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Coenzyme Q 10 , a cutaneous antioxidant and energizer

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  • SkinNEXT Consulting

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The processes of aging and photoaging are associated with an increase in cellular oxidation. This may be in part due to a decline in the levels of the endogenous cellular antioxidant coenzyme Q10 (ubiquinone, CoQ10). Therefore, we have investigated whether topical application of CoQ10 has the beneficial effect of preventing photoaging. We were able to demonstrate that CoQ10 penetrated into the viable layers of the epidermis and reduce the level of oxidation measured by weak photon emission. Furthermore, a reduction in wrinkle depth following CoQ10 application was also shown. CoQ10 was determined to be effective against UVA mediated oxidative stress in human keratinocytes in terms of thiol depletion, activation of specific phosphotyrosine kinases and prevention of oxidative DNA damage. CoQ10 was also able to significantly suppress the expression of collagenase in human dermal fibroblasts following UVA irradiation. These results indicate that CoQ10 has the efficacy to prevent many of the detrimental effects of photoaging.
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BioFactors 9 (1999) 371–378 371
IOS Press
Coenzyme Q10, a cutaneous antioxidant
and energizer
U. Hoppea,,J.Bergemanna,W.Diembecka, J. Ennena,S.Gohlaa, I. Harrisa, J. Jacob b,
J. Kielholza,W.Meia,D.Polleta, D. Schachtschabel c,G.Sauermanna,V.Schreinera,
F. Stäb aand F. Steckela
aPaul Gerson Unna Research Center, Beiersdorf AG, Unnastraße 48, Hamburg, Germany
bDepartment of Biology, University of Hamburg, Germany
cClinical Department of Physiological Chemistry, Philipps-University, Marburg, Germany
Abstract. The processes of aging and photoaging are associated with an increase in cellular oxidation. This may be in part
due to a decline in the levels of the endogenous cellular antioxidant coenzyme Q10 (ubiquinone, CoQ10 ). Therefore, we have
investigated whether topical application of CoQ10 has the beneficial effect of preventing photoaging.
Wewere able to demonstrate that CoQ10 penetrated into the viable layers of the epidermis and reduce the level of oxidation
measured by weak photon emission. Furthermore, a reduction in wrinkle depth following CoQ10 application was also shown.
CoQ10 was determined to be effective against UVA mediated oxidative stress in human keratinocytes in terms of thiol depletion,
activation of specific phosphotyrosine kinases and prevention of oxidative DNA damage. CoQ10 was also able to significantly
suppress the expression of collagenase in human dermal fibroblasts following UVA irradiation. These results indicate that
CoQ10 has the efficacy to prevent many of the detrimental effects of photoaging.
1. Introduction
The skin is the body’s largest organ with an area of approximately 2 m2. One of its functions is to
protect the body from a hostile environment of toxins, pathogens and UV radiation. UVA is absorbed by
a number of molecules in the skin including flavinoids and pheomelanin which initiate the formation of
reactive oxygen species within cells. These reactive oxygen species include hydrogen peroxide, singlet
oxygen, and hydroxyl radicals, which are the most abundant. The radicals produce oxidative damage
to lipids, proteins and DNA [1,2]. To be able to cope with oxidative stress produced by UV light and
endogenous metabolism, the skin has both enzymatic and non-enzymatic (antioxidant) mechanisms for
protection [27,30]. Examples of enzymes involved in preventing radical damage include superoxide dis-
mutase (SOD), catalase, and glutathione peroxidase. Antioxidants found in the skin include vitamin E,
coenzyme Q10 (ubiquinone, CoQ10) and ascorbate [27]. Members of the coenzyme Q family have devel-
oped together with biological evolution over millions of years (Fig. 1). CoQ10 is ubiquitous in human tis-
sues, although its level is variable. The level of CoQ10 is highest in organs with high rates of metabolism
such as the heart, kidney and liver (114, 66.5 and 54.9 µg/g tissue, respectively), where it functions as
an energy transfer molecule [22]. In skin CoQ10 also act as an antioxidant, with 10-fold higher levels in
the epidermis than the dermis [27]. From our own data the level of reduced and oxidized CoQ10 from the
forearm of a 44 year old male is approximately 300 pmol/cm2or 0.26 µg/cm2. Although the epidermis
*Correspondence to: Professor Dr Udo Hoppe, Paul Gerson Unna Research Center, Beiersdorf AG, Unnastraße 48, D-20245
Hamburg, Germany.
