**12. Trace elements and sleep**

Certain nutritional imbalances appear to influence sleep quality and play an important role in the maintenance of redox homeostasis:

#### **12.1. Zinc**

present in large amounts in the brain and retina. DHA is the omega-3 fatty acid required for normal development of the nervous system and optimum visual acuity. Furthermore, when an omega-3 fatty acid deficiency exists, the body compensates by replacing it with the corresponding fatty acid of the omega-6 series, omega-6 docosapentaenoic acid (DPAn-6). These findings strongly suggest that DHA has an essential biochemical function. The most likely possibility is a membrane structural effect involving the packing of phospholipid head groups or the interaction of the lipid domains with membrane proteins. The lipids that contain the highest percentages of DHA are ethanolamine plasmalogen, phosphatidylethanolamine and phosphatidylserine. Therefore, it is likely that the function of DHA involves the metabo‐ lism, trafficking or physical properties of these phospholipids. Other possibilities that must be considered include the conversion of DHA to a lipid mediator, binding of DHA to a nuclear receptor that regulates gene expression, or formation of a DHA-centered free radical. It is thought that omega-3 fatty acids in fish oils may reduce inflammation of the brain and play a part in brain development and nerve cell regeneration [125]. However, there has been mixed evidence as to the benefits of omega-3 fish oils on the brain and whether they may protect against memory decline and dementia [126,127]. A combination of omega-3 fatty acid and vitamin B12 enriched diet may exert beneficial effects on synaptic plasticity and cognition, which may prove beneficial for mental health, particularly in preventing neurocognitive

202 Pharmacology and Nutritional Intervention in the Treatment of Disease

A central question concerning the essentiality of omega-3 fatty acids is why DHA rather than the corresponding member of the omega-6 series, DPAn-6, fulfils this purpose. The usual Western diet contains 10-to 20-times more omega-6 fatty acid, and the same metabolic pathway is utilized by both fatty acid classes. One possibility is that DHA is utilized more efficiently

However, studies with neural cells in culture indicate that there is no appreciable difference in the uptake, retention or incorporation into phospholipids of DHA as compared with DPAn-6. While more detailed measurements may reveal a functional difference between DHA and DPAn-6, no such evidence is currently available. This suggests that DHA is utilized rather than DPAn-6 because it is more available to the tissues. Although the absolute amounts of these fatty acids in the plasma lipids are very small, there ordinarily is about five-times more DHA than DPAn-6. Furthermore, the main product formed by cultured astrocytes from omega-3 fatty acid precursors is DHA, whereas the main omega-6 product is AA. Astrocytes are the site where most of the polyunsaturated fatty acid precursors are elongated and desaturated in the brain. Thus, much more DHA than DPAn-6 appears to be available in the

Polyunsaturated fatty acids (PUFA) are essential fatty acids in many mammals including humans. Both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are omega-3 acids and they may also be obtained by eating fish oils. There is some evidence showing that a reduced amount of ingested omega-3 fatty acids is associated with fatigue, depression and problems of attention. [130-136] A sufficient amount of PUFA from food is necessary for health

disorders [128].

than DPAn-6.

central nervous system [129].

**11.1. Fish oils and omega-3 fatty acids**

Zinc is an important cofactor for metabolism relevant to neurotransmitters, prostaglandins, and melatonin, and indirectly affects dopamine metabolism [139]. The role of zinc is thought to transduce oxidative stress and other signals converging at the production of nitric oxide into an specific intracellular response, suggesting an intriguing task of "signal transducer" [140]. It contributes to structure and function of brain [141], and low levels of zinc can cause a range of symptoms including hyperactivity and jitters [142]. Epidemiological studies on the influence of zinc/diet and lifestyle implications on degenerative disease and in particular on autism has been documented. Interestingly, antioxidant and micronutrients in the diet, such as zinc, influence the development and function of immune cells, the activity of stress-related proteins and antioxidant enzymes and help to maintain genomic integrity and stability [143, 144]. Zinc is included in many enzymatic processes. [145, 146] In CNS zinc is abundant in the so-called "zinc containing" synapses of glutamatergic neurons. Such neurons are located mainly in the prefrontal lobe. Frontal dysfunction may follow lack of zinc. On the other hand, bivalent zinc may cause excitotoxic damage. Also other minerals (e.g., magnesium, manga‐ nese) are important for proper functioning of the CNS. [145, 147, 148]

