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Lower plasma Coenzyme Q10 in depression: A marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness

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There is now evidence that major depression is accompanied by an induction of inflammatory and oxidative and nitrosative stress (IO&NS) pathways and by a lowered antioxidant status. Coenzyme Q10 (CoQ10) is a strong antioxidant that has anti-inflammatory effects. This paper examines the plasma concentrations of CoQ10 in 35 depressed patients and 22 normal volunteers and the relationships between plasma CoQ10 and treatment resistant depression (TRD), the severity of illness as measured by means of the Hamilton Depression Rating Scale (HDRS) and the presence of chronic fatigue syndrome (CFS). We found that plasma CoQ10 was significantly (p=0.0002) lower in depressed patients than in normal controls. 51.4% of the depressed patients had plasma CoQ10 values that were lower than the lowest plasma CoQ10 value detected in the controls. Plasma CoQ10 was significantly lower in patients with TRD and with CFS than in the other depressed patients. There were no significant correlations between plasma CoQ10 and the HDRS. The results show that lower CoQ10 plays a role in the pathophysiology of depression and in particular in TRD and CFS accompanying depression. It is suggested that depressed patients may benefit from CoQ10 supplementation. The findings that lower CoQ10 is a risk factor to coronary artery disease and chronic heart failure (CHF) and mortality due to CHF suggest that low CoQ10 is another factor explaining the risk to cardiovascular disorder in depression. Since statins significantly lower plasma CoQ10, depressed patients and in particular those with TRD and CFS represent populations at risk to statin treatment.
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Neuroendocrinol Lett 2009; 30(4): 101–000
ORIGINAL ARTICLE
Neuroendocrinology Letters Volume 30 No. 4 2009
Lower plasma Coenzyme Q10 in depression:
a marker for treatment resistance and chronic
fatigue in depression and a risk factor to
cardiovascular disorder in that illness
Michael M 1, Ivanka M 1, Marta K 2, Marc U 3,
Nicolas V 3, Eugene B 3
1 Maes Clinics, Belgium;
2 Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of
Sciences, Krakow, Poland;
3 AML Laboratory, Antwerp, Belgium;
Correspondence to:
Prof. Dr. Michael Maes, MD., PhD.
Director of the Maes ClinicsGroenenborgerlaan 206
2610 Wilrijk – Antwerp, Belgium.
.: +32-3-4809282; -: crc.mh@telenet.be; www.michaelmaes.com
Submitted: 2009-07-30 Accepted: 2009-08-24 Published online: 2009-10-02
Key words: coenzyme Q10; major depression; chronic fatigue syndrome; inflammation;
cytokines; oxidative stress; mitochondria; cardiovascular disorder; statins
Neuroendocrinol Lett 2009; 30(4): 1–000 PMID: ----- NEL300409A06 © 2009 Neuroendocrinology Letters www.nel.edu
Abstract
There is now evidence that major depression is accompanied by an induction of
inflammatory and oxidative and nitrosative stress (IO&NS) pathways and by a
lowered antioxidant status. Coenzyme Q10 (CoQ10) is a strong antioxidant that
has anti-inflammatory effects.
This paper examines the plasma concentrations of CoQ10 in 35 depressed patients
and 22 normal volunteers and the relationships between plasma CoQ10 and treat-
ment resistant depression (TRD), the severity of illness as measured by means of
the Hamilton Depression Rating Scale (HDRS) and the presence of chronic fatigue
syndrome (CFS). We found that plasma CoQ10 was significantly (p=0.0002) lower
in depressed patients than in normal controls. 51.4% of the depressed patients
had plasma CoQ10 values that were lower than the lowest plasma CoQ10 value
detected in the controls. Plasma CoQ10 was significantly lower in patients with
TRD and with CFS than in the other depressed patients. There were no significant
correlations between plasma CoQ10 and the HDRS.
The results show that lower CoQ10 plays a role in the pathophysiology of depres-
sion and in particular in TRD and CFS accompanying depression. It is suggested
that depressed patients may benefit from CoQ10 supplementation.
The findings that lower CoQ10 is a risk factor to coronary artery disease and
chronic heart failure (CHF) and mortality due to CHF suggest that low CoQ10 is
another factor explaining the risk to cardiovascular disorder in depression. Since
statins significantly lower plasma CoQ10, depressed patients and in particular
those with TRD and CFS represent populations at risk to statin treatment.
102
Copyright © 2009 Neuroendocrinology Letters ISSN 0172–780X •  www.nel.edu
Michael Maes, Ivanka Mihaylova, Marta Kubera, Marc Uytterhoeven, Nicolas Vrydags, Eugene Bosmans
INTRODUCTION
There is now evidence that major depression is accom-
panied by an induction of inflammatory and oxidative
and nitrosative stress (IO&NS) pathways, which cause
depressive symptomatology. This theory was called the
monocyte-T-lymphocyte, cytokine or inflammatory
hypothesis of depression (Maes, 1993; 1995; 1999; 2008;
Schiepers et al. 2005). The first papers which showed
that T cell and monocytic activation are new pathways
in depression were published in 1990 and 1991 (Maes
et al. 1990; 1991). Since then many consistent reports
have been published on increased levels of proinflam-
matory cytokines, e.g. interleukin-1 (IL-1), IL-2, IL-6,
IL-8, IL-12, interferon-γ (IFNγ) and tumor necrosis
factor-α (TNFα), and acute phase proteins (Schiepers et
al. 2005). Also translational research shows that inflam-
matory processes and neural-immune interactions
in the brain are new pathways in depression (Maes et
al. 2009b; Goshen et al. 2008). In animal models, the
increased production of pro-inflammatory cytokines,
such as IL-1β, IL-6 and TNFα, and consequent brain
neuroinflammation may induce depressive symptoms,
such as anorexia, soporific effects, reduction of loco-
motor activity and exploration, anhedonia and cog-
nitive disturbances (Maes et al. 2009b; Goshen et al.