0951-6433/99/$8.00 1999 – IOS Press. All rights reserved
372 U. Hoppe et al. / CoQ10, a cutaneous antioxidant and energizer
Fig. 1. In general as organisms have evolved the structure of the coenzyme molecule has increased in length from 2–10 isoprene
units. The correlation coefficient between the evolutionary age of an organism and its coenzyme CoQ form is 0.992.
Fig. 2. CoQ10 levels decrease in the epidermis between the ages of 30 and 80 years (R2=0.802, p=0.0014). Values are
normalized to the cholesterol content of the samples.
is composed mainly of cells, the amount of CoQ10/g of tissue is relatively low. Furthermore, the level
of CoQ10/µg cholesterol declines between the ages of 30 and 80 years of age (R2=0.79, p=0.0012)
(Fig. 2), as it has been reported in organs such as heart and brain [14,29]. The epidermis is therefore a
tissue that would potentially benefit from exogenously supplied CoQ10.
Oxidative stress is thought to play a role in the aging process [6]. In the skin there is both chrono-
logical and photoaging, although they are two distinct processes, the effects are superimposed on each
other [9]. Chronological aging is inherent and genetically determined and possibly with some hormonal
influence [23,28]. There are numerous theories as to the cause of chronological aging [33]. One of the
U. Hoppe et al. / CoQ10, a cutaneous antioxidant and energizer 373
most compelling theories is that of telomere shortening, where aging cells progressively loose part of the
DNA at the ends of chromosomes in each cell division [19]. Photoaging, on the other hand, is caused
by UVA and UVB. Due to the penetration characteristics of the UV light UVA and UVB have differ-
ent effects. UVA is able to penetrate further into the dermis whereas UVB penetrates only just through
the epidermis. Oxidative stress may result in DNA damage and malignant changes in the epidermis and
disorganization in the dermal matrix [16,20]. Photoaged skin is characterized by wrinkles, and lack of
tensile strength, which is normally provided by the dermis. In the dermal matrix of aged skin there is an
increase in the levels of elastin and a decrease in the levels of glycosaminoglycans and collagen I and
III [4]. There is also an increase in collagenase expression which further reduce the levels of collagen.
The cumulative result is that the dermis can no longer provide the structural support and elasticity it once
had due to the disorganization of the collagen fibers.
There were three aims of this study: (1) To determine if CoQ10 is an antioxidant in cultured skin cells,
(2) to demonstrate that CoQ10 can act as an antioxidant when topically applied to human skin, and (3) to
investigate whether CoQ10 can prevent or reverse the effects of photoaging.
2. CoQ10 prevents oxidative effects in cultured human skin cells
In the all of the following experiments CoQ10 produced by fermentation was used (Kaneka, Japan),
which is conformationally identical to human CoQ10. To demonstrate that CoQ10 is an effective antiox-
idant, either directly or indirectly, we first measured the levels of phosphotyrosine kinase activity and
glutathione levels, which are two indicator of oxidative stress in human keratinocytes [8,18,24]. When
keratinocytes are exposed to 1 mM hydrogen peroxide for 30 min the activity of the phosphotyrosine
kinase increases. This can be significantly suppressed by 150 µMCoQ
10. Conversely glutathione levels
decrease by approximately 20% compared to the level of unstressed cells when treated with 1mM hy-
drogen peroxide for 30 min. CoQ10 (5–50 µM) increases glutathione levels in unstressed keratinocytes
in a dose responsive manner by approximately 10–20%. Pretreatment of keratinocytes for 24 hours with
50 µMCoQ
10 is able to maintain glutathione levels at about the level found in non-stressed cells. UVA
irradiation also reduces the mitochondrial membrane potential [31]. 0.3% CoQ10 has the beneficial ef-
fect of suppressing the reduction of the mitochondrial membrane potential following UVA irradiation
(20 J/cm2) in fibroblasts from both young and old donors. These experiments demonstrate that CoQ10
can act as an antioxidant in cultured human cells from young or old donors.