Zinc was shown to play a role in inducing the synthesis of metallothionein that acts as a scavenger of metals and free radicals [149]. It is necessary for 100 different metalloen‐ zymes and metal–enzyme complexes [150], many of them in the central nervous system. Zinc supplementation of young children in low income countries improves their neurophy‐ siological performance [151], also in combination with iron supplements [152]. Some behavioural abnormalities in adults also seem to respond favourably to zinc supplementa‐ tion, such as mood changes, emotional lability, anorexia, irritability and depression [153]. All these physiological functions occur through the action of proteins involved in the regulation of zinc homeostasis, such as metallothioneins, which bind zinc with high affinity but, at the same time, release free zinc ions in response to oxidative/nitrosative stress to modulate the expression of zinc-dependent genes and to activate antioxidant enzymes and impact immune response [154].

population observed that the erythrocyte SOD activities were negatively associated with the plasma zinc concentrations, and positively associated with age. They also observed that the plasma catalase and GPX activities were similar among groups having different plasma

Nutrition, Sleep and Sleep Disorders – Relations of Some Food Constituents and Sleep

http://dx.doi.org/10.5772/58345

205

Zinc is one of the micronutrients involved in behavior, learning and mental functions. Zinc is necessary for proper immune function, and to create protein and DNA. The administra‐ tion of nightly melatonin, magnesium, and zinc appears to improve the quality of sleep and the quality of life in long-term care facility residents with primary insomnia [167]. micronutrients such as zinc and magnesium may play a role in facilitating sleep. Zinc exhibits an antidepressant-like activity, as stated in a preclinical model of depression [168]. Significant clinical correlates were shown by Sowa-Kućma et al. [169] related to its action as an antagonist of the glutamate/N-methyl-D-aspartate receptor. Magnesium has benefi‐ cial effects on mood and is crucial, together with zinc, in the endogenous synthesis of

Zinc is an essential bio-element, which plays a fundamental role in a wide range of biochemical processes. This metal is a major component of various proteins and is an important modulator of the mammalian immune and nervous systems [171]. Zinc is one of the mineral that has such a wide application in human health. A deficiency may result in sleep disturbances. Most sleeping pills, especially when taken over long periods of time, can have multiple side effects. Alterations of blood zinc homeostasis may accompany mood disturbances as well as affect functions of the immune system [172]. Recent data indicate that alterations in zinc (a natural modulator of amino-acidergic neurotransmission) homeostasis may contribute to mood disorders and may be involved in antidepressant-

Iron has an important role in many enzymatic processes. Sufficient iron in the CNS is necessary for normal functioning of the dopamine system. Iron has an effect on functioning of the dopamine receptors. Tyrosine hydroxlase regulates dopamine synthesis. Iron and tetrahydro‐ biopterin are cofactors of tyrosinehydroxylase. Iron is also linked to functions of GABA, serotonin and opidiod-peptides. In experimental cell cultures dopaminergic cells of the substantia nigra can be destroyed by chelation of iron by desferoxamine. Adding opioids in these cell cultures is protective. Iron also has a catalytic effect in oxidative mechanisms of the CNS and epilepsy [173]. Measuring serum ferritin and soluble transferring receptor from a venous blood sample allows estimation of tissue iron levels. In restless legs syndrome S-ferritin is often low, in which case, giving iron per os, or intravenously in more severe cases, should

In patients with RLS 45 µg/L is usually used as a limit when one should consider giving iron supplement even if hemoglobin is normal. Usually the soluble transferrin receptor values are also low. Iron should be gioven as Fe2+(bivalent iron) together with vitamin C to increase absorption of iron from the gut. If ferritin levels do not rise and the symptoms are bothersome

zinc concentrations [158].

melatonin [170].