2008; Anisman et al. 2005; Qin et al. 2007). In humans,
cytokine-based immunotherapy may induce depression
through cytokine-induced changes in the metabolism
of serotonin (Maes et al. 2001; Bonaccorso et al. 2002;
Wichers et al. 2005; Forlenza and Miller, 2006).
Inflammatory responses are known to be accompa-
nied by an induction of oxidative and nitrosative stress
(O&NS) pathways. Likewise, depression is accompa-
nied by indicants of oxidative stress, such as increased
levels of malondialdehyde (MDA), a byproduct of
polyunsaturated fatty acid peroxidation and arachi-
donic acid; 8-hydroxy-2-deoxyguanosine, indicating
oxidative damage to DNA by oxygen radicals; and IgM
responses against phosphatidyl inositol (Forlenza and
Miller, 2006; Sarandol et al. 2007; Maes et al. 2007c).
Other findings in depression point toward nitrosative
stress, e.g. increased IgM responses against NO-bovine
serum albumin (Maes et al. 2008). Moreover, depression
in characterized by a significantly reduced antioxidant
status, as indicated by lowered blood levels of antioxi-
dants, such as serum zinc, vitamin E and C, tryptophan
and tyrosine, glutathione peroxidase, and albumin
(Maes and Meltzer, 1995; van Hunsel et al. 1996; Maes et
al. 1994; 1997b; 2000; Ozcan et al. 2004; Khanzode et al.
2003). In animals models of stress-induced depression
reduced concentrations of brain glutathione, another
antioxidant, are observed (Pal and Dandiya, 1994; Gut-
teridge and Halliwell, 1994).
There is ample evidence that depression is associated
with neurodegeneration and a reduced neurogenesis in
the brain (Maes et al. 2009b; Campbell and MacQueen,
2006; Stockmeier et al. 2004; Koo and Duman, 2008)
and that both factors are caused by neuroinflamma-
tory processes (Maes et al. 2009b). Different neurotoxic
mechanisms that are induced or altered by IO&NS
pathways may be involved, e.g. neurotoxic cytokines;
O&NS pathways; glucocorticoids; neurotoxic TRYCATs
(tryptophan catabolites), which production is enhanced
by inflammation; and lowered ω3 polyunsaturated fatty
acids (Maes et al. 2009b). Recently, these new pathways
in depression have been described in the inflammatory
& neurodegenerative (I&ND) hypothesis of depression
(Maes et al. 2009b).
Up to 15% of the depressed patients suffer from
treatment resistant depression (TRD). There is now
evidence that IO&NS and I&ND pathways are involved
in TRD (Maes et al. 2009b) as evidenced by for example
an increased CD4+/CD8+ T cell ratio; serum IL-6 and
production of IL-6 and TNFα; and significantly lower
serum zinc (Maes et al. 1997b; Kubera et al. 1999; Maes
et al. 1997a; O’Brien et al. 2007).
Another factor that may participate in the IO&NS
and I&ND pathways in depression is a deficiency of
plasma coenzyme Q10 (CoQ10). CoQ10 is a strong
anti-oxidant that confers resistance to mitochondrial
damage by O&NS and an anti-inflammatory agent
that decreases the production of, for example, TNFα
(Chaturvedi and Beal, 2008; Schmelzer et al. 2007a;
2007b; 2008). Moreover, CoQ10 has neuroprotective
properties, protecting neurons and brain cells against
central neurotoxic damages (Chaturvedi and Beal, 2008;
You n g et al. 2007; Li et al. 2005; Matthews et al. 1998).
Recently, we found that plasma CoQ10 is significantly
reduced in patients with myalgic encephalomyelitis /
chronic fatigue syndrome (ME/CFS), another illness
characterized by induction of the IO&NS pathways
(Maes et al. 2009a; 2007a; 2007b). However, to the best
of our knowledge, no research has examined plasma
CoQ10 in depression, TRD and CFS in depression.
The present study has been carried out in order to
examine whether major depression is accompanied by
lowered plasma CoQ10 and to examine the relation-
ships between lower CoQ10 and TRD, chronicity of
depression, depressive symptomatology and CFS in
depression.
SUBJECTS AND METHODS
Subjects
Fifty-seven subjects participated in the present study, i.e.
22 healthy volunteers and 35 major depressed patients.
The latter were admitted to the Maes Clinics, Antwerp,
Belgium. The patients were classified as major depres-
sion according to DSM-IV-TR criteria (APA, 2000),
using a semistructured interview. Severity of depres-
sion was measured with the Hamilton Depression
Rating Scale (HDRS) (Hamilton, 1960). The presence
of the symptoms of ME/CFS was assessed by means of
the Center for Disease Control and Prevention (CDC)
criteria (Fukuda et al. 1994). The CDC criteria rule
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Coenzyme Q10 in depression
out to make the ME/CFS diagnosis when melancholia
is present. Nevertheless, we employed the CDC crite-
ria to delineate the presence of the CFS according to
the following criteria: a) the patient has to suffer from
severe chronic fatigue for at least six months; and b) at
least four of the following symptoms should be pres-
ent: substantial impairment in short – term memory or
concentration; sore throat; muscle pain; multi joint
pain without selling or redness; headache of new type;
unrefreshing sleep; and post exertion malaise lasting
more than 24 hours. The severity of CFS was scored by
means of the Fibromyalgia and CFS Rating Scale (FF
scale) (Zachrisson et al. 2002). The FF scale measures
12 symptoms which are characteristic for fibromyalgia
and CFS, i.e. pain, muscular tension, fatigue, concen-
tration difficulties, failing memory, irritability, sadness,
sleep disturbances, autonomic disturbances, irritable
bowel, headache, and subjective experience of infec-
tion. Staging of treatment resistance was based on prior
treatment responsivity according to the criteria of Thase
and Rush (1995). We classified the patients as suffering
from TRD when they fulfilled the following criteria: a)
nonresponse to two adequate trials with antidepressant
agents from different classes, e.g. tricyclics (TCSs) or
selective serotonin reuptake inhibitors (SSRIs); b) the
previous stage (stage a) plus a failure to respond to one
augmentation therapy; c) the previous stage plus failure
to respond to two augmentation strategies; and d) the
previous stage plus a nonresponse to electroconvulsive
treatment. Nineteen of the depressed patients included
in this study fulfilled the abovementioned criteria for
TRD. The others (n=16) had never had a single ade-
quate trial with antidepressants or showed a nonre-
sponse to one adequate trial. Of those patients 15 were
treated successfully in the Maes Clinics and therefore
were classified as non-TRD patients. One patient who
previously did not respond to one trial with SSRIs did
not respond to our treatment and therefore was clas-
sified as a patient with TRD. Consequently, in total 20
patients were classified as suffering from TRD and 15
were classified as non-TRD.
