidence for this comes from *connecting the dots* from glaucoma
research to research in other fields. The present paper is just that: an
exercise in connecting the dots.

Future experimental research will have to be designed to test this
hypothesis. The value of this paper is to stimulate thinking about this
paradox (as well as to make people aware that there is a paradox). I hope
it leads to deeper investigation of one-carbon metabolism in glaucoma.

On the basis of a better understanding of one-carbon metabolism in
glaucoma, I expect to find more evidence that vitamins B9 (folate) and B12
(cobalamin) play an important role in glaucoma management. Understanding
the selenium paradox takes us a step in that direction. It also helps us
unify the findings about selenium, certain genetic polymorphisms, and the
potential of several other nutrients for treating glaucoma such as
carnitine, coenzyme Q10, glutathione, choline / citicoline, NAC
(N-acetyl-cysteine), and more. For example, optimizing one carbon
metabolism is likely to be a better approach than simply taking glutathione
supplements or other antioxidants.

Let me provide some evidence in support of my hypothesis. One specific
piece of information that has not been discussed in glaucoma research so
far is the special role of selenium and folate (B9) together (termed an
"interaction") in the methylation cycle ("one-carbon metabolism").

>From a 2003 Journal of Nutrition article, we know the following:

"Although both selenium and folate deficiency have been shown to cause
global DNA hypomethylation and increased cancer susceptibility, the
nutrients have different effects on one-carbon metabolism [9]."

In this study, selenium and folate strongly *interacted* (P < 0.0001) to
influence one-carbon metabolism. The nature of this interaction is a key to
understanding the selenium paradox in glaucoma.

The primary biochemical role of folate is "the transfer of one-carbon
moieties" [10] as part of the methylation cycle.

Folate functions in DNA synthesis and repair, and in methylation, by
providing methylene and formyl groups for the synthesis of thymidine and
purines and methyl groups for the synthesis of S-adenosylmethionine (SAM).
SAM is the methyl donor for DNA methylation reactions. DNA methylation is
an important epigenetic mechanism exerting control on gene expression [10].
Folate deficiency can cause DNA hypomethylation [10]. Both selenium and
folate deficiency result in global DNA hypomethylation [10].

When vitamin B9 (folate) is low, elevated selenium was shown to be
pathological (colorectal cancer) in this study. Low folate impairs the
methylation cycle.

In addition, if folate is low, *selenium should be low as well* [9] to
avoid more pathology.

Those research findings are *critical* to our understanding. I believe that
explains selenium's general behavior in glaucoma. But glaucoma researchers
are not yet aware of those findings. And no one has thought about their
implications (connected the dots).

When folate and the methylation cycle are functioning normally, I
hypothesize that selenium will not be pathological. And this concept leads
to some therapeutic ideas for glaucoma.

In a 2004 study in the American Journal of Nutrition, the block in the
methylation cycle and glutathione deficiency were found to be linked.
Dietary supplements used to restore the methylation cycle to normal
operation (methylcobalamin, folinic acid and trimethylglycine) also
restored the levels of reduced and oxidized glutathione [17].

My hypothesis is that when the methylation cycle is restored to normal
operation in glaucoma patients, normal levels of selenium supplementation
will no longer be pathological.

However, we can state this another way. The pathological role of selenium
in the glaucoma disease process is (hypothesized to be) a consequence of
impaired methylation in the one carbon metabolism pathways.

A 2012 study found a significant decrease of antioxidant enzymes: catalase
(P<0.001), superoxide dismutase (P<0.05), and glutathione peroxidase
(P<0.001) in glaucoma patients. The authors concluded, "our data revealed
that oxidative stress had a pathogenic role in primary open-angle glaucoma.
[15, 18]."