**12.2. Iron**

be part of the treatment.

like actions in laboratory models [171].

#### *12.1.1. Antioxidant properties of zinc*

Zinc deficiency is difficult to evaluate due to the lack of sensitive and specific biomarkers [155]. Studies observed improved neurophysiologic performance, positive growth response, and significantly reduced mortality and morbidity with zinc supplementation in Chinese children [156]. Zinc effect on immune/inflammation responses has been reported [157]. It has been suggested that the bioavailability of zinc ion regulates the expression of pro-inflammatory cytokines and heat shock proteins such as IL-6, TNF-α and Hsp70 [158], and affects TH1/TH2 balance [159]. Several mechanisms could be involved in antioxidant function of zinc. One, zinc may protect protein sulfhydryl groups from oxidative modification by influencing the conformation and reducing potential of thiol groups. Since the sulfhydryl groups are required for the catalytic activities of several enzymes, zinc protects the enzyme's activity from oxidative inactivation.

Second, zinc may antagonize the activity of transition metals such as iron and copper. A number of studies have linked RLS to deficiencies of dopamine and iron. The disorder may result from inefficient processing of iron in certain brain cells [160]. A decrease in iron levels in the substantia nigra and, to a lesser degree, in idiopathic RLS patients was reported [161]. Ferritin levels were lower in cerebrospinal fluid, whereas transferrin levels were higher in patients with RLS compared to controls [162]. Connor et al. [163] found that receptors which help cells absorb iron are abnormally regulated in cells that produce the nerve-signaling chemical dopamine. Zago and Oteiza [164] showed that zinc may compete with copper and iron ions and prevent transition metal mediated oxidative modifications, and third mechanism for the antioxidant property of zinc is that zinc may reduce oxidative damage indirectly by modulating antioxidant defence including (a) enzymes which catalytically remove free radicals and reactive species, like superoxide dismutase, catalase, and glutathione peroxidase; (b) proteins which minimize the availability of pro-oxidants, like transferrins, ceruloplasmin and metallothioneins; (c) low-molecular-mass ROS and RNS scavengers, like glutathione, ascorbic acid, uric acid and alpha-tocopherol.

Antioxidant enzymes such as CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPX) and catalase are located in different cellular compartments and have different functions. Mice defective in CuZnSOD develop neurological damage and cancer at an accelerated rate as they age [165]. GPX-1 knockout mice are much more sensitive to paraquat toxicity than the wide type mice [166]. One human study done in a European population observed that the erythrocyte SOD activities were negatively associated with the plasma zinc concentrations, and positively associated with age. They also observed that the plasma catalase and GPX activities were similar among groups having different plasma zinc concentrations [158].

Zinc is one of the micronutrients involved in behavior, learning and mental functions. Zinc is necessary for proper immune function, and to create protein and DNA. The administra‐ tion of nightly melatonin, magnesium, and zinc appears to improve the quality of sleep and the quality of life in long-term care facility residents with primary insomnia [167]. micronutrients such as zinc and magnesium may play a role in facilitating sleep. Zinc exhibits an antidepressant-like activity, as stated in a preclinical model of depression [168]. Significant clinical correlates were shown by Sowa-Kućma et al. [169] related to its action as an antagonist of the glutamate/N-methyl-D-aspartate receptor. Magnesium has benefi‐ cial effects on mood and is crucial, together with zinc, in the endogenous synthesis of melatonin [170].

