**4. Caffeine and sleep**

to sleep disorders. The total European cost of brain disorders in 2010 was €798 billion [5], headaches and sleep disorders, meanwhile, only cost 285 and 348 euros respectively [6]. "The human brain is not only the site of our personality, thoughts, feelings and other human characteristics; it is also the seat of many chronic disabling diseases. These diseases have not received the attention that has been devoted to heart disease, cancer or AIDS, but in recent years there has been a growing awareness of their importance" [5]. A growing body of evidence indicates that free radical formation is a mediator of the excessive lipid peroxidation and cell damage seen in neurological disorders [7]. Antioxidant vitamins and trace elements have been shown to have biological activity in acting as scavengers for free radical's delays the onset of defined milestones in the development of a disease. Therefore, micronutrients such as vitamins, minerals or trace elements are supported by evidence that it can delay deterioration

192 Pharmacology and Nutritional Intervention in the Treatment of Disease

Different nutritional factors, and eating, can have an effect on the CNS by different mechanisms: direct nervous connections through the vagus nerve and nucleus tractus solitarius, humoral effects, affecting absorption of different molecules, emotional and

**2. Substances involved in the sleep-wake regulation and food intake**

**3. Neurotransmitters in the Enteric Nervous System (ENS)**

Many different neurotransmitters, neuromodulators and hormones have an important role in regulation of sleep and wakefulness, and in eating behaviour. These substances include (in alphabetical order): acetylcholine, adenosine, alpha-MSH (alpha melanocyte-stimulating hormone), cholecystokinin, dopamine, GABA, ghrelin, glutamate, glycine, insulin, histamine, hypocretin (orexin), leptin, MCH (melanin-concentrating hormone), melatonin, norepinephr‐ ine, NPY (neuropeptide Y), prostaglandins, serotonin, somatotrophin and thyrotropin. Little is known about the effect of vitamins and minerals on sleep. They will be discussed shortly

The enteric nervous system (ENS) can be considered the body's second brain with more than 100 million neurons of different types. Neural signals may be transmitted from gut to the CNS by neural connection and by humoral mechanisms. The afferent fibers of the gut-brain neural are vagal (parasympathetic) and (ortho)sympathetic. Different sensors respond also to distension of stomach and contractions of the intestine. Chemical stimuli (e.g. spices), gut hormones, neurotransmitters, neuromodulators, cytokines and inflammatory mediators produced by the bacterial flora in the gut-are all important. In the brainstem most afferent vagal fibers terminate on the nucleus tractus solitarius (NTS). There is a viscerotopic repre‐ sentation of different parts of the enteric system in the NTS. The NTS is in connection with hypothalamus and amygdala, which also plays a role in regulation of hunger and satiety. We

of the disease.

cognitive processes.

later in this review.

Coffee is the world's most common psychoactive drug. Coffee includes caffeine, which is also present in coffee, tea, cola and chocolate. The stimulant and wake-producing properties of caffeine depend on its ability to reduce adenosine transmission in the brain. Caffeine acts as an antagonist to adenosine A1 and especially to adenosine A2 receptors. [20, 13]

In experimental studies the concentration of adenosine is higher during wakefulness than during sleep, it accumulates in the brain during prolonged wakefulness, and local perfusions as well as systemic administration of adenosine and its agonists induce sleep and decrease wakefulness.2, 18 Supportive findings have been observed in humans. The longer the previous wakefulness period is, the longer and deeper is the following sleep. [22] The increase in extracellular adenosine concentration decreases the activity of the wakefulness-promoting cell groups, especially the cholinergic cells in the basal forebrain. [2, 22]

[35, 36] Examples of endogenous molecules with neurohormetic actions are nitric oxide, carbon monoxide, glutamate and calcium. Examples of neuroprotective substances include alphatocopherol, lycopene, resveratrol (red grapes, red wine, peanuts and soy), sul-foraphanes (broccoli), catechins (green tea), allicin and allium (garlic), curcumin (turmeric) and hypericin

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

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

195

Hot spices may disturb sleep. Tabasco and mustard in the evening may reduce slow wave and reduce total time awake and increase time to fall asleep. The spicy food in the evening elevated body temperature during the first sleep cycle, which explains probably some of the effects of