We have excluded all subjects with life-time diag-
noses of psychiatric DSM IV-R disorders other than
major depression, e.g. psychotic, substance use and
organic mental disorders. Patients with substance abuse
(last 6 months prior to the studies) were excluded to
participate in this study. We also omitted subjects with
other medical illnesses, e.g. endocrine (e.g. Cushing,
thyroid disease), metabolic (e.g. diabetes type 1 or type
2), immune, like autoimmune and inflammatory bowel
disorders) and cardio-vascular (e.g. hypertension, arte-
riosclerosis) disorders. Moreover, we have excluded
subjects with abnormal blood tests, such as alanine
aminotransferase (ALT), alkaline phosphatase (ALP),
creatinine, and thyroid stimulating hormone (TSH).
Subjects who had suffered from infections during the
last two months prior to the study were excluded. We
have excluded depressed patients who were treated with
anti-psychotic drugs, anticonvulsants or mood stabiliz-
ers the year prior to the studies. All subjects were free of
drugs known to affect immune or endocrine functions.
None had been taking statins or beta-blockers and sup-
plements with CoQ10. The normal volunteers were free
of any medication for at least 1 month prior to blood
sampling; no one had ever been taking psychotropic
drugs or was a regular drinker. Patients and controls
gave written informed consent after the study protocol
was fully explained; the study has been approved by the
local ethical committee.
Methods
Plasma for the assay of CoQ10 was sampled in the
morning hours after an overnight fast. CoQ10 was
determined using a HPLC method manufactured by
Chromsystems Diagnostics (Munich, Germany). This
reagent kit allows the reliable chromatographic deter-
mination of CoQ10 in an isocratic HPLC run using UV
detection (275 nm). CoQ10 is released by precipitating
the proteins and then concentrated using solid phase
extraction. Inclusion of an internal standard minimizes
any analytical variation. We followed the instructions
as provided by Chromsystems Diagnostics. The Intra-
assay coefficient of variation (CV) was < 5%, and the
inter-assay CV < 6%.
Statistics
Differences between group means were checked
by analysis of variance (ANOVA) or covariance
(ANCOVA). The independence of classification sys-
tems was ascertained by means of analysis of contin-
gence tables 2-test) and Fisher’s exact probability
test. The diagnostic performance of plasma CoQ10 for
depression and TRD was checked by means of ROC
(receiver operating characteristics) analysis with com-
putation of the area under the ROC curve, sensitivity,
specificity and predictive value of a positive test result
(PV+) and with kappa statistics (Zweig and Campbell,
1993). Relationships between variables were ascertained
by means of Pearson’s product-moment correlation
coefficients, regression analyses and multiple regres-
sion analyses with an p–to-enter of p=0.05. In order to
check the symptomatic profiles of diagnostic groups we
employed stepwise linear discriminant analysis (LDA)
with an F-to-enter of p=0.05. The significance was set
at α=0.05 (two tailed).
RESULTS
Figure 1 shows the plasma CoQ10 values in depressed
patients and normal controls. ANOVA showed that
plasma CoQ10 was significantly lower in the major
depressed patients than in the normal volunteers
(F=23.6, df=1/55, p=0.00006). Covarying for age and
sex in an ANCOVA did not change these results (F=20.7,
df=1/53, p=0.0001). Neither gender (F=0.11, p=0.7)
nor age (F=0.00, p=0.9) were significant in this analy-
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Michael Maes, Ivanka Mihaylova, Marta Kubera, Marc Uytterhoeven, Nicolas Vrydags, Eugene Bosmans
sis. There were no significant differences in age (F=1.3,
df=1/55, p=0.2) between normal controls (mean age
±SD = 45.4 ±10.1 years) and major depressed patients
(mean age = 42.1 ±10.5 years). There was no significant
difference (χ2 =1.6, df=1, p=0.0.2) in the gender distri-
bution between normal controls (5 male/17 female) and
major depressed patients (15 male/20 female patients).
The lower plasma CoQ10 showed a significant diagnos-
tic performance for major depression: the area under
the ROC curve was AUC=81.7%; at a cut-off point of
CoQ10 < 490 g/L (that is the lowest CoQ10 value
established in the normal controls) we found a sensi-
tivity = 51.4%, specificity = 100.0%, and PV+ = 100%
(κ=0.45, t=4.02, p=0.0004).
Depressed patients with TRD (mean CoQ10=420.0
± 107.0 g/L, n=15) had significantly (F=15.3, df=1/33,
p=0.0007) lower plasma CoQ10 than patients without
TRD (mean CoQ10=581.7 ± 125.8 g/L, n=20). There
were no significant differences in age (F=0.0, df=1/33,
p=0.98) between depressed patients with (mean
age=42.1 ±10.3 years) and without (mean age=42.1
±11.1 years) TRD. There was no significant difference
2 =0.5, df=1, p=0.5) in the male/female ratio between
TRD (8 male/7 female) and non-TRD (7 male/13
female) patients. Lower plasma CoQ10 showed a sig-
nificant diagnostic performance for TRD versus non-
TRD: the area under the ROC curve was AUC=83.5%;
at a cut-off point of CoQ10 < 415 g/L we found:
sensitivity=60.0%, specificity=95.0%, and PV+=90%
(κ=0.57, t=3.98, p=0.0006).