When the methylation cycle is restored to normal operation in glaucoma
patients many innate antioxidant systems, including glutathione, will
return to normal.
*Fixing one carbon metabolism could be the single most important step a
glaucoma patient can take toward reducing abnormal levels of oxidative
stress.*
What does this say about the future direction of glaucoma treatments? Some
researchers have concluded that, "the modulation of a
pro-oxidant/antioxidant status might be a relevant target for glaucoma
prevention and therapy." I agree, but I go one step further and suggest
that the methylation cycle is where we need to put our attention when it
comes to developing the next treatment for glaucoma. Getting the
methylation cycle working will underpin the proper modulation of
pro-oxidant/antioxidant status of the patient. Without doing that, any
treatment will simply be a band-aid. Ideally, that treatment approach will
be nutrigenomic in character.

*References (and abstracts)*

*1. Relationship between glaucoma and selenium levels in plasma and aqueous
humour.*

Abstract

AIM:

The aim of the study was to compare selenium levels in plasma and aqueous
humour in subjects with and without primary open-angle glaucoma (POAG).

METHODS:

Forty-seven POAG cases and 54 controls in this case-control study were
recruited from surgery patients at the University Physician's Ophthalmology
Clinic in Tucson, Arizona, USA. Aqueous humour and plasma selenium were
determined by high-performance liquid chromatography ion channel plasma
mass spectrometry (HPLC ICP-MS). Potential confounders were assessed via a
questionnaire. Biological samples were collected and processed at surgery
and analysed for selenium content after collection was complete. Outcome
measures included the odds of glaucoma in relationship to plasma selenium,
aqueous humour selenium, and the ratio of levels of aqueous humour selenium
to plasma selenium.

RESULTS:

Tertile of selenium and its relationship to POAG was examined. After
adjustment for common glaucoma risk factors, the odds of glaucoma in the
highest tertile of plasma selenium (OR = 11.3; p = 0.03) and the middle
tertile of aqueous humour selenium (OR = 0.06; p = 0.02) was significantly
associated with glaucoma.

CONCLUSION:

Although a causal pathway cannot be inferred from our analysis, our data,
added to that of others, suggest that the pathology is selenium-related.

Br J Ophthalmol. 2009 Sep;93(9):1155-8. doi: 10.1136/bjo.2007.125997. Epub
2008 Jun 12.
PMID: 18556426
Authors: Bruhn RL1, Stamer WD, Herrygers LA, Levine JM, Noecker RJ.


*2. The role of oxidative stress in glaucoma*

Abstract

DNA damage is related to a variety of degenerative diseases such as cancer,
atherosclerosis and neurodegenerative diseases, depending on the tissue
affected. Increasing evidence indicates that reactive oxygen species (ROS)
play a key role in the pathogenesis of primary open angle glaucoma (POAG),
the main cause of irreversible blindness worldwide. Oxidative DNA damage is
significantly increased in the ocular epithelium regulating aqueous humor
outflow, i.e., the trabecular meshwork (TM), of glaucomatous patients
compared to controls. The pathogenic role of ROS in glaucoma is supported
by various experimental findings, including (a) resistance to aqueous humor
outflow is increased by hydrogen peroxide by inducing TM degeneration; (b)
TM possesses remarkable antioxidant activities, mainly related to
superoxide dismutase–catalase and glutathione pathways that are altered in
glaucoma patients; and (c) intraocular-pressure increase and severity of
visual-field defects in glaucoma patients parallel the amount of oxidative
DNA damage affecting TM. Vascular alterations, which are often associated
with glaucoma, could contribute to the generation of oxidative damage.
Oxidative stress, occurring not only in TM but also in retinal cells,
appears to be involved in the neuronal cell death affecting the optic nerve
in POAG. The highlighting of the pathogenic role of ROS in POAG has
implications for the prevention of this disease as indicated by the growing
number of studies using genetic analyses to identify susceptible
individuals and of clinical trials testing the efficacy of antioxidant
drugs for POAG management.
Abbreviations

