Melatonin Therapy in Patients with Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a major health problem and a growing recognition exists that efforts to prevent it must be undertaken by both governmental and non-governmental organizations. In this context, the pineal product, melatonin, has a promising significance because of its chronobiotic/cytoprotective properties potentially useful for a number of aspects of AD. One of the features of advancing age is the gradual decrease in circulating melatonin levels. A limited number of therapeutic trials have indicated that melatonin has a therapeutic value as a neuroprotective drug in the treatment of AD and minimal cognitive impairment (which may evolve to AD). Both in vitro and in vivo, melatonin prevented the neurodegeneration seen in experimental models of AD. For these effects to occur, doses of melatonin about two orders of magnitude higher than those required to affect sleep and circadian rhythmicity are needed. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects, which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50-100 mg/day are urgently needed to assess its therapeutic validity in neurodegenerative disorders such as AD.

Keywords: Alzheimer’s disease; aging; free radicals; melatonin; melatonin analogs; mild cognitive impairment; neurodegeneration; oxidative stress.

Figure 1

Effect of melatonin on impaired brain insulin signaling in AD. The figure schematizes the processes linking impaired insulin/insulin receptor with senile plaques and neurofibrillary tangles. In parentheses, the demonstrated action of melatonin as discussed in the text.

Figure 2

Possible targets for medication in AD. As discussed in the text, melatonin has the potential to affect all the mechanisms depicted in the figure. (*) Approved by the FDA.