Depressed patients with CFS (mean CoQ10=445.8
±123.6 g/L, n=17) had significantly (F=8.7, df=1/33,
p=0.006) lower plasma CoQ10 than patients without
CFS (mean CoQ10=575.3 ±131.2 g/L, n=18). There
was no significant difference 2 =0.3, df=1, p=0.6) in
the male/female ratio between those with (6 male/11
female) and without (9 male/9 female) CFS. Those
with CFS (mean age=45.9 ±10.5 years) were somewhat
(F=4.9 df=1/33, p=0.03) older than those without (mean
age=38.4 ±9.3 years). Covarying for age (and gender)
in an ANCOVA did not change the significant differ-
ences in CoQ10 between both groups (F=8.2, df=1/31,
p=0.007), while age was not significant in this analysis
(F=0.00, p=0.9). The number of patients with CFS was
not significantly different between patients with (10/5)
and without (7/13) TRD. The presence of CFS (F=4.3,
df=1/31, p=0.04) and TRD (F=10.3, df=1/31, p=0.003)
independently from each other predicted low CoQ10
values (F=7.1, df=3/31, p=0.001; results of a factorial
design ANOVA with TRD and CFS as treatments; the
interaction pattern was non-significant: F=0.0, df=1/31,
p=0.8).
In the depressed patients, there were no significant
correlations between plasma CoQ10 and age (r=0.13,
p=0.6), gender (point biserial correlation: r=-0.08,
p=0.6), the HDRS score (r=0.13, p=0.5) and the total FF
scale score (r=0.19, p=0.3). In the depressed subgroup
we were unable to detect any differences in plasma
CoQ10 between subjects who suffered from a chronic
major depression for more than 2 years and those who
did not. There was no significant correlation between
plasma CoQ10 and the number of depressive episodes.
Part of the depressed patients took antidepressants by
the time of blood samplings (n=15), while the others
Figure 1. Scatter plot of the measurements of Co-enzyme Q10 (CoQ10 in ln transformation) in 33 major
depressed patients and 22 normal volunteers (NV).
7.5
7.0
6.5
6.0
5.5
5.0
7.5 2.0
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Coenzyme Q10 in depression
were unmedicated. There were no significant differences
in plasma CoQ10 between depressed patients who were
taking antidepressants (mean CoQ10=547.7 ±116.0
g/L, n=15) and those without (mean CoQ10=485.9
±156.9 g/L, n=20). In depressed patients no significant
relationships could be detected between plasma CoQ10
and any of the 12 FF scale items, either by stepwise mul-
tiple regression analysis of plasma CoQ10 on the 12 FF
items or by stepwise LDA with as groups the depressed
patients divided into groups with lower (<490 g/L)
versus higher (>490 g/L) CoQ10 values.
DISCUSSION
This is a first study which shows that major depression
is accompanied by a CoQ10 deficiency and that lower
plasma CoQ10 is significantly related to treatment
resistance and the presence of CFS in depression.
The first major finding of this study is that depres-
sion is characterized by a low CoQ10 syndrome: up to
51.4% of the depressed patients showed plasma CoQ10
values that were lower than 490 g/L, i.e. the lowest
CoQ10 value established in the normal volunteers. In
the next paragraphs we discuss that lower CoQ10 play a
role in the IO&NS and I&ND pathways in depression.
The findings of this study reinforce the existent
literature which shows that depression is accompa-
nied by a significantly decreased antioxidant status, as
evidenced by lower serum zinc, vitamin E and C, glu-
tathione peroxidase, tryptophan and tyrosine and albu-
min (see Introduction). It is safe to posit that the “low
CoQ10 syndrome” in depression and the more general
reduced antioxidative capacity in those patients may
have impaired the anti-oxidative protection against
the damaging effects IO&NS and, consequently, may
be involved in the neurotoxic damage which occurs in
depression (Maes et al. 2009b). It is now well established
that CoQ10 has significant neuroprotectant properties,
whereby this compound may protect neuronal cells
against neuronal damages (Chaturvedi and Beal, 2008;
You n g et al. 2007; Li FC et al. 2005; Li G et al. 2005; Mat-
thews et al. 1998; Kooncumchoo et al. 2006; Ishrat et al.
2006; Somayajulu et al. 2005). This explains why CoQ10
has the potential to be employed as a therapeutic inter-
vention in neurodegenerative disorders (Somayajulu et
al. 2005).
CoQ10 has also anti-inflammatory effects, e.g. by
decreasing Nuclear Factor κB-gene expression and the
production of pro-inflammatory cytokines, such as
TNFα, and protecting against endoxin or LPS-induced
inflammatory reactions (Schmelzer et al. 2007a; 2007b;
2008; Abd El-Gawad et al. 2001; Sugino et al. 1987).
Thus, the deficiency of CoQ10 in depression may pre-
dispose toward greater inflammatory responses and a
greater production of proinflammatory cytokines, such
as TNFα, which eventually cause more damage and
neurodegeneration (Maes et al. 2009b).
CoQ10 is also of paramount importance in the elec-
tron transport chain (ETC) within the mitochondria
(Butler et al. 2003; Crane, 2001). On the inner mem-
brane of the mitochondria, CoQ10 transfers electrons
from complexes I and II to complex III which take part
in the respiratory chain and the synthesis of ATP that
powers the energy in our cells and our body (Butler et
al. 2003; Crane, 2001; Dutton et al. 2000). CoQ10 and
other mitochondrial constituents, such as lipoic acid,
have protective properties against the generation and
damaging effects of free radicals that are released during
the abovementioned oxidative processes in the mito-
chondria (Chaturvedi and Beal, 2008; Liu, 2008). Thus,
lowered plasma CoQ10 in depression may predispose
towards a decreased mitochondrial respiratory chain
and mitochondrial dysfunctions including damage
to mitochondrial DNA. Mitochondrial disturbances
including decreased gene expression and deletions of
mitochondrial DNA were detected in major depression
(Shao et al. 2008; Gardner et al. 2003; Suomalainen et
al. 1992). In a rat model of depression, i.e. chronic mild
stress, the mitochondrial complexes I, III and IV were
inhibited in the cerebral cortex and cerebellum (Rezin
et al. 2008).