   GSH, reduced glutathione;
   GST, glutathione-S-transferase;
   8-OH-dG, 8-hydroxy-2′-deoxyguanosine;
   IOP, intra-ocular pressure;
   NO, nitric oxide;
   POAG, primary open angle glaucoma;
   ROS, reactive oxygen species;
   TM, trabecular meshwork

http://www.sciencedirect.com/science/article/pii/S1383574205000608
doi:10.1016/j.mrrev.2005.11.001
Authors: Alberto Izzottia, Alessandro Bagnisb, Sergio C. Saccàc

See list of references here:
http://www.sciencedirect.com/science?_ob=ArticleListURL&_method=list&_ArticleListID=-746703532&_sort=v&_st=17&view=c&_origin=related_art&panel=citeRelatedArt&_mlktType=Journal&md5=e4e714e1918c1f07c3302e0c1aa754a1&searchtype=a


3. Vestn. Oftalmol 180: 13-15 1992 Bunin AI, Filina AA, Erichev VP *A
glutathione deficiency in open-angle glaucoma and the approaches to its
correction.*


*4. Evaluation of oxidative stress markers in aqueous humor of primary open
angle glaucoma and primary angle closure glaucoma patients.*

Abstract

PURPOSE:

The present study was designed to determine the levels of antioxidant
enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and
non-enzymatic antioxidants (vitamins C and E) in aqueous humor of primary
open angle glaucoma (POAG) and primary angle closure glaucoma (PACG)
patients.
MATERIALS AND METHODS:

In this study, aqueous humor of POAG (n = 30) and PACG (n = 30) patients
was obtained. For control, aqueous humor of 30 age-matched cataract
patients (n = 30) was collected. Activities of antioxidant enzymes and
non-enzymatic antioxidants levels were measured spectrophotometrically.

RESULTS:

A significant increase in superoxide dismutase (SOD) and glutathione
peroxidase (GPx) activities was found in aqueous humor of POAG and PACG
patients as compared to cataract patients (p < 0.001). No significant
changes were observed in catalase activity. The levels of vitamins C and E
were significantly lower in the aqueous humor of POAG and PACG as compared
to cataract patients (p < 0.001).

CONCLUSION:

These results suggest that a significant increase in oxidative stress may
play a role in the pathogenesis of POAG and PACG. Determination of
oxidative stress in aqueous humor may help in understanding the course of
this disease, and oxidative damage might be a relevant target for both
prevention and therapy.

KEYWORDS:

Antioxidant enzymes; cataract; glaucoma; vitamin C; vitamin E

Curr Eye Res. 2014 Aug;39(8):823-9. doi: 10.3109/02713683.2011.556299. Epub
2014 Jun 9.
PMID:    24912005
Authors: Goyal A1, Srivastava A, Sihota R, Kaur J.


5.
http://www.huffingtonpost.com/dr-mark-hyman/glutathione-the-mother-of_b_530494.html


6. Epp O, Ladenstein R, Wendel A (June 1983). "*The refined structure of
the selenoenzyme glutathione peroxidase at 0.2-nm resolution*". Eur. J.
Biochem. 133 (1): 51–69. doi:10.1111/j.1432-1033.1983.tb07429.x. PMID
6852035.


7. http://lpi.oregonstate.edu/infocenter/minerals/selenium/


*8. Alterations in human trabecular meshwork cell homeostasis by selenium.*

Abstract

Epidemiological evidence indicates that selenium supplementation may
increase risk for glaucoma and ocular hypertension. The purpose of this
study was to determine the effects of selenium on trabecular meshwork
cells, a likely site of pathology for glaucoma. Human trabecular meshwork
(HTM) cells and human umbilical vein endothelial cells (HUVECs) were
treated with selenium (MSeA) at or near physiologically relevant
concentrations. Selenium uptake by cells was monitored using mass
spectrometry. Alterations in protein secretion, intracellular signaling,
and cell morphology were monitored; and the role of integrin signaling in
MSeA-induced morphological alterations was investigated using divalent
cation treatments. Radiolabeling was used to assess protein synthesis and
secretion, while luciferase and MTT assays monitored total cellular ATP and
cell viability, respectively. Whereas detectible changes in intracellular
selenium were observed after exposure to 1-10 microM MSeA for 24hr, the
majority remained in the conditioned medium. Selenium-induced morphological
changes (< or =3 hr) occurred before alterations in protein secretion and
intracellular signaling (3-6 hr). Zinc treatment prevented
selenium-mediated alterations in protein secretion and changes in
cell-matrix adhesion. MSeA treatment (5 microM) led to a 60% decrease in
protein synthesis after 3 hr and a 30% reduction in secretion, although
significant alterations in cell viability and total ATP were not observed
after MSeA treatment. Selenium altered several indicators of HTM cell
homeostasis, but did not affect viability at physiologically relevant
doses. Similar results with HUVECs have implications for understanding
selenium's mechanisms of action as an anti-angiogenic agent.