Zinc is an essential bio-element, which plays a fundamental role in a wide range of biochemical processes. This metal is a major component of various proteins and is an important modulator of the mammalian immune and nervous systems [171]. Zinc is one of the mineral that has such a wide application in human health. A deficiency may result in sleep disturbances. Most sleeping pills, especially when taken over long periods of time, can have multiple side effects. Alterations of blood zinc homeostasis may accompany mood disturbances as well as affect functions of the immune system [172]. Recent data indicate that alterations in zinc (a natural modulator of amino-acidergic neurotransmission) homeostasis may contribute to mood disorders and may be involved in antidepressantlike actions in laboratory models [171].

#### **12.2. Iron**

siological performance [151], also in combination with iron supplements [152]. Some behavioural abnormalities in adults also seem to respond favourably to zinc supplementa‐ tion, such as mood changes, emotional lability, anorexia, irritability and depression [153]. All these physiological functions occur through the action of proteins involved in the regulation of zinc homeostasis, such as metallothioneins, which bind zinc with high affinity but, at the same time, release free zinc ions in response to oxidative/nitrosative stress to modulate the expression of zinc-dependent genes and to activate antioxidant enzymes and

Zinc deficiency is difficult to evaluate due to the lack of sensitive and specific biomarkers [155]. Studies observed improved neurophysiologic performance, positive growth response, and significantly reduced mortality and morbidity with zinc supplementation in Chinese children [156]. Zinc effect on immune/inflammation responses has been reported [157]. It has been suggested that the bioavailability of zinc ion regulates the expression of pro-inflammatory cytokines and heat shock proteins such as IL-6, TNF-α and Hsp70 [158], and affects TH1/TH2 balance [159]. Several mechanisms could be involved in antioxidant function of zinc. One, zinc may protect protein sulfhydryl groups from oxidative modification by influencing the conformation and reducing potential of thiol groups. Since the sulfhydryl groups are required for the catalytic activities of several enzymes, zinc protects the enzyme's activity from oxidative

Second, zinc may antagonize the activity of transition metals such as iron and copper. A number of studies have linked RLS to deficiencies of dopamine and iron. The disorder may result from inefficient processing of iron in certain brain cells [160]. A decrease in iron levels in the substantia nigra and, to a lesser degree, in idiopathic RLS patients was reported [161]. Ferritin levels were lower in cerebrospinal fluid, whereas transferrin levels were higher in patients with RLS compared to controls [162]. Connor et al. [163] found that receptors which help cells absorb iron are abnormally regulated in cells that produce the nerve-signaling chemical dopamine. Zago and Oteiza [164] showed that zinc may compete with copper and iron ions and prevent transition metal mediated oxidative modifications, and third mechanism for the antioxidant property of zinc is that zinc may reduce oxidative damage indirectly by modulating antioxidant defence including (a) enzymes which catalytically remove free radicals and reactive species, like superoxide dismutase, catalase, and glutathione peroxidase; (b) proteins which minimize the availability of pro-oxidants, like transferrins, ceruloplasmin and metallothioneins; (c) low-molecular-mass ROS and RNS scavengers, like glutathione,

Antioxidant enzymes such as CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPX) and catalase are located in different cellular compartments and have different functions. Mice defective in CuZnSOD develop neurological damage and cancer at an accelerated rate as they age [165]. GPX-1 knockout mice are much more sensitive to paraquat toxicity than the wide type mice [166]. One human study done in a European

impact immune response [154].

204 Pharmacology and Nutritional Intervention in the Treatment of Disease

*12.1.1. Antioxidant properties of zinc*

ascorbic acid, uric acid and alpha-tocopherol.

inactivation.

Iron has an important role in many enzymatic processes. Sufficient iron in the CNS is necessary for normal functioning of the dopamine system. Iron has an effect on functioning of the dopamine receptors. Tyrosine hydroxlase regulates dopamine synthesis. Iron and tetrahydro‐ biopterin are cofactors of tyrosinehydroxylase. Iron is also linked to functions of GABA, serotonin and opidiod-peptides. In experimental cell cultures dopaminergic cells of the substantia nigra can be destroyed by chelation of iron by desferoxamine. Adding opioids in these cell cultures is protective. Iron also has a catalytic effect in oxidative mechanisms of the CNS and epilepsy [173]. Measuring serum ferritin and soluble transferring receptor from a venous blood sample allows estimation of tissue iron levels. In restless legs syndrome S-ferritin is often low, in which case, giving iron per os, or intravenously in more severe cases, should be part of the treatment.