The second major finding of this study is that patients
with simultaneous CFS have significantly lower CoQ10
than patients without. Our results that CoQ10 is much
lower in depressed patients with CFS is in agreement
with those of another study showing that a low CoQ10
syndrome is a hallmark of genuine ME/CFS (Maes et
al. 2009a). The findings are also in agreement with pre-
vious reports that statins may induce fatigue, myalgia
and neurocognitive disorders, e.g. concentration and
memory disturbances through a depletion of CoQ10
(Langsjoen et al. 2005; Passi et al. 2003). Indeed, statins
inhibit the conversion of 3-hydroxy-3-methylglutaryl-
coenzyme A to mevalonate, a precursor for cholesterol
and the side chain of CoQ10 (Mabuchi et al. 2005; Chu
et al. 2006). The results are also in agreement with those
of other studies reporting that fatigue and exercise
intolerance are common in illnesses characterized by
low plasma CoQ10, such as autosomal recessive CoQ10
deficiency, mitochondrial disorders, Prader-Willi syn-
drome, Friedrich’s ataxia, Steinert’s myotonic dystrophy,
cardiac and skeletal muscle dysfunctions, and cancers
(Butler et al. 2003; Cooper et al. 2008; Siciliano et al.
2001; Rusciani et al. 2006; Palan et al. 2003). The fatigue
in those patients is often treatable with CoQ10 supple-
mentation (Cooper et al. 2008; Bonakdar and Guarneri,
2005; Singh et al. 2003).
A third major finding of this study is that lowered
CoQ10 is a hallmark for TRD. Previously, it has been
shown that another antioxidant confers resistance to
treatment resistance with antidepressants, i.e. lower
serum zinc (Maes et al. 1997b). As described before,
TRD is characterized by more severe disorders in dif-
ferent I&ND pathways, including increased TNFα
production (Maes et al. 2009b). Thus, the lower CoQ10
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Michael Maes, Ivanka Mihaylova, Marta Kubera, Marc Uytterhoeven, Nicolas Vrydags, Eugene Bosmans
syndrome in major depression may have lowered the
protection against the neuroinflammatory and neuro-
toxic effects of IO&NS.
The low CoQ10 syndrome in major depression
provides another explanation for the high comorbid-
ity between cardiovascular disorders and depression,
which has been detected in Caucasian and Asian popu-
lations (Huang et al. 2009). It is now well established
that major depression is a significant risk factor to
coronary artery disease (CAD) (Jakobsen et al. 2008)
and that the comorbidity between depression and CAD
results in an increased cardiovascular mortality (Som-
berg and Arora, 2008; Dickens et al. 2008). Also, primate
data are consistent with the hypothesis that depression
may cause coronary artery arteriosclerosis (Shively et
al. 2009). CoQ10 is a protective factor preventing coro-
nary artery disease (Yalcin et al. 2004). CoQ10 increases
the resistance to the initiation of lipid peroxidation and
has direct anti-atherogenic effect (Littarru and Tiano,
2007; Chapidze et al. 2005). There is now evidence that
cardiac disorders, such as chronic heart failure (CHF),
may be caused by a low CoQ10 syndrome and that low
CoQ10 is an independent risk factor to mortality in
CHF (Molyneux et al. 2008). Moreover, there are data
that CoQ10 supplementation is of therapeutic value in
congestive heart failure (Singh et al. 2007). CoQ10 may
affect heart function through different mechanisms. A)
low CoQ10 predisposes towards greater activity of the
IO&NS pathways and therefore to increased inflamma-
tory processes, including increased C-reactive protein
and IL-6, and increased damage to membrane fatty acids
by O&NS, including increased oxidized LDL cholesterol
(Maes et al. 2009b), which are all known pathophysio-
logical mechanisms in CAD. B) Direct effects of CoQ10
on the heart include enhancement of systolic function,
left ventricular ejection fraction and myocardium con-
tractility (Sander et al. 2006; Belardinelli, 2005) and
improvement of the endothelium-dependent relaxation
and endothelium-bound extracellular superoxide dis-
mutase (Tiano et al. 2007).
As discussed before, statins may significantly lower
plasma CoQ10 and induce symptoms that occur in CFS,
such as myalgia, fatigue, neurocognitive symptoms and
neuropathies (Langsjoen et al. 2005; Passi et al. 2003;
Mabushi et al. 2005; Chu et al. 2006; Berthold et al. 2006).
In rats, administration of simvastatin decreased CoQ10
levels in the heart and skeletal muscles (Kucharska et al.
2007). In HepG2 cells, simvastatin decreases mitochon-
drial CoQ10 and at higher doses increased cell death
and damage to DNA caused by O&NS (Tavintharan et
al. 2007). Littarru and Langsjoen (2007) state that in
some conditions where depleted CoQ10 situations exist
treatment with statins may seriously impair plasma and
possible tissue levels of CoQ10, thus impairing skeletal
muscle and myocardial bioenergetics. Since depression
is accompanied by lower plasma CoQ10 and since very
low CoQ10 values are observed in TRD and in depres-
sion with CFS, the latter represent populations at-risk to
treatment with statins that would benefit from CoQ10
supplementation. Indeed, CoQ10 supplementation will
reverse the depleted plasma CoQ10 concentrations
(Mabushi et al. 2007; Keith et al. 2008) and statin-in-
duced symptoms as well (Langsjoen et al. 2005; Caso et
al. 2007).