Exp Eye Res. 2006 Apr;82(4):637-47. Epub 2005 Nov 10.
PMID: 16289047
Authors: Conley SM1, McKay BS, Gandolfi AJ, Stamer WD.


*9. Dietary folate and selenium affect dimethylhydrazine-induced aberrant
crypt formation, global DNA methylation and one-carbon metabolism in rats.*

Abstract

Several observations suggest a role for DNA methylation in cancer
pathogenesis. Although both selenium and folate deficiency have been shown
to cause global DNA hypomethylation and increased cancer susceptibility,
the nutrients have different effects on one-carbon metabolism. Thus, the
purpose of this study was to investigate the interactive effects of dietary
selenium and folate. Weanling, Fischer-344 rats (n = 23/diet) were fed
diets containing 0 or 2.0 mg selenium (as selenite)/kg and 0 or 2.0 mg
folate/kg in a 2 x 2 factorial design. After 3 and 4 wk of a 12-wk
experiment, 19 rats/diet were injected intraperitoneally with
dimethylhydrazine (DMH, 25 mg/kg) and 4 rats/diet were administered saline.
Selenium deficiency decreased (P < 0.05) colonic DNA methylation and the
activities of liver DNA methyltransferase and betaine homocysteine
methyltransferase and increased plasma glutathione concentrations. Folate
deficiency increased (P < 0.05) the number of aberrant crypts per aberrant
crypt foci, the concentration of colonic S-adenosylhomocysteine and the
activity of liver cystathionine synthase. Selenium and folate interacted (P
< 0.0001) to influence one-carbon metabolism and cancer susceptibility such
that the number of aberrant crypts and the concentrations of plasma
homocysteine and liver S-adenosylhomocysteine were the highest and the
concentrations of plasma folate and liver S-adenosylmethionine and the
activity of liver methionine synthase were the lowest in rats fed
folate-deficient diets and supplemental selenium. These results suggest
that selenium deprivation ameliorates some of the effects of folate
deficiency, probably by shunting the buildup of homocysteine (as a result
of folate deficiency) to glutathione.

J Nutr. 2003 Sep;133(9):2907-14.
PMID: 12949386
Authors: Davis CD1, Uthus EO.
Free full text: http://jn.nutrition.org/content/133/9/2907.full


*10. Relevance of folate metabolism in the pathogenesis of colorectal
cancer.*

Abstract

The purpose of this review is to outline the principal mechanisms involved
in folate metabolism and how they may relate to the pathogenesis of
colorectal cancer (CRC). In recent years, mild folate depletion (low normal
level) has been associated with an increased risk of developing certain
cancers, in particular colorectal neoplasia. The epidemiologic and
mechanistic evidence linking folate deficiency with carcinogenesis is
reviewed, with a particular emphasis on colorectal neoplasia.
Methylenetetrahydrofolate reductase (MTHFR) is a critical folate
metabolizing enzyme, and a functional polymorphic variant of this enzyme,
the so-called thermolabile variant, caused by a C677T transition in the
MTHFR gene, is common in the general population. This review critically
examines the evidence that suggests that carriers of this C677T variant may
be at increased risk of developing colorectal neoplasia. Although folate
depletion may predispose to the initiation of the neoplastic process,
folate supplementation, on the other hand, might potentiate the progression
of an already established early neoplastic clone (eg, a colorectal
adenoma). This could have potential public health implications, given an
increasingly widespread policy of folate supplementation of food staples.

