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

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

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

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

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

Mediterranean diets rich in fibres, vegetables, fruits and olive oils are associated with reduced risk of cardiovascular disease and many neurological diseases. [32-34]Some effects are explained by antioxidative effects of different phytochemicals, but there is also evidence that

Hormesis is the paradoxical, stimulatory or beneficial action of toxins. Hormetic effects explain why, sometimes, low doses of a given toxic substance, or radiation, may induce beneficial effects while larger doses of the same substance or radiation are toxic to cells and organisms.

some effects may be due to subtoxic effects of some neurotoxic molecules in the gut.

groups, especially the cholinergic cells in the basal forebrain. [2, 22]

194 Pharmacology and Nutritional Intervention in the Treatment of Disease

withdrawal symptoms if they do not have their coffee.

respiratory functions.

**5. Neurohormetic phytochemicals**

1-2 cups of coffee depending on strength of the coffee and size of the cup.

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– 11 days.