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... Despite the ambiguity in study findings related to the exact role of CoQ10, researchers established a role of low CoQ10 in the path physiology of depression (54,55). Consistent with this study, previous studies revealed that overwork was associated with burnout and that burnout significantly predicted the inflammatory cytokines TNF-a, IL6, and CoQ10 (23,51,52). ...
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Objectives: This study aimed to investigate the technostress creators and outcomes among University medical and nursing faculties and students as direct effects of the remote working environment during the COVID-19 pandemic. Background: Due to the current COVID-19 pandemic, shifting to virtual learning that implies utilizing the information and communication technologies (ICTs) is urgent. Technostress is a problem commonly arising in the virtual working environments and it occurs due to misfitting and maladaptation between the individual and the changeable requirements of ICTs. Methods: A multicenter cross-sectional study was conducted in medicine and nursing colleges of 5 Egyptian universities and included both staff members and students. The data were collected through personal interviews, from January to May 2021. All the participants took a four-part questionnaire that asked about personal and demographic data, technostress creators, job or study, and technical characteristics and technostress outcomes (burnout, strain, and work engagement). Furthermore, participants' blood cortisol and co-enzyme Q10 (CoQ10) levels were tested in a random sample of the students and medical staff. Results: A total of 3,582 respondents participated in the study, 1,056 staff members and 2,526 students where 33.3% of the staff members and 7.6% of students reported high technostress. Among staff members, total technostress score significantly predicted Cortisol level (β = 2.98, CI 95%: 0.13-5.83), CoQ10(β = -6.54, CI 95%: [(-8.52)-(-4.56), strain (β = 1.20, CI 95%: 0.93-1.47), burnout (β = 0.73, CI 95%: 0.48-0.97) and engagement (β = -0.44, CI 95%: [(-0.77)-(-0.11)]) whereas among students, total technostress score significantly predicted cortisol level (β = 6.64, CI 95%: 2.78-10.49), strain (β = 1.25, CI 95%: 0.72-1.77), and burnout (β = 0.70, CI 95%: 0.37-1.04). Among staff members and students, technology characteristics were significantly positive predictors to technostress while job characteristics were significantly negative predictors to technostress. Conclusion: The Egyptian medical staff members and students reported moderate-to-high technostress which was associated with high burnout, strain, and cortisol level; moreover, high technostress was associated with low-work engagement and low CoQ10 enzyme. This study highlighted the need to establish psychological support programs for staff members and students during the COVID-19 pandemic.
... It has been recently shown how TRD is characterized by increased oxidative stress coupled to inflammation (Sowa-Kućma et al., 2018). Furthermore, plasma levels of Coenzyme Q10 (CoQ10), a strong antioxidant with anti-inflammatory activity, are lower in TRD patients compared to responders depressed patients (Maes et al., 2009) and CoQ10 (200 mg/die) has been proposed as an adjuvating agent for the treatment of depression (Mehrpooya et al., 2018). According to this scenario second-generation antidepressant drugs, endowed with antioxidant activity, may display an increased clinical efficacy in TRD patients; studies in animal models are useful to test this hypothesis. ...
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Depression is a risk factor for the development of Alzheimer’s disease (AD). A neurobiological and clinical continuum exists between AD and depression, with neuroinflammation and oxidative stress being involved in both diseases. Second-generation antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are currently investigated as neuroprotective drugs in AD. By employing a non-transgenic AD model, obtained by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ) oligomers in 2-month-old C57BL/6 mice, we recently demonstrated that the SSRI fluoxetine (FLX) and the multimodal antidepressant vortioxetine (VTX) reversed the depressive-like phenotype and memory deficits induced by Aβ oligomers rescuing the levels of transforming growth factor-β1 (TGF-β1). Aim of our study was to test FLX and VTX for their ability to prevent oxidative stress in the hippocampus of Aβ-injected mice, a brain area strongly affected in both depression and AD. The long-term intraperitoneal (i.p.) administration of FLX (10 mg/kg) or VTX (5 and 10 mg/kg) for 24 days, starting 7 days before Aβ injection, was able to prevent the over-expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (Nox2) induced by Aβ oligomers. Antidepressant pre-treatment was also able to rescue the mRNA expression of glutathione peroxidase 1 (Gpx1) antioxidant enzyme. FLX and VTX also prevented Aβ-induced neurodegeneration in mixed neuronal cultures treated with Aβ oligomers. Our data represent the first evidence that the long-term treatment with the antidepressants FLX or VTX can prevent the oxidative stress phenomena related to the cognitive deficits and depressive-like phenotype observed in a non-transgenic animal model of AD.
... Activation of oxidative and nitrosative stress (O&NS) is important in the pathophysiology of depression. Inflammation is accompanied by the generation of reactive oxygen species and reactive nitrogen species (ROS and RNS), which may cause oxidative damage to DNA, lipids, and proteins in the cells, which results in neurodegeneration or cell death [94][95][96]. Various theories suggest that inflammation and neurodegeneration induce depression [95,97,98]. ...
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Reactive oxygen species are found to be having a wide range of biological effects ranging from regulating functions in normal physiology to alteration and damaging various processes and cell components causing a number of diseases. Mitochondria is an important organelle responsible for energy production and in many signalling mechanisms. The electron transport chain in mitochondria where oxidative phosphorylation takes place is also coupled with the generation of reactive oxygen species (ROS). Changes in normal homeostasis and overproduction of reactive oxygen species by various sources are found to be involved in multiple neurological and major neurodegenerative diseases. This review summarises the role of reactive oxygen species and the mechanism of neuronal loss in major neuronal disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Depression, and Schizophrenia.