J Lab Clin Med. 2001 Sep;138(3):164-76.
PMID: 11528369
Ryan, B. M. & Weir, D. G. (2001) Relevance of folate metabolism in the
pathogenesis of colorectal cancer. J. Lab. Clin. Med. 138:164-176.
CrossRefMedline



*11. Glutathione Metabolism and Its Implications for Health*

Abstract

Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant
low-molecular-weight thiol, and GSH/glutathione disulfide is the major
redox couple in animal cells. The synthesis of GSH from glutamate,
cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes,
gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence
shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine
synthetase activity, cysteine availability, and GSH feedback inhibition.
Animal and human studies demonstrate that adequate protein nutrition is
crucial for the maintenance of GSH homeostasis. In addition, enteral or
parenteral cystine, methionine, N-acetyl-cysteine, and
L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for
tissue GSH synthesis. Glutathione plays important roles in antioxidant
defense, nutrient metabolism, and regulation of cellular events (including
gene expression, DNA and protein synthesis, cell proliferation and
apoptosis, signal transduction, cytokine production and immune response,
and protein glutathionylation). Glutathione deficiency contributes to
oxidative stress, which plays a key role in aging and the pathogenesis of
many diseases (including kwashiorkor, seizure, Alzheimer's disease,
Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia,
HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of
the nutritional regulation of GSH metabolism is critical for the
development of effective strategies to improve health and to treat these
diseases.

J Nutr. 2004 Mar;134(3):489-92.
PMID: 14988435
Free full text
http://jn.nutrition.org/content/134/3/489.full
http://www.ncbi.nlm.nih.gov/pubmed/14988435
Authors: Wu G1, Fang YZ, Yang S, Lupton JR, Turner ND.


*12. Systemic Reduction in Glutathione Levels Occurs in Patients with
Primary Open-Angle Glaucoma*

Abstract

PURPOSE:

To assess the level of plasma glutathione in patients with untreated
primary open-angle glaucoma.

METHODS:

Twenty-one patients with newly diagnosed primary open-angle glaucoma and 34
age- and gender-matched control subjects were subjected to a blood analysis
to detect the level of circulating glutathione in its reduced and oxidized
forms. The effect of age, gender, and systemic blood pressure on
circulating glutathione levels was also analyzed.

RESULTS:

Age had a negative effect on the level of both reduced and total
glutathione (P = 0.002, r = -0.52 and P = 0.002, r = -0.52, respectively)
in control subjects but not in patients with glaucoma (P > 0.05, r = 0.27,
and P > 0.05, r = 0.22, respectively). In the control group, men
demonstrated higher levels of both reduced and total glutathione than did
women (P = 0.024 and P = 0.032, respectively). After correction for age and
gender influences on blood glutathione levels, patients with glaucoma
exhibited significantly lower levels of reduced and total glutathione than
did control subjects (P = 0.010, F = 7.24 and P = 0.006, F = 8.38,
respectively). No differences between study groups were observed in either
oxidized glutathione levels or redox index (P > 0.05, F = 0.50; and P >
0.05, F = 0.30, respectively).

CONCLUSIONS:

Patients with glaucoma exhibit low levels of circulating glutathione,
suggesting a general compromise of the antioxidative defense.

Invest Ophthalmol Vis Sci. 2005 Mar;46(3):877-83.
PMID: 15728543
Authors: Gherghel D1, Griffiths HR, Hilton EJ, Cunliffe IA, Hosking SL.
Free full text
http://www.researchgate.net/profile/Helen_Griffiths/publication/8004235_Systemic_reduction_in_glutathione_levels_occurs_in_patients_with_primary_open-angle_glaucoma/links/00b7d5245bb630decc000000.pdf


*13. Oxidative stress markers in patients with primary open-angle glaucoma.*

Abstract

PURPOSE:

To investigate the levels of antioxidant enzymes catalase (CAT),
glutathione peroxidase (GPO), superoxide dismutase (SOD), and
malondialdehyde (MDA) in human eyes with primary open-angle glaucoma (POAG)
and to correlate their concentrations with severity of glaucoma.