In patients with RLS 45 µg/L is usually used as a limit when one should consider giving iron supplement even if hemoglobin is normal. Usually the soluble transferrin receptor values are also low. Iron should be gioven as Fe2+(bivalent iron) together with vitamin C to increase absorption of iron from the gut. If ferritin levels do not rise and the symptoms are bothersome one might consider IV iron. Iron dextrane should be avoided because of potential risks but safe formulations exist, such as Venofer®. Several studies have already shown the benefits of IV iron starting from the early experiences from Sweden in the 1950's. [174, 175]

matory properties, and there is particular interest in the potential of Se to modulate oxidative stress and induce anticancer activity [183, 184]. Selenium is required for the production of certain prostaglandins which decrease platelet aggregation [185]. Selenium deficiency has been linked to adverse mood states [183]. Several lines of evidence have shown that selenium is crucially important in the maintenance and modulation of different brain functions. [186-189] Selenium may have some role in regulation of sleep and in develop‐ ment of insomnia as lack of selenium was statistically significantly associated with difficulty

Nutrition, Sleep and Sleep Disorders – Relations of Some Food Constituents and Sleep

http://dx.doi.org/10.5772/58345

207

Selenium supplementation together with other vitamins has been found beneficial in the treatment of mood lability [190, 191].In synergy with vitamin E, selenium promotes normal growth and fertility, and improves the function of certain energy producing cells [192, 193]. Also, selenium also plays a role in your immune system and thyroid function and may contribute to sleeping abnormalities. Infusion of selective inhibitors of PGDS, e.g., tetrava‐ lent selenium compounds, reversibly, time-and dose-dependently inhibited both nonrapid eye movement (NREM) and rapid eye movement (REM) sleep during the daytime [194], which shows that PGDS plays a crucial role in the regulation of physiological sleep. Selenium deficit may result in severe disorders [195, 196], including mood disorders. Gosney et al [197] reported the effects of micronutrient supplementation on mood in nursing home residents; selenium supplementation was directly correlated with decreases in depression scores and increases in serum levels. Supplementation with selenium resulted in reduced serum thyroid hormone T4 and increased serum thyroid hormone T3, suggesting that the additional selenium helped the rather boring T4 become the metabolically active T3. Effects of sleep deprivation (SD) and selenium (Se) on wound healing were studied [198], the number of fibroblasts and capillary vessels were higher in control and Se groups than in sleep deprivation groups, and the number of PNLs and the radiolabeled polyvalent IgG levels were higher in SD groups than in control and Se groups. OSA patients had lower concentrations of plasma Zn and erythrocyte Se [199]. Furthermore, the effect of selenium on restless leg syndrome treatment was studied [200, 201], selenium supplementation would

Little is still known about the effects of different constituents of meals on sleep. There is evidence that a heavy lunch and rapidly absorbing carbohydrates enhance sleepiness in the afternoon. This may add to daytime sleepiness and for that reason they should be avoided when one wants to avoid fatigue. On the contrary, a light evening meal which is rich in carbohydrates may help one to fall asleep in the evening. The relationships between the enteric nervous system and CNS, and different roles of dietary nutrients and CNS need to be studied

falling asleep in a recent large survey. [130]

be an alternative treatment in improvement of RLS symptoms.

**13. In summary**

much more in the future.