... Many nutrients have antioxidant actions which induce therapeutic effects, such as coenzyme-Q10 (CQ10), vitamin C and E, selenium, and pyrroloquinoline quinone (PQQ). CQ10 is an electron carrier involved in OX-PHOS (Andalib et al., 2019) that is decreased in the plasma of 51.4% of depressed patients (Maes et al., 2009). Interestingly, CQ10-supplemented rats had lower levels of hydroperoxide and higher levels of glutathione peroxidase and cytochrome oxidase activity in heart mitochondria (Ochoa et al., 2005). ...
Chapter
Affective disorders, including major depression and bipolar disorder, are thought to stem from alterations in neurotransmitter transduction pathways, but recent evidence implicates broader forms of dampened neural plasticity, inflammation, and points to a possible important role on mitochondrial alterations. Mitochondria modulate proper brain function by producing energy and regulating oxidative stress and apoptosis. Human and animal studies implicate deficient energy metabolism, increased production of reactive oxygen species and pro-apoptotic factors, and membrane permeability in the pathology of affective disorders. Exercise and improving one’s diet can improve mitochondrial function and mood. Studies investigating the effects of medications on mitochondria often reveal contradictory findings, in that their therapeutic or detrimental effects are dose dependent. Overall, several lines of research indicate that deficient mitochondrial activity is implicated in the pathology of affective disorders and suggest that novel compounds could be developed to target mitochondria, or that specific patterns of alterations could be identified as biomarkers to personalize treatment or aid in their diagnosis.
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Decomposing the structure of human cerebral function in its domains, such as affect regulation or cognition, forms the backbone of psychiatric diagnosis and treatment. Research continues to decipher the domains and hierarchical structure of cerebral function. So far, the findings strongly suggest two higher-order latent factors of general psychopathology (p factor) and general intelligence (g factor). Both general factors are functions of the same organ, covary, share risk factors as well as biomarkers, and benefit from the same treatments. However, to our knowledge, a model that connects both components of cerebral function within a higher-order latent factor and describes its potential biological underpinning is lacking. First, we suggest the general factor of cerebral function (c factor) as the shared variance of the measures of g and p in a bi-factor model. Second, we propose and provide evidence that mitochondrial bioenergetics (MB) is one core biological underpinning of c. Third, we describe how this c factor mito-bioenergetics (CMB) model may transform research and clinical practice by advancing knowledge of treatment effects, risk factors, biomarkers and clinical outcomes. Finally, we present a CMB model-based hypothesis stating that fatigue—as a phenotypical correlate of MB—directly loads on c.
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Studies show that administration of interferon (IFN)-α causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-α-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-α treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood–brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-α treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-α-induced depressive symptoms, through its induction of neurotoxic KYN metabolites.
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1.1. This paper reviews recent findings on cellular and humoral immunity and inflammatory markers in depression.2.2. It is shown that major depression may be accompanied by systemic immune activation or an inflammatory response with involvement of phagocytic (monocytes, neutrophils) cells, T cell activation, B cell proliferation, an “acute” phase response with increased plasma levels of positive and decreased levels of negative acute phase proteins, higher autoantibody (antinuclear, antiphospholipid) titers, increased prostaglandin secretion, disorders in exopeptidase enzymes, such as dipeptidyl peptidase IV, and increased production of interleukin (IL)-1β and IL-6 by peripheral blood mononuclear cells.3.3. It is hypothesized that increased monocytic production of interleukins (Il-1β and Il-6) in severe depression may constitute key phenomena underlying the various aspects of the immune and “acute” phase response, while contributing to hypothalamic-pituitary-adrenalaxis hyperactivity, disorders in serotonin metabolism, and to the vegetative symptoms (i.e. the sickness behavior) of severe depression.
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Depression and coronary heart disease (CHD) are leading contributors to disease burden in women. CHD and depression are comorbid; whether they have common etiology or depression causes CHD is unclear. The underlying pathology of CHD, coronary artery atherosclerosis (CAA), is present decades before CHD, and the temporal relationship between depression and CAA is unclear. The evidence of involvement of depression in early CAA in cynomolgus monkeys, an established model of CAA and depression, is summarized. Like people, monkeys may respond to the stress of low social status with depressive behavior accompanied by perturbations in hypothalamic–pituitary–adrenal (HPA), autonomic nervous system, lipid metabolism, ovarian, and neural serotonergic system function, all of which are associated with exacerbated CAA. The primate data are consistent with the hypothesis that depression may cause CAA, and also with the hypothesis that CAA and depression may be the result of social stress. More study is needed to discriminate between these two possibilities. The primate data paint a compelling picture of depression as a whole-body disease.
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Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may-at least partly-be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites-and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo-in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.
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Objective: Major depression is associated with defective antioxidant defenses. Vitamin E is the major fat soluble antioxidant in the body. The aim of the present study is to examine serum vitamin E concentrations in major depressed patients versus normal volunteers. Method: Serum vitamin E concentrations were measured in 26 healthy volunteers and 42 major depressed patients by means of HPLC. Since vitamin E is a fat soluble vitamin, and serum vitamin E concentrations are strongly related to these of low-density-lipoprotein cholesterol (LDL-C) and triglycerides, we have adjusted the results for possible differences in these lipids. The numbers of peripheral blood leukocytes were measured. Results: Patients with major depression had significantly lower serum vitamin E concentrations than healthy controls. The area under the ROC (receiver operating characteristics) curve was 83%. There were significant and negative correlations between serum vitamin E and number of total leukocytes and neutrophils. Conclusions: Major depression is accompanied by significantly lower serum vitamin E concentrations, suggesting lower antioxidant defenses against lipid peroxidation. The results could, in part, explain previous findings, which suggest increased lipid peroxidation in major depression.