DESIGN:

A prospective cases control study.

PATIENTS AND METHODS:

Thirty patients with primary open-angle glaucoma and twenty-five patients
with senile cataracts of matched age and gender were included in the study
prospectively. Aqueous humor samples were obtained by paracentesis at the
time of elective surgery for glaucomatous and cataractous patients. Aqueous
humor were analyzed for CAT, GPO, SOD, and MDA status.

RESULTS:

GPO, SOD, and MDA enzyme levels revealed a high significant increase in
aqueous humor of POAG patients with respect to the comparative group of
cataract patients (P < 0.001). No significant difference in the activity of
CAT enzyme in aqueous humor of POAG and cataract patient (P = 0.201).
Significant correlation was found between the MDA enzyme level and severe
visual field loss (P < 0.001) in POAG patients.

CONCLUSION:

Increased levels of aqueous humor GPO, SOD, and MDA may be associated with
POAG. In addition, they may be useful antioxidant enzyme levels in aqueous
humor of POAG patients as a result of glaucoma disease and not a cause.

Curr Eye Res. 2010 Apr;35(4):295-301. doi: 10.3109/02713680903548970.
PMID: 20373896
Authors: Ghanem AA1, Arafa LF, El-Baz A.


*14. Oxidative stress markers in aqueous humor of glaucoma patients.*

Abstract

PURPOSE:

Oxidative stress and antioxidant status in eye tissues may be associated
with glaucomatous damage. The aim of this study was to establish the
antioxidant status of aqueous humor of patients with primary open-angle
glaucoma. For this purpose the authors measured the total reactive
antioxidant potential (TRAP) and the activities of the antioxidant enzymes
superoxide dismutase (SOD), catalase, and glutathione peroxidase.
DESIGN:

Case control study.

METHODS:

Aqueous humor was obtained at the time of surgery from 24 patients with
glaucoma and 24 cataract patients; TRAP was measured by chemiluminescence.
Activities of the antioxidant enzymes were measured spectrophotometrically.
Superoxide dismutase activity was determined by inhibition of the rate of
adrenochrome formation at 480 nm. Catalase activity was evaluated by
decrease of H(2)O(2) absorbance at 240 nm. Glutathione peroxidase (GPx)
activity was determined following nicotinamide adenine dinucleotide
phosphate oxidation at 340 nm.

RESULTS:

Total reactive antioxidant potential value of the cataract group was 124
+/- 5 micromol/l Trolox. This value was significantly decreased, by 64%, in
glaucoma patients. An increase of 57% in SOD activity was observed in
glaucoma patients when compared with cataract patients (41.7 +/- 2.7 U
SOD/ml). Glutathione activity was threefold higher in glaucoma patients
than in the cataract group (6.1 +/- 0.6 U/ml). No significant changes were
found in catalase levels.

CONCLUSIONS:

Oxidative stress may lead to an induction of antioxidant enzymes and
contribute to TRAP decrease. Superoxide dismutase, GPx activities, and TRAP
may be useful oxidative stress markers in aqueous humor of glaucoma
patients.

Am J Ophthalmol. 2004 Jan;137(1):62-9.
PMID: 14700645
Authors: Ferreira SM1, Lerner SF, Brunzini R, Evelson PA, Llesuy SF.

NOTE: One of the results of [14] appears to conflict with other published
results (other papers, e.g., 15). But it agrees with [13].

In summary, [14] says:

We evaluated total reactive antioxidant potential (TRAP)
We evaluated activities of the antioxidant enzymes:
superoxide dismutase (SOD),
catalase,
glutathione peroxidase (GPx)
Total reactive antioxidant potential (TRAP) was significantly reduced, by
64%, in glaucoma patients [14]. No surprise.
Glutathione peroxidase activity was threefold higher in glaucoma patients
[14]. <-- what's wrong here? That question is outside the scope of this
paper.