To demonstrate that CoQ10 can protect the keratinocytes from UV induced oxidative DNA damage we
used the COMET assay [21]. In the comet assay cells are embedded in an agarose gel, irradiated with
5J/cm
2UVA and then treated with alkaline to lyse the cells and unwind the DNA. During electrophoresis
the damaged DNA migrates out of the nucleus, and when stained, the DNA looks like a comet. The
length of the tail is related to the level of oxidative DNA damage. Using the comet assay we can clearly
demonstrate that 24 hours pretreatment with 23 µMCoQ
10 can protect, either immortalized HaCaT
keratinocytes, or primary human keratinocytes from UVA induced oxidative DNA damage. The 60–70%
decrease in DNA damage is statistically very significant.
3. CoQ10 protects dermal fibroblasts from chronological and photoaging
We next investigated the effects of CoQ10 on dermal matrix synthesis. Chronologically aged skin
has lower levels of hyaluronic acid and the collagen fibers are clearly disorganized. Hyaluronic acid is
374 U. Hoppe et al. / CoQ10, a cutaneous antioxidant and energizer
a glycosaminoglycan comprising alternating D-glycuronic acid and N-acetyl-D-glucosamine residues.
Hyaluronic acid has a large hydrated volume which regulates hydration in the dermis and favors a dis-
persed hydrated organization of collagen fibers. Chronological aging can be mimicked in cell culture.
When cells are cultured for a prolonged period they exhibit many of the characteristics of chronologi-
cally aged cells [7,15]. Using human fibroblasts that were treated in this way we were able to demonstrate
that 50 µMCoQ
10 significantly increased levels of radiolabelled glycosaminoglycan when expressed as
the amount of radiolabelled glycosaminoglycan/mg of cell protein. 50 µMCoQ
10 also increased the pro-
liferation of these artificially aged cells by approximately 20%, as measured by the levelof radiolabelled
thymidine incorporation expressed as per mg of cellular protein.
Another factor contributing to the disorganization of the dermal matrix in photoaging is the degrada-
tion of collagen fibers by the enzyme collagenase [26]. Collagenase is produced by the dermal fibroblasts
in response to UVA in a dose dependent manner. The expression of collagenase mRNA induced by UVA
can be significantly reduced by pretreatment with antioxidants such as vitamin E and CoQ10.10µg/ml
CoQ10 is able to reduce collagenase mRNA expression by 50%. CoQ10 (11 µM) is as effective as 3 mM
vitamin E. CoQ10 can also suppress collagenase expression over a longer period of time (6 weeks) with
weekly irradiations. These experiments demonstrate that CoQ10 can significantly reduce the detrimental
effects of UVA on dermal fibroblasts which maintain the dermal matrix.
4. Topically applied CoQ10 penetrates into the skin
To be able to act as an antioxidant in the skin CoQ10 needs to penetrate into the living layers. The
outermost layer of the skin, called the stratum corneum, acts as an effective barrier to many compounds.
To determine whether CoQ10 can penetrate into the skin we have used porcine skin, which is very similar
to human skin in terms of permeability, and HPLC to quantify levels of CoQ10. Due to the skin not
being viable we can measure penetration without the complication of further metabolism of CoQ10.
Application of CoQ10, in ethanol as a vehicle, results in penetration into the stratum corneum, with
approximately 20% penetrating further into the viable layers of the epidermis, and 2% into the dermis.
This data demonstrates that CoQ10 is able to penetrate into the living cell layers in a simple ethanol
vehicle.
5. CoQ10 acts as an antioxidant in human skin
Oxidative events in the skin in vivo can be detected by means of ultra weak photon emissions [25].