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Studies in humans and cell culture as well as bioinformatics suggested that Coenzyme Q10 (CoQ10 ) functions as an anti-inflammatory molecule. Here we studied the influence of CoQ10 (Kaneka QTM ) on secretion of the pro-inflammatory 10 cytokine tumor necrosis factor-alpha (TNF-α) by using the human and murine monocytic cell lines TH P-1 and RAW264.7 expressing human apolipoprotein E3 (apoE3) or pro-inflammatory apoE4. Incubation of cells with physiological (0.1–10 μM) and supra-physiological (> 10 to ≤ 100 μM) concentrations of CoQ10 led to an intracellular accumulation of its reduced form without any cytotoxic effects. Stimulation of cell models with lipopolysaccharide (LPS) resulted in a substantially release of TNF-α. When THP-1 cells were pre-incubated with 10 μM CoQ10, the LPS-induced TNF-α release was significantly decreased to 72 ± 32%. This effect is similar to those obtained by 10 μM N-Acetyl-Cysteine, a well known reference antioxidant. In RAW264.7-apoE3 and -apoE4 cells, significant reductions of LPS-induced TNF-α secretion to 73.3 ± 2.8% and 74.7 ± 8.9% were found with 2.5 μM and 75 μM CoQ10, respectively. In conclusion, CoQ10 has moderate anti-inflammatory effects in two monocytic cell lines which could be mediated by its antioxidant activity.
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Aims: Accumulating evidence from Caucasian patients has shown that depression, bipolar and anxiety disorders are associated with an increased risk of cardiovascular diseases (CVD), but reports in the Asian population are limited, and age effect is rarely investigated. This population-based study was carried out to examine and compare the CVD comorbidities among patients with mood and anxiety disorders in different age groups. Method: A 4-year cross-sectional survey was carried out using the Taiwan National Health Insurance Research Database from 2000 to 2003. Results: An average total of 1,031,557 patients with mood and anxiety disorders were enrolled as study participants, including 76,430 cases of major depressive disorder, 41,557 cases of bipolar disorder, and 913,570 cases of anxiety disorder. When compared with the insured population without mood or anxiety disorders (average 21,356,304 people), the average relative risk (RR) of developing ischemic heart disease and hypertensive disorders in 1,031,557 study participants was 2.0 and 2.05, respectively. The highest RR was found in the age group under 20 years (RR = 4.74 and 4.08, respectively), and the lowest RR in the age group equal to or older than 65 years (RR = 0.47 and 0.58, respectively). Conclusions: Taiwanese patients with mood and anxiety disorders experience high cardiovascular morbidity, especially patients with anxiety disorders. Age acted as an important modifier variable that influenced the relationship between mood, anxiety disorder and CVD. This study highlights the need for future research in different age groups, in order to elucidate the causality and the trajectory of developing CVD among patients with mental disorders.
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Clinical studies demonstrated the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapeutic in cardiovascular diseases, mitochondrial myopathies and neurodegenerative diseases. More recently, expression profiling revealed that Coenzyme Q10 (CoQ10) influences the expression of several hundred genes. To unravel the functional connections of these genes, we performed a text mining approach using the Genomatix BiblioSphere. We identified signalling pathways of G-protein coupled receptors, JAK/STAT, and Integrin which contain a number of CoQ10 sensitive genes. Further analysis suggested that IL5, thrombin, vitronectin, vitronectin receptor, and C-reactive protein are regulated by CoQ10 via the transcription factor NFkappaB1. To test this hypothesis, we studied the effect of CoQ10 on the NFkappaB1-dependent pro-inflammatory cytokine TNF-alpha. As a model, we utilized the murine macrophage cell lines RAW264.7 transfected with human apolipoprotein E3 (apoE3, control) or pro-inflammatory apoE4. In the presence of 2.5 microM or 75 microM CoQ10 the LPS-induced TNF-alpha response was significantly reduced to 73.3 +/- 2.8% and 74.7 +/- 8.9% in apoE3 or apoE4 cells, respectively. Therefore, the in silico analysis as well as the cell culture experiments suggested that CoQ10 exerts anti-inflammatory properties via NFkappaB1-dependent gene expression.
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A large body of evidence from postmortem brain tissue and genetic analysis in humans and biochemical and pathological studies in animal models (transgenic and toxin) of neurodegeneration suggest that mitochondrial dysfunction is a common pathological mechanism. Mitochondrial dysfunction from oxidative stress, mitochondrial DNA deletions, pathological mutations, altered mitochondrial morphology, and interaction of pathogenic proteins with mitochondria leads to neuronal demise. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. This review discusses the potential therapeutic efficacy of creatine, coenzyme Q10, idebenone, synthetic triterpenoids, and mitochondrial targeted antioxidants (MitoQ) and peptides (SS-31) in in vitro studies and in animal models of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We have also reviewed the current status of clinical trials of creatine, coenzyme Q10, idebenone, and MitoQ in neurodegenerative disorders. Further, we discuss newly identified therapeutic targets, including peroxisome proliferator-activated receptor-gamma-coactivator and sirtuins, which provide promise for future therapeutic developments in neurodegenerative disorders.
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A pilot study of high dose coenzyme Q(10) (CoQ(10))/vitamin E therapy in Friedreich's ataxia (FRDA) patients resulted in significant clinical improvements in most patients. This study investigated the potential for this treatment to modify clinical progression in FRDA in a randomized double blind trial. Fifty FRDA patients were randomly divided into high or low dose CoQ(10)/ vitamin E groups. The change in International Co-operative Ataxia Ratings Scale (ICARS) was assessed over 2 years as the primary end-point. A post hoc analysis was made using cross-sectional data. At baseline serum CoQ(10) and vitamin E levels were significantly decreased in the FRDA patients (P < 0.001). During the trial CoQ(10) and vitamin E levels significantly increased in both groups (P < 0.01). The primary and secondary end-points were not significantly different between the therapy groups. When compared to cross-sectional data 49% of all patients demonstrated improved ICARS scores. This responder group had significantly lower baseline serum CoQ(10) levels. A high proportion of FRDA patients have a decreased serum CoQ(10) level which was the best predictor of a positive clinical response to CoQ(10)/vitamin E therapy. Low and high dose CoQ(10)/vitamin E therapies were equally effective in improving ICARS scores.