Analía M. Furio

Possible therapeutic value of melatonin in mild cognitive impairment : a retrospective study

Abstract:  Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome characterized by cognitive impairment preceding dementia. Approximately 12% of MCI patients convert to Alzheimer’s disease (AD) or other dementia disorders every year. In the present report we retrospectively examined the initial and final neuropsychological assessment of 50 MCI outpatients, 25 of whom had received daily 3–9 mg of a fast‐release melatonin preparation p.o. at bedtime for 9–18 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin showed significantly better performance in Mini Mental State Examination and the cognitive subscale of the Alzheimer’s Disease Assessment Scale. After application of a battery of neuropsychological tests including Mattis’ test, Digit‐symbol test, Trail A and B tasks and the Rey’s verbal test, better performance was found in melatonin‐treated patients, except for the Digit‐symbol test score which remained unchanged. Abnormally high Beck Depression Inventory scores decreased in melatonin‐treated patients, concomitantly with an improvement in wakefulness and sleep quality. The results suggest that melatonin can be a useful add‐on drug for treating MCI in a clinical setting.

Clinical Aspects of Melatonin Intervention in Alzheimer's Disease Progression

Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called “sundowning”). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were “Alzheimer” and “melatonin”. Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated.

Clinical perspectives for the use of melatonin as a chronobiotic and cytoprotective agent

The circadian time system involves periodic gene expression at the cellular level, synchronized by a hierarchically superior structure located in the hypothalamic suprachiasmatic nuclei. Treatment of circadian rhythm disorders has led to the development of a new type of agent called “chronobiotics” among which melatonin is the prototype. In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency, particularly slow‐wave sleep. The effect of melatonin on sleep is the consequence of increasing sleep propensity (by augmenting the amplitude of circadian clock oscillation via MT1 receptors) and of synchronizing the circadian clock via MT2 receptors. Daily melatonin production decreases with age and in several pathologies, attaining its lowest values in Alzheimers disease (AD) patients. About 45% of AD patients have disruptions in their sleep and “sundowning” agitation. Generally, melatonin treatment decreases sundowning in AD patients and reduced variability of sleep onset time. Both open and controlled studies have indicated a significant decrease of cognitive deterioration in AD patients treated with melatonin. The mechanisms accounting for the possible therapeutic effect of melatonin in AD patients may be manifold. On one hand, melatonin treatment promotes slow‐wave sleep in the elderly and could be beneficial by augmenting the restorative phases of sleep. On the other hand, melatonin protects neurons against β‐amyloid toxicity. By its combined chronobiotic and cytoprotective properties melatonin provides an innovative neuroprotective strategy to reduce the cost of lifetime treatment of some neuropsychiatric disorders.

Effect of Melatonin on Changes in Locomotor Activity Rhythm of Syrian Hamsters Injected with Beta Amyloid Peptide 25–35 in the Suprachiasmatic Nuclei

Abstract1. Alzheimers disease is associated with circadian rhythm disturbances, probably because of beta amyloid-induced neuronal damage of hypothalamic suprachiasmatic nuclei (SCN).2. Since there is no published study on the circadian consequences of injecting beta amyloid peptide in experimental animals, one objective of the present study was to examine circadian locomotor activity in Syrian hamsters injected with beta amyloid peptide 25–35 into both SCN.3. Because one of the proposed therapies for circadian alterations in dementia is the administration of melatonin, a chronobiotic agent with antioxidant properties, the preventive effect of melatonin on the circadian changes produced by beta amyloid microinjection into SCN was also assessed.4. Wheel running activity was recorded by using the Dataquest III system in male golden hamsters kept under 14:10 light–dark photoperiods. Animals received microinjections of beta amyloid peptide 25–35 (100 μM solution, 1 μL) or saline in each SCN. Only those animals with neuronal lesions larger than 10% of SCN after beta amyloid injection were considered for further analysis.5. To assess the effect of melatonin on beta-amyloid peptide activity, melatonin was given in the drinking water (25 μg/mL) starting 15 days in advance to the microinjection of beta amyloid peptide into SCN.6. Beta amyloid-treated hamsters exhibited a significant phase advance of onset of running activity of about 22 min as compared to saline-injected animals. They also showed a significantly greater variability in onset time of wheel running activity, mainly evident from 6 to 15 days of treatment.7. Melatonin administration in the drinking water prevented the phase advance of onset time and the increased variability of onset time brought about by beta amyloid peptide.8. The results support the existence of a neuroprotective effect of melatonin on beta amyloid-induced circadian changes in hamsters.

Neuroprotective Effect of Melatonin on Glucocorticoid Toxicity in the Rat Hippocampus

Dexamethasone has a neurotoxic action on rodent hippocampus. The objective of this study was to examine the extent of neuroprotection exerted by melatonin on that neurotoxic effect. A group of 24 rats received 9 daily subcutaneous injections of 0.5 mg/kg of dexamethasone. Half of them received 25 μg/ml of melatonin in the drinking water for 10 days. Controls included rats injected with vehicle or rats injected with vehicle plus melatonin in the drinking water. At the end of treatment, the brains were processed for a morphometric analysis, the results being expressed as percent number of ab- normal hipoccampal neurons (defined as necrotic cells) per field. Melatonin decreased by 77 % the effect of dexametha- sone (p< 0.001). A laterality of neurotoxic effect of dexamethasone was apparent in rats that did not receive melatonin (percent of necrotic cells in left and right hippocampus: 32.0 ± 4.4 and 19.6 ± 1.9 %, respectively, p< 0.01). The results indicate a protective effect of melatonin on glucocorticoid neurotoxicity in the rat hippocampus.

Melatonin Efficacy to Treat Circadian Alterations of Sleep in Alzheimer’s Disease

Alzheimer’s disease (AD) patients show a greater disruption of the circadian sleep-wake cycle as compared to similarly aged non-demented controls. When this occurs demented patients spend their nights in a state of frequent restlessness and their days in a state of frequent sleepiness. These sleep-wake disturbances became increasingly more marked with the progression of the disease and may contribute to cognitive decay. Sleep architecture in AD is characterized by decreases of slow wave sleep and rapid eye movement sleep and increases of time and frequency of awakening compared to aged-matched control subjects. The sleep-wake disturbances in elderly people and AD patients appear to result from changes at different levels: reduction of environmental synchronizers, neurosensorial deficit or lack of mental and physical activity. However, increasing evidence exists about the loss of functionality of the hypothalamic suprachiasmatic nuclei (SCN), the principal oscillator in the circadian system. A chronobiological approach including melatonin, bright-light therapy, restricted time in bed and programmed diurnal activity is a promising therapeutic alternative in the management of sleep-wake disorders in AD patients. In elderly insomniacs melatonin treatment decreased sleep latency and increased sleep efficiency. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect); typically the latter takes several weeks to occur. Generally, melatonin decreased sundowning in AD patients and reduced variability of sleep onset time, with improvement in mood and memory. The effect of melatonin was seen regardless of the concomitant medication employed to treat cognitive or behavioral signs of disease. The mechanisms accounting for the possible therapeutic effect of melatonin in AD patients remain unknown. Melatonin treatment could be beneficial in AD by augmenting the restorative phase of sleep. In addition, in vitro and in vivo data indicated that melatonin protects neurons against β amyloid toxicity, prevents β amyloid-induced lipid peroxidation and alters the metabolism of the β amyloid precursor protein. Melatonin prevented the chronobiological consequences of injecting β amyloid peptide 25–35 in the SCN of hamsters and cognitive decay in transgenic mice overexpressing β-amyloid.