Behavioral and Brain Functions 2006, 2:15doi:10.1186/1744-9081-2-15
© 2006 Srinivasan et al; licensee BioMed Central Ltd.
Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation.
Oxidative damage has been suggested to be the primary cause of aging and age-associated neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Many reviews on AD present compelling evidence for a decisive participation of severe oxidative stress in the development of neuropathology seen in this disease.
It is the physiological age of an individual rather than the chronological age that determines one’s melatonin production. The varying extent of degenerative changes of cells and tissues may correspond to differences of melatonin production in the body
Melatonin is involved in the control of various physiological functions such as coordination of other circadian rhythms including that of the central pacemaker, the suprachiasmatic nucleus , sleep regulation , immune function , growth inhibition of malignant cells , blood pressure regulation , retinal functions , modulation of mood and behavior , free radical scavenging and other antioxidant actions.
Contrary to classical antioxidants, melatonin exerts several additional effects, which contribute either directly or indirectly to the decrease of free radicals, and some of these actions are particularly relevant to or specific for the brain. Antioxidant enzymes were repeatedly shown to be upregulated by melatonin.
Several studies show that melatonin levels are lower in AD patients compared to age-matched control subjects . Decreased CSF, cerebrospinal fluid, melatonin levels observed in AD patients reflect a decrease in pineal melatonin production rather than a diluting effect of CSF. CSF melatonin levels decrease even in preclinical stages when the patients do not manifest any cognitive impairment (at Braak stages I-II), suggesting thereby that the reduction in CSF melatonin may be an early marker for the first stages of AD.
A chronobiological phenomenon in AD observed in conjunction with disturbances of the sleep-wake cycle is “sundowning “, symptoms appearing in the late afternoon or early evening, which include reduced ability to maintain attention to external stimuli, disorganized thinking and speech, a variety of motor disturbances including agitation, wandering and repetitious physical behaviours and perceptual and emotional disturbances .
Melatonin as a sleep-promoting agent has been tried in a small non-homogenous group of elderly patients with primary insomnia (3 mg p.o. for 21 days) associated with dementia or depression. Seven out of ten dementia patients having sleep disorders treated with melatonin (3 mg p.o. at bed time) showed a significant decrease in sundowning and reduced variability of sleep onset time .
In another study, administration of 6 mg of melatonin to 10 individuals with mild cognitive impairment improved sleep, mood, and memory . Similar observations were made by other groups, too. Seven AD patients who exhibited irregular sleep-wake cycles, treated with 6 mg for 4 weeks, showed a significantly reduced percentage of nighttime activity compared to a placebo group . The efficacy of 3 mg melatonin/day at bedtime in improving the sleep and alleviating sundowning was shown in 11 elderly AD patients and in 7 patients of another study Long-term administration of melatonin in the dose of 6–9 mg to 14 AD patients with sleep disorders and sundowning agitation for a period of 2–3 years improved sleep quality . Sundowning, diagnosed clinically in all patients examined was no longer detectable in 12 patients. Another study on 45 AD patients with sleep disturbances, in which 6 mg of melatonin was given daily for 4 months, confirmed sleep improvement and suppression of sundowning .
Along with these ameliorations, which can already be seen as an important improvement, also with regard to the efforts of a caregiver, the evolution of cognitive alterations in melatonin receiving patients seemed to be halted in several individuals, as compared to AD patients not receiving melatonin.
The electronic version of this article is the complete one and can be found online at: http://www.behavioralandbrainfunctions.com/content/2/1/1
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