**6. β-Carotene**

Carotene is called a provitamin because it can be stored in the liver and converted into vitamin A when necessary. There are two main types of carotene: alphacarotene (α-carotene) and beta-carotene (β-carotene). β-Carotene consists of two retinyl groups and is destroyed by beta-carotene dioxygenase in the small intestinal mucosa and transformed into retinol that is a type of vitamin A.

β-Carotene is also a lipid-soluble antioxidant as α-tocopherol, interferes with lipid peroxidation by clearing away singlet oxygen, and reacts with peroxy radicals. According to Kikugawa et al. [46], β-carotene plays a preventative role in the oxidative damage process. In the literature, beneficial effects of β-carotene were shown in I/R injuries in the liver, myocardium, kidneys, and ovaries.

Karabulut et al. [47] compared vitamin A with control group in rat epigastric island skin flap venous I/R injury model in rat. By the fact in their study, after reperfusion of flaps, surviving flap area was 16% in the control group and 90% in the vitamin A group, respectively. They also combined vitamin A and vitamin E, where it was 92%.

#### **6.1 Glutathione**

Glutathione is present in all mammalian cells and has a variety of cellular functions, including amino acid transport, the maintenance of sulfhydryl groups of proteins, and the protection against oxidizing molecules and electrophilic xenobiotics. It is a tripeptide composed of glutamic acid, cysteine, and glycine. Because of strong antioxidant features, it is very popular in media in terms of healthy nutrition.

Glutathione shows its functions by clearing away O2 − and protecting thiol groups against oxidation so that it supplies cellular integrity. In order to protect the thiol groups of proteins, a relatively high concentration of GSH is necessary. Moreover, other free radical scavengers and antioxidants (such as α-tocopherol and ascorbic acid) converted to their reduced state by GSH. Pretreatment with exogenous GSH can provide protection against gross mucosal ischemia-reperfusion injury [48]. Also, it is shown that application of intravenous GSH reduces the myocardial infarct size and decreases postischemic left ventricular dysfunction [32].

On the other hand, according to Van den Heuvel et al. [31], I/R did not significantly alter GSH concentrations in their study. They had taken biopsies from 17 DIEP flaps at the different time of surgeries but there was no immediate change in GSH concentrations compared to the concentrations at the start of surgery. They explained this finding that because the skin is less sensitive to I/R than other tissues (such as muscle, liver, and fat tissue), it may prevent antioxidant defense reactions from occurring. That could be the reason for normal levels of GSH.

#### **6.2 Coenzyme Q10 (CQ10)**

Coenzyme Q10 is an organic, natural, fat-soluble, antioxidant, endogenous vitamin-like substance (similar structure to vitamins K and E). Also called ubiquinone,

**395**

**6.4 Melatonin**

*The Effect of Antioxidants on Ischemia-Reperfusion Injury in Flap Surgery*

it is an auxiliary factor in the intercellular electron transport chain. It has become one of the most popular nutritional supplements in recent years. It was shown in the literature as an effective antioxidant for the prevention of oxidative damage. What is more, CQ10 breaks down macromolecules to prohibit inflammatory responses [49]. Also, CQ10 is able to balance mitochondrial Ca2+-dependent ion channels and prevents energy depletion in the cell [50]. In cardiovascular diseases, exogenous CQ10 has been widely applied as a dietary supplement, and it may be suggested as a

CQ10 has inhibitory effects for tumor necrosis factor-α (TNF-α), which may be responsible for muscle damage in I/R injury as well [52]. Moreover, it prevents the peroxidation of the cell membrane and subcellular lipids, which happens during I/R injury [53]. Hwang et al. [54] were proved that pretreatment with CQ10 had posi-

According to Ozalp et al. [55], who compared CQ10 with control group in rat inferior epigastric island flap I/R injury model, mean flap survival ratios were 88% in CQ10 group, markedly higher than the control group (51%). They also emphasized that CQ10 group had high levels of SOD and GSH compared with control group because of CQ10's antioxidant effect, which prevented lipid peroxidation

ALA is an antioxidant that is found in various foods and also can be synthesized in the human cells. It is also an endogenous short-chain fatty acid and a cofactor for multiple mitochondrial dehydrogenase enzymes [56]. ALA shows its antioxidant properties by the use of free radical scavenging, chelating with metals, increasing

There have been a lot of articles written about ALA because of its wide range of antioxidant capabilities. The efficiency of ALA has been shown in atherosclerosis,