In the basal state, cells emit low levels of photons. When UVA irradiation is applied there is an excited
state with a large increase in the level of photons which decays with time. The level of photons emitted
is an indication of the antioxidant status of the skin. If there is an increase in antioxidants, the excitation
is less and the level of photons emitted will be reduced. The ultra weak photon emission (UPE) was
measured after UVA irradiation in two age groups: (1) aged 18–25 years, (2) aged 60–72 years. The level
of UPE in the skin was increased in the elderly group by approximately 33% indicating a reduction in the
level of antioxidants. Thus demonstrating that the level of antioxidants in the skin decreases with age.
To demonstrate that application of CoQ10 can act as an effective antioxidant in vivo we measured the
UPE of 13 volunteers (mean age 49 ±6 years) treated on the volar aspect of the forearm, twice daily for
7 days with 0.3% CoQ10 or vehicle alone. Following exposure to 50 mJ/cm2UVA the skin sites treated
with 0.3% CoQ10 had significantly lower levels of UPE. Therefore CoQ10 is able to act as an antioxidant
in vivo against the oxidative effects of UVA.
U. Hoppe et al. / CoQ10, a cutaneous antioxidant and energizer 375
6. CoQ10 reduces the effects of photoaging
The clearest demonstration of photoaging is the presence of deep wrinkles, as described earlier. To
demonstrate the efficacy of CoQ10 against photoaging in vivo 0.3% CoQ10 or vehicle control was ap-
plied to 20 elderly volunteers, once daily around the eyes for six months. CoQ10 was applied around one
eye and vehicle around the other eye. Casts were then prepared for quantitative microtopography [13].
Photographs of the skin before treatment shows deep wrinkles, which are characteristic of photoaging,
whereas fine wrinkles are associated with chronological aging. Following treatment with CoQ10 the depth
of these deep wrinkles is visibly reduced (Fig. 3). Using microtopography we can measure a reduction
in the depth of wrinkles in aged skin. Two important parameters can be calculated from the microtopog-
raphy. They are: Rtwhich is the mean peak to valley measurement of a defined unit distance, and Rq
which is the intergrated area of the peaks and troughs, this indicates the variation of the microtopography
from a flat surface. There was a 27% reduction in the mean peak to valley depth of the skin and a 26%
reduction in the Rqvalue, compared to vehicle treated controls.
Although the stratum corneum, the outermost layer of the epidermis, is being continuously sloughed
off and replaced, it can display evidence of aging in the underlying living cells [11]. The area of cor-
neocytes, which make up the stratum corneum, is proportional to the time taken for the keratinocyte to
differentiate and move from the basal layer to the stratum corneum. In aged skin, the time taken to move
through the epidermis increases, and corneocytes become larger. The surface can develop fine lines and
may become dry and scaly (senile xerosis) [12]. For example, at age 18 the average surface area of a
corneocyte is 1020 µm2this increases to 1080 µm2at age 38. Therefore, the size of the corneocytes
Fig. 3. CoQ10 reduces the depth of wrinkles in the area around the eyes over a 6 month period of use.
376 U. Hoppe et al. / CoQ10, a cutaneous antioxidant and energizer
Fig. 4. CoQ10 reduces the corneocyte area over a 24 week period of use.
indicates the effectiveness of a treatment to decrease the transit time. Following treatment of the volar
aspect of the forearm daily with 0.3% CoQ10 we can demonstrate a decrease in the corneocyte area over
time (Fig. 4). The decrease in corneocyte area is equivalent to a difference of 20 years, from 38 years old
to 18 years.
7. CoQ10 is suitable for cosmetic use
CoQ10 demonstrates no cytotoxicity in cultured keratinocytes even at 200 µg/ml CoQ10 which is the
limit of solubility. To determine the irritancy potential in vivo occlusive patch tests were conducted on
volunteers in a double blind randomized trial. The vehicle and 0.3% CoQ10 gave similar results and had
no irritancy potential. In another study we were also able to demonstrate that CoQ10 can be tolerated by
people who have sensitive skin, and can suffer from stinging around the nose when certain cosmetics are
applied [5].