*15. Evaluation of oxidative stress markers in pathogenesis of primary
open-angle glaucoma.*

Abstract

Primary open-angle glaucoma (POAG) is the leading cause of blindness in the
industrial countries. It is reported that oxidative stress might be an
important risk factor in the pathogenesis of POAG. Forty subjects including
20 patients with open-angle glaucoma (9 men and 12 women, mean age
61.8±12.1yr) and 20 controls without glaucoma symptoms (9 men and 12 women,
mean age 58.1±17.7yr) were enrolled in our study. The main aim of the work
was to evaluate oxidative stress markers in the pathogenesis of open-angle
glaucoma. In our work the activity of antioxidant enzymes: catalase (CAT),
superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as the
total antioxidant status (TAS) was estimated. An alkaline comet assay was
used to measure DNA damage of strand breaks (SB), oxidized purines as
glicosylo-formamido-glicosylase (Fpg) sites, and oxidized pirmidines as
endonuclease III (Nth) sites. We measured endogenous as well as exogenous
DNA damage after 10μM hydrogen peroxide treatment (H(2)O(2)). We did not
observe any statistical changes of DNA strand break lesion in examined POAG
patients according to healthy subjects (P>0.05). However, either endogenous
(P<0.01) or exogenous (P<0.001) levels of oxidative DNA damage in POAG
patients were found to be statistically higher than controls. A significant
decrease of antioxidant enzymes: CAT (P<0.001), SOD (P<0.05), and GPX
(P<0.001) and a non-statistical decrease of TAS status (P>0.05) in glaucoma
patients according to controls were also indicated. In conclusion our data
revealed that oxidative stress had a pathogenic role in primary open-angle
glaucoma. Therefore, we suggested that the modulation of a
pro-oxidant/antioxidant status might be a relevant target for glaucoma
prevention and therapy.

Exp Mol Pathol. 2011 Apr;90(2):231-7. doi: 10.1016/j.yexmp.2011.01.001.
Epub 2011 Jan 15.
PMID: 21241689
Authors: Majsterek I1, Malinowska K, Stanczyk M, Kowalski M, Blaszczyk J,
Kurowska AK, Kaminska A, Szaflik J, Szaflik JP.



*16. The ratio of oxidized/reduced glutathione as an index of oxidative
stress in various experimental models of shock syndrome.*

Abstract

Red blood cells are well equipped to handle intracellular oxidative stress,
their membranes are permeable to O2- and H2O2, and in this way they are
important regulators of oxygen reactions occurring in their surroundings.
The protective effect against reduced oxygen species - generated during the
endothelial cell injury of various tissues - is attributed mainly to the
glutathione metabolism of red blood cells. The blood concentration of
reduced (GSH) and oxidized glutathione (GSSG) was determined by a sensitive
method using glutathione reductase in experimental shock syndromes induced
by paraquat toxicity, tourniquet ligature and endotoxin in rats, by
bleeding and reperfusion in dogs and by transient ligature of thoracic
aorta in newborn piglets. Under these conditions the concentration of GSSG
was elevated and GSH was lowered, resulting in an increase in the redox
ratio: [GSSG/(GSH + GSSG)] x 100 (GSSG/GSH); particularly during
reperfusion. Determination of the GSSG/GSH seems to be a reliable index to
assess the degree of oxidative stress "in vivo".

Biomed Biochim Acta. 1989;48(2-3):S53-7.
PMID:  2730630
Németh I1, Boda D.



*17. Metabolic biomarkers of increased oxidative stress and impaired
methylation capacity in children with autism.*
Abstract

BACKGROUND:

Autism is a complex neurodevelopmental disorder that usually presents in
early childhood and that is thought to be influenced by genetic and
environmental factors. Although abnormal metabolism of methionine and
homocysteine has been associated with other neurologic diseases, these
pathways have not been evaluated in persons with autism.