In severe oxidative damage caused by I/R, levels of malondialdehyde (MDA) and nitric oxide (NO) increases [58]. ALA is capable of cleaning up MDA and NO within brain tissue [59]. Deng et al. [60] found out diminished MDA and NO levels in ALA group compared with control group in rat brain I/R injury model. They also discovered that ALA has enhanced the activities of total antioxidant capacity and SOD in rat brains. According to these findings, administration of ALA before skin

Melatonin is a type of ethionamide that is secreted from the pineal gland, which determines the biorhythm. Moreover, it is an effective free radical scavenger and received significant attention because of its antioxidative feature. In spite of its ability to neutralize free radicals directly, also it has indirect effects, such as stimulating the activity of antioxidative enzymes (such as glutathione peroxidase and SOD) [61, 62]. Mitochondrion, which is an organelle for ATP production in the cell, has been proved to play critical roles in I/R injury. Therefore, the protection of mitochondrion can decrease I/R injury in vital organs [63]. Melatonin has been shown to restore the disturbance caused by I/R injury in mitochondria and has become a

The effect of melatonin on I/R injury has been investigated in the literature for a long time. It has been shown that melatonin could be an effective neuroprotective agent for treatment of ischemic spinal cord injury [65]. Singhanat et al. [66]

tive effects on spinal cord I/R injury and improved neurological function.

during the initial phase (reduce GSH and SOD destruction).

flap surgery may have benefits to improve I/R ınjury.

remarkable therapeutic strategy [64].

the reusability of other antioxidants, and repairing oxidative damage.

diabetes mellitus, I/R injury, multiple sclerosis, and senile dementia [57].

*DOI: http://dx.doi.org/10.5772/intechopen.85500*

therapeutic agent [51].

**6.3 Alpha-lipoic acid (ALA)**

*The Effect of Antioxidants on Ischemia-Reperfusion Injury in Flap Surgery DOI: http://dx.doi.org/10.5772/intechopen.85500*

it is an auxiliary factor in the intercellular electron transport chain. It has become one of the most popular nutritional supplements in recent years. It was shown in the literature as an effective antioxidant for the prevention of oxidative damage. What is more, CQ10 breaks down macromolecules to prohibit inflammatory responses [49]. Also, CQ10 is able to balance mitochondrial Ca2+-dependent ion channels and prevents energy depletion in the cell [50]. In cardiovascular diseases, exogenous CQ10 has been widely applied as a dietary supplement, and it may be suggested as a therapeutic agent [51].

CQ10 has inhibitory effects for tumor necrosis factor-α (TNF-α), which may be responsible for muscle damage in I/R injury as well [52]. Moreover, it prevents the peroxidation of the cell membrane and subcellular lipids, which happens during I/R injury [53]. Hwang et al. [54] were proved that pretreatment with CQ10 had positive effects on spinal cord I/R injury and improved neurological function.

According to Ozalp et al. [55], who compared CQ10 with control group in rat inferior epigastric island flap I/R injury model, mean flap survival ratios were 88% in CQ10 group, markedly higher than the control group (51%). They also emphasized that CQ10 group had high levels of SOD and GSH compared with control group because of CQ10's antioxidant effect, which prevented lipid peroxidation during the initial phase (reduce GSH and SOD destruction).

#### **6.3 Alpha-lipoic acid (ALA)**

*Antioxidants*

**6. β-Carotene**

where it was 92%.

**6.1 Glutathione**

There are several studies related to the effect of ascorbic acid I/R injury skin flap model. Zaccaria et al. [44] demonstrated positive effects of ascorbic acid compared with control group in rat epigastric island skin flap model. They determined higher percentage of flap survival in ascorbic acid group. On the other hand, according to Yoshida and Campos [45], vitamin c and mannitol (antioxidant group) group did not prevent or reduce the necrosis area compared with control group in rat groin flap I/R injury model.