Yehuda has noted that in young children sleep disturbances, fatigue and possible learn‐ ing disturbances may be related to iron deficiency early in life. These findings require further studies. [176] To determine if there is a relationship between low serum ferritin and sleep disturbance in children with autism spectrum disorder, an eight-week open-label treat‐ ment trial on 33 children with oral iron supplementation has been done. Seventy-seven percent had restless sleep at baseline, which improved significantly with iron therapy, suggesting a relationship between sleep disturbance and iron deficiency in children with autism spectrum disorder. Sixty-nine percent of preschoolers and 35% of school-aged children had insufficient dietary iron intake. Mean ferritin increased significantly (16 µg/L to 29 µg/L). It may be that children with autism spectrum disorder should be screened for iron deficiency. [177]

Kuhn et al. studied the effects of five days of sleep deprivation on the circadian rhythm of serum iron in a group of six healthy male volunteers. The results were compared with a control group of five individuals, whose normal sleep cycle was preserved, but whose daily regimen was otherwise identical with the sleep deprivation group. Their biorhythm was analyzed using cosinor analysis. Sleep deprivation markedly reduced the mean level of iron, diminished the absolute and relative amplitude of oscillations, disturbed the shape of the daily course of serum iron and gradually decreased the computative acrophase, i.e., shortened the period of rhythm. Forty-eight hours of recovery resulted in only a partial normalization of all the observed changes. The potential mechanisms of the observed changes are discussed. [178]

#### **12.3. Copper**

Copper acts as a cofactor in many enzymatic processes including ceruloplasmin, monoami‐ nexidases, cytochromoxidase, and superoxide dismutase. The largest part of copper (96%) is binded into cerluloplasmin and ferro-oxidase, which is needed in many phases of iron metabolism. [179] Lack of copper can manifest as neutropenia, microcytic anemia, growth disturbances or slowing of erythropoiesis. Large amount of vitamine C, zinc, iron and cysteine worsen the absorption of copper from the gut. Menkes syndrome is an example of a genetic disturbance of copper metabolism causing deficiency of copper. Wilson's disease is an autosomal recessive disease that causes accumulation of copper in the liver and brain [180]. It is practically impossible to have too much copper from a normal diet. Lack of copper may follow poor diet or excessive consumption of zinc tablets.

#### **12.4. Selenium**

Selenium (Se) is a natural antioxidant which delays the oxidation of polyunsaturated fatty acids and preserves the elasticity of tissue [181, 182]. Se is an essential component of thioredoxinreductase and glutathione peroxidases, with strong antioxidative and antiinflam‐ matory properties, and there is particular interest in the potential of Se to modulate oxidative stress and induce anticancer activity [183, 184]. Selenium is required for the production of certain prostaglandins which decrease platelet aggregation [185]. Selenium deficiency has been linked to adverse mood states [183]. Several lines of evidence have shown that selenium is crucially important in the maintenance and modulation of different brain functions. [186-189] Selenium may have some role in regulation of sleep and in develop‐ ment of insomnia as lack of selenium was statistically significantly associated with difficulty falling asleep in a recent large survey. [130]

Selenium supplementation together with other vitamins has been found beneficial in the treatment of mood lability [190, 191].In synergy with vitamin E, selenium promotes normal growth and fertility, and improves the function of certain energy producing cells [192, 193]. Also, selenium also plays a role in your immune system and thyroid function and may contribute to sleeping abnormalities. Infusion of selective inhibitors of PGDS, e.g., tetrava‐ lent selenium compounds, reversibly, time-and dose-dependently inhibited both nonrapid eye movement (NREM) and rapid eye movement (REM) sleep during the daytime [194], which shows that PGDS plays a crucial role in the regulation of physiological sleep. Selenium deficit may result in severe disorders [195, 196], including mood disorders. Gosney et al [197] reported the effects of micronutrient supplementation on mood in nursing home residents; selenium supplementation was directly correlated with decreases in depression scores and increases in serum levels. Supplementation with selenium resulted in reduced serum thyroid hormone T4 and increased serum thyroid hormone T3, suggesting that the additional selenium helped the rather boring T4 become the metabolically active T3. Effects of sleep deprivation (SD) and selenium (Se) on wound healing were studied [198], the number of fibroblasts and capillary vessels were higher in control and Se groups than in sleep deprivation groups, and the number of PNLs and the radiolabeled polyvalent IgG levels were higher in SD groups than in control and Se groups. OSA patients had lower concentrations of plasma Zn and erythrocyte Se [199]. Furthermore, the effect of selenium on restless leg syndrome treatment was studied [200, 201], selenium supplementation would be an alternative treatment in improvement of RLS symptoms.