CoQ10 is essentially photostable. Using a Sol 500 source (Dr Hönle, Germany) and HPLC measure-
ment. CoQ10 demonstrated only 10% degradation at 5 times the minimal erythemal dose (MED), that is
approximately 150 mJ/cm2UVB, and 60% degradation at 10 times the minimal erythemal dose. Both
of these UVB doses are well above the range normally encountered. CoQ10 is stable in the presence of
oxygen (under pressure) for up to 30 min at 75C.
8. Conclusion
Our experiments have demonstrated that CoQ10 is able to act as an antioxidant against the effects of
both hydrogen peroxide and UVA in cultured epidermal keratinocytes and UVA in dermal fibroblasts.
The use of ultra weak photon emission has allowed us to demonstrate a significant reduction in oxidation
in vivo.CoQ
10 is highly effective at protecting keratinocytes from DNA damage induced by UVA.
CoQ10 was also clearly effective at reducing photoaging in vivo with a reduction in wrinkle depth
and a decrease in the turnover time of the epithelium. CoQ10 is also stable in a formulation suitable for
U. Hoppe et al. / CoQ10, a cutaneous antioxidant and energizer 377
topical use and is well tolerated with no irritation or stinging. CoQ10 is clearly able to penetrate into the
living layers of the epidermis, where it must be reduced from ubiquinone to ubiquinol, to be acting as
an antioxidant. We know that the epidermis has relatively high levels of NADPH quinone reductase (EC
1.6.99.2), which has been postulated to produce the reduced form of CoQ10 [3,32]. CoQ10 is clearly able
to protect cells from the adverse effects of UVA, both in cell culture, where we have demonstrated the
protection from DNA damage and effects on dermal matrix turnover, and also in vivo where we have
demonstrated a reduction in wrinkles and increased epidermal turnover. CoQ10 hasefcacyintheskin
following topical application without the adverse effects, such as irritation, which are associated with the
current treatments for photoaging, such as all-trans retinoic acid [10,17].
Acknowledgments
We thank Dr B. Finckh and Professor Dr A. Kohlschütter, Department of Biochemistry, University
Hospital-Eppendorf, University of Hamburg, Germany and Dr M. Podda, University of Frankfurt for the
measurements of CoQ10 in epidermal samples.
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... Furthermore, curcumin is a bifunctional antioxidant and exerts both direct and indirect antioxidant roles by scavenging reactive oxygen species and inducing the expression of antioxidant/detoxifying enzymes and scavengers such as superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase 1 in a nuclear factor E2-related factor 2 (Nrf2)-dependent pathway, respectively. [39,40] Finally, evidence shows that the gut-brain axis may impact on migraine despite the mechanism explaining this interaction is not entirely clear. It can be hypothesized that supplementation with curcumin could lead to improvements in migraine associated features through beneficial effects on gut microbiota. ...
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ackground: Migraine is a prevalent health condition associated with significant pain and disability. Neurogenic inflammation has a key role in migraine pathophysiology. Curcumin is a well-known herb compound with anti-inflammatory function. This study was aimed to evaluate the effects of curcumin supplementation on clinical features, as well as on serum levels of calcitonine gene-related peptide (CGRP) and interleukin-6 (IL-6). Methods: This randomized double-blind placebo-controlled clinical trial was carried out on 44 women with migraine, receiving either 500 mg curcumin twice a day or placebo supplements for 8 weeks. Serum CGRP and IL-6 concentration, and clinical symptoms including headache severity, duration and frequency were measured at the baseline and end of study. Results: After 8-week intervention, compared with placebo, curcumin supplementation led to significand reduction in CGRP (P < 0.001), IL-6 (P = 0.041), severity (P = 0.001), and duration of headache (P = 0.007). Headache frequency showed marginal improvement in curcumin group, compared to controls (P = 0.052). Within-analysis indicated significant decrease in CGRP and severity (P < 0.001), frequency (P = 0.014) and duration (P = 0.003) and no significant decrease in IL-6 (P = 0.454), compared to baseline in curcumin group. There were no significant changes in body mass index (BMI), weight, percent body fat (PBF), and percent body muscle (PBM) between the two groups. Conclusions: Curcumin supplementation improved the pro-inflammatory markers and clinical features of migraine headaches and that could be contributed to could be to its anti-inflammatory properties.
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