OBJECTIVE:

The purpose of this study was to evaluate plasma concentrations of
metabolites in the methionine transmethylation and transsulfuration
pathways in children diagnosed with autism.

DESIGN:

Plasma concentrations of methionine, S-adenosylmethionine (SAM),
S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine,
cysteine, and oxidized and reduced glutathione were measured in 20 children
with autism and in 33 control children. On the basis of the abnormal
metabolic profile, a targeted nutritional intervention trial with folinic
acid, betaine, and methylcobalamin was initiated in a subset of the
autistic children.

RESULTS:

Relative to the control children, the children with autism had
significantly lower baseline plasma concentrations of methionine, SAM,
homocysteine, cystathionine, cysteine, and total glutathione and
significantly higher concentrations of SAH, adenosine, and oxidized
glutathione. This metabolic profile is consistent with impaired capacity
for methylation (significantly lower ratio of SAM to SAH) and increased
oxidative stress (significantly lower redox ratio of reduced glutathione to
oxidized glutathione) in children with autism. The intervention trial was
effective in normalizing the metabolic imbalance in the autistic children.

CONCLUSIONS:

An increased vulnerability to oxidative stress and a decreased capacity for
methylation may contribute to the development and clinical manifestation of
autism.

Am J Clin Nutr. 2004 Dec;80(6):1611-7.
Authors: James SJ1, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW,
Neubrander JA.
PMID:     15585776


*18. Note:* Interestingly, while all studies I know of show low glutathione
status in glaucoma patients, there is not an agreement among the studies
when it comes to glutathione peroxidase, the enzyme that uses glutathione
-- except to say that it's levels are not normal. I do not (yet) have an
explanation for that discrepancy. However, it does fit into the hypothesis
that restoring normal methylation cycle function will resolve the
paradoxically pathological role of selenium in glaucoma.


*19. Oxidative stress markers in aqueous humor of glaucoma patients.*

Abstract

PURPOSE:

Oxidative stress and antioxidant status in eye tissues may be associated
with glaucomatous damage. The aim of this study was to establish the
antioxidant status of aqueous humor of patients with primary open-angle
glaucoma. For this purpose the authors measured the total reactive
antioxidant potential (TRAP) and the activities of the antioxidant enzymes
superoxide dismutase (SOD), catalase, and glutathione peroxidase.

DESIGN:

Case control study.

METHODS:

Aqueous humor was obtained at the time of surgery from 24 patients with
glaucoma and 24 cataract patients; TRAP was measured by chemiluminescence.
Activities of the antioxidant enzymes were measured spectrophotometrically.
Superoxide dismutase activity was determined by inhibition of the rate of
adrenochrome formation at 480 nm. Catalase activity was evaluated by
decrease of H(2)O(2) absorbance at 240 nm. Glutathione peroxidase (GPx)
activity was determined following nicotinamide adenine dinucleotide
phosphate oxidation at 340 nm.

RESULTS:

Total reactive antioxidant potential value of the cataract group was 124
+/- 5 micromol/l Trolox. This value was significantly decreased, by 64%, in
glaucoma patients. An increase of 57% in SOD activity was observed in
glaucoma patients when compared with cataract patients (41.7 +/- 2.7 U
SOD/ml). Glutathione activity was threefold higher in glaucoma patients
than in the cataract group (6.1 +/- 0.6 U/ml). No significant changes were
found in catalase levels.

CONCLUSIONS:

Oxidative stress may lead to an induction of antioxidant enzymes and
contribute to TRAP decrease. Superoxide dismutase, GPx activities, and TRAP
may be useful oxidative stress markers in aqueous humor of glaucoma
patients.

Am J Ophthalmol. 2004 Jan;137(1):62-9.
PMID: 14700645
Authors: Ferreira SM1, Lerner SF, Brunzini R, Evelson PA, Llesuy SF.

Copyright (2015) David Shields. All rights reserved.