Increasing evidence associates sleep deprivation and sleep-related disorders with oxidative stress. Oxidative metabolism and energy production in the body generate free radicals and nonradical derivatives of oxygen and of nitrogen [38]. Normally, the mitochondrial respiratory chain generates a low level of free radicals during the process of making ATP. These free radicals, in turn, may cause further damage to the mtDNA creating a vicious cycle of damage and free radical production. It's unclear exactly how large a role the generation of free radicals plays in causing or worsening the symptoms of mitochondrial disease. Antioxidants, usually in the form of vitamins or trace elements, help neutralize free radicals. Although these products are involved in normal cell regulation and signal transduction, an imbalance between their generation and the antioxidant defense system results in oxidative stress. At the cellular level, the stress response can be initiated by external environmental factors that cause damage to biological macromolecules including lipids, proteins, and nucleic acids [39]. Oxidative stress in sleep apnea is thought to be produced by hypoxic events and by hypoxia-reperfusion injury, and in this way it contributes to cardiovascular complications and inflammatory processes [40, 41]. A role for disrupted sleep itself in the metabolic complications of sleep apnea has been implied by some of the evidence but not fully explored [42]. Ramanathan et al. [43] reported a significant decrease in superoxide dismutase (SOD) activity in the hippocampus and brain stem, but not in the cerebral cortex, hypothalamus, or cerebellum in rats sleep deprived for 5–

Prostaglandins (PGs) are synthesized from arachidonic acid by activated cyclo-oxygenase (COX) in response to various stimuli in various types of cells. When synthesized, PGs are immediately released and exert their actions on cells in the vicinity of their synthesis [44]. PGs act in many parts of the body, including the reproductive system, the nervous system, the cardiovascular system, the immune system and gastrointestinal system [45]. Due to their diverse biological activity, there is potential for prostaglandin analogs (prostanoids) to

(St John's Wort).

11 days.

**7. Prostaglandins and sleep**

function as effective therapeutic agents.

capsaicin on sleep. [37]

**6. Free radicals, oxidative stress and sleep**

In addition to coffee caffeine is found in tea (20-100 mg per 3.5 dl cup of tea), Cola-drinks (30-50 mg per 3.3 dl bottle), energy drinks and chocolate. In chocolate also theobromine is present in large quantities. Dark chocolate is stimulating and 100 grams of 70% chocolate corresponds to 1-2 cups of coffee depending on strength of the coffee and size of the cup.

One small cup (30 ml) of espresso contains 30-50 mg of caffeine, and one large cup (2-4 dl) of ordinary coffee contains 75-150 mg of caffeine. Caffeine is absorbed rapidly and the peak of action occurs in 30 to 60 minutes. The duration of action is usually 4 to 6 hours, but in elderly subjects with slower metabolism the duration may last up to more than 16 hours. A large amount of caffeine, usually over 300-500 mg, i.e. more than 4 to 8 cups of coffee, depending on individual sensitivity, causes restlessness, anxiety, trembling, tinnitus and feelings of euphoria / delirium. Everyday use of more than 500 mg caffeine leads to caffeinism with insomnia, fatigue, and different psychosomatic symptoms. Some chronic coffee drinkers have developed tolerance to caffeine, and may drink more than 10 cups of coffee daily. They have withdrawal symptoms if they do not have their coffee.

Coffee is a well-known factor disturbing sleep. [23-31]Two or three cups (or in sensitive persons just one cup of coffee) in the evening is followed by difficulty falling asleep and restless sleep. Insomniacs are usually advised to avoid coffee after 6 p.m. but in some sensitive persons with insomnia coffee at noon or early afternoon may disturb falling asleep in the evening. It is important to recognize that energy drinks such as Battery and Red Bull contain large amounts of caffeine, which is a known cause for insomnia in adolescents. [31] Paradoxically, in some persons one or two cups of coffee may ameliorate quality of sleep. The reason can be behavioral conditioning, but it is also known that caffeine is inotropic and it stimulates respiratory functions.