Carotene is called a provitamin because it can be stored in the liver and converted into vitamin A when necessary. There are two main types of carotene: alphacarotene (α-carotene) and beta-carotene (β-carotene). β-Carotene consists of two retinyl groups and is destroyed by beta-carotene dioxygenase in the small intestinal

β-Carotene is also a lipid-soluble antioxidant as α-tocopherol, interferes with lipid peroxidation by clearing away singlet oxygen, and reacts with peroxy radicals. According to Kikugawa et al. [46], β-carotene plays a preventative role in the oxidative damage process. In the literature, beneficial effects of β-carotene were shown in

Karabulut et al. [47] compared vitamin A with control group in rat epigastric island skin flap venous I/R injury model in rat. By the fact in their study, after reperfusion of flaps, surviving flap area was 16% in the control group and 90% in the vitamin A group, respectively. They also combined vitamin A and vitamin E,

Glutathione is present in all mammalian cells and has a variety of cellular functions, including amino acid transport, the maintenance of sulfhydryl groups of proteins, and the protection against oxidizing molecules and electrophilic xenobiotics. It is a tripeptide composed of glutamic acid, cysteine, and glycine. Because of strong antioxidant features, it is very popular in media in terms of healthy nutrition.

against oxidation so that it supplies cellular integrity. In order to protect the thiol groups of proteins, a relatively high concentration of GSH is necessary. Moreover, other free radical scavengers and antioxidants (such as α-tocopherol and ascorbic acid) converted to their reduced state by GSH. Pretreatment with exogenous GSH can provide protection against gross mucosal ischemia-reperfusion injury [48]. Also, it is shown that application of intravenous GSH reduces the myocardial infarct

On the other hand, according to Van den Heuvel et al. [31], I/R did not significantly alter GSH concentrations in their study. They had taken biopsies from 17 DIEP flaps at the different time of surgeries but there was no immediate change in GSH concentrations compared to the concentrations at the start of surgery. They explained this finding that because the skin is less sensitive to I/R than other tissues (such as muscle, liver, and fat tissue), it may prevent antioxidant defense reactions

Coenzyme Q10 is an organic, natural, fat-soluble, antioxidant, endogenous vitamin-like substance (similar structure to vitamins K and E). Also called ubiquinone,

−

and protecting thiol groups

mucosa and transformed into retinol that is a type of vitamin A.

I/R injuries in the liver, myocardium, kidneys, and ovaries.

Glutathione shows its functions by clearing away O2

size and decreases postischemic left ventricular dysfunction [32].

from occurring. That could be the reason for normal levels of GSH.

**394**

**6.2 Coenzyme Q10 (CQ10)**

ALA is an antioxidant that is found in various foods and also can be synthesized in the human cells. It is also an endogenous short-chain fatty acid and a cofactor for multiple mitochondrial dehydrogenase enzymes [56]. ALA shows its antioxidant properties by the use of free radical scavenging, chelating with metals, increasing the reusability of other antioxidants, and repairing oxidative damage.

There have been a lot of articles written about ALA because of its wide range of antioxidant capabilities. The efficiency of ALA has been shown in atherosclerosis, diabetes mellitus, I/R injury, multiple sclerosis, and senile dementia [57].

In severe oxidative damage caused by I/R, levels of malondialdehyde (MDA) and nitric oxide (NO) increases [58]. ALA is capable of cleaning up MDA and NO within brain tissue [59]. Deng et al. [60] found out diminished MDA and NO levels in ALA group compared with control group in rat brain I/R injury model. They also discovered that ALA has enhanced the activities of total antioxidant capacity and SOD in rat brains. According to these findings, administration of ALA before skin flap surgery may have benefits to improve I/R ınjury.

#### **6.4 Melatonin**

Melatonin is a type of ethionamide that is secreted from the pineal gland, which determines the biorhythm. Moreover, it is an effective free radical scavenger and received significant attention because of its antioxidative feature. In spite of its ability to neutralize free radicals directly, also it has indirect effects, such as stimulating the activity of antioxidative enzymes (such as glutathione peroxidase and SOD) [61, 62].

Mitochondrion, which is an organelle for ATP production in the cell, has been proved to play critical roles in I/R injury. Therefore, the protection of mitochondrion can decrease I/R injury in vital organs [63]. Melatonin has been shown to restore the disturbance caused by I/R injury in mitochondria and has become a remarkable therapeutic strategy [64].

The effect of melatonin on I/R injury has been investigated in the literature for a long time. It has been shown that melatonin could be an effective neuroprotective agent for treatment of ischemic spinal cord injury [65]. Singhanat et al. [66]

explained that melatonin has cardioprotective effects against cardiac I/R injury. However, they also mentioned that the mechanism of the cardioprotective effects of melatonin were still unclear. Gurlek et al. [67] showed beneficial effects of melatonin in rat inferior epigastric flap I/R ınjury model. The determined melatonin replacement therapy causes reduction in I/R-induced flap injury.