### **13. In summary**

one might consider IV iron. Iron dextrane should be avoided because of potential risks but safe formulations exist, such as Venofer®. Several studies have already shown the benefits of

Yehuda has noted that in young children sleep disturbances, fatigue and possible learn‐ ing disturbances may be related to iron deficiency early in life. These findings require further studies. [176] To determine if there is a relationship between low serum ferritin and sleep disturbance in children with autism spectrum disorder, an eight-week open-label treat‐ ment trial on 33 children with oral iron supplementation has been done. Seventy-seven percent had restless sleep at baseline, which improved significantly with iron therapy, suggesting a relationship between sleep disturbance and iron deficiency in children with autism spectrum disorder. Sixty-nine percent of preschoolers and 35% of school-aged children had insufficient dietary iron intake. Mean ferritin increased significantly (16 µg/L to 29 µg/L). It may be that children with autism spectrum disorder should be screened for

Kuhn et al. studied the effects of five days of sleep deprivation on the circadian rhythm of serum iron in a group of six healthy male volunteers. The results were compared with a control group of five individuals, whose normal sleep cycle was preserved, but whose daily regimen was otherwise identical with the sleep deprivation group. Their biorhythm was analyzed using cosinor analysis. Sleep deprivation markedly reduced the mean level of iron, diminished the absolute and relative amplitude of oscillations, disturbed the shape of the daily course of serum iron and gradually decreased the computative acrophase, i.e., shortened the period of rhythm. Forty-eight hours of recovery resulted in only a partial normalization of all the observed changes. The potential mechanisms of the observed

Copper acts as a cofactor in many enzymatic processes including ceruloplasmin, monoami‐ nexidases, cytochromoxidase, and superoxide dismutase. The largest part of copper (96%) is binded into cerluloplasmin and ferro-oxidase, which is needed in many phases of iron metabolism. [179] Lack of copper can manifest as neutropenia, microcytic anemia, growth disturbances or slowing of erythropoiesis. Large amount of vitamine C, zinc, iron and cysteine worsen the absorption of copper from the gut. Menkes syndrome is an example of a genetic disturbance of copper metabolism causing deficiency of copper. Wilson's disease is an autosomal recessive disease that causes accumulation of copper in the liver and brain [180]. It is practically impossible to have too much copper from a normal diet. Lack of copper may

Selenium (Se) is a natural antioxidant which delays the oxidation of polyunsaturated fatty acids and preserves the elasticity of tissue [181, 182]. Se is an essential component of thioredoxinreductase and glutathione peroxidases, with strong antioxidative and antiinflam‐

IV iron starting from the early experiences from Sweden in the 1950's. [174, 175]

206 Pharmacology and Nutritional Intervention in the Treatment of Disease

iron deficiency. [177]

changes are discussed. [178]

follow poor diet or excessive consumption of zinc tablets.

**12.3. Copper**

**12.4. Selenium**

Little is still known about the effects of different constituents of meals on sleep. There is evidence that a heavy lunch and rapidly absorbing carbohydrates enhance sleepiness in the afternoon. This may add to daytime sleepiness and for that reason they should be avoided when one wants to avoid fatigue. On the contrary, a light evening meal which is rich in carbohydrates may help one to fall asleep in the evening. The relationships between the enteric nervous system and CNS, and different roles of dietary nutrients and CNS need to be studied much more in the future.
