Melatonin Therapy in Patients with Alzheimer’s Disease

Cardinali, Daniel P.; Vigo, Daniel Eduardo; Olivar, Natividad; Vidal, María Florencia; Brusco, Luis I.

doi:10.3390/antiox3020245

Cited by 62 publications

(53 citation statements)

References 203 publications

(215 reference statements)

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“…Therapeutic effects of melatonin in AD have been tested in 14 trials including AD patients and 8 trials including MCI patients (reviewed in Cardinali et al, 2014). Melatonin supplementation slows the progression of cognitive impairment in AD and MCI patients, ameliorates sundowning and improves sleep (reviewed in Cardinali et al, 2010).…”

Section: Monoaminergic Systems In Admentioning

confidence: 99%

“…A search of ClinicalTrials.gov on 15 th February 2016 yielded two studies that tested the effect of melatonin on cognitive functions in MCI patients (phase II) and sleep disturbance associated with AD (phase III). However, some clinical trials in AD patients showed no effects of melatonin on sleep disturbance and agitation (Serfaty et al, 2002; Gehram et al, 2009), suggesting that its efficacy in AD should be further investigated possibly at higher doses (Cardinali et al, 2014). The focus of recent studies is the development of melatonin analogs that could prolong the effect of melatonin.…”

Section: Monoaminergic Systems In Admentioning

confidence: 99%

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Monoaminergic neuropathology in Alzheimer’s disease

Šimić

Leko

Wray³

et al. 2017

Progress in Neurobiology

233

142

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None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

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Section: Monoaminergic Systems In Admentioning

confidence: 99%

Section: Monoaminergic Systems In Admentioning

confidence: 99%

Monoaminergic neuropathology in Alzheimer’s disease

Šimić

Leko

Wray³

et al. 2017

Progress in Neurobiology

233

142

View full text Add to dashboard Cite

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“…175 Thus, there is increasing interest in potential benefits of melatonin in AD. 176,177 Hypoxia exposure of Wistar rats steadily increased plasma melatonin activity to a plateau at seven days. 178 To what extent the beneficial actions of IHT in AD are due to increased release of melatonin by the pineal gland remains to be determined.…”

mentioning

confidence: 99%

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease

Манухина

Downey

Shi

et al. 2016

Exp Biol Med (Maywood)

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Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso-and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic epilepsy, spinal cord injury, and alcohol withdrawal stress have also been reported. Further research on the potential benefits of IHT in AD and other brain pathologies is warranted.

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“…[127]). For these effects to occur, doses of melatonin about one order of magnitude higher than those required to affect sleep and circadian rhythmicity are needed.…”

Section: Melatonin and Bzd Use In Insomnia Disorder Patientsmentioning

confidence: 93%

Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse

Cardinali

Golombék

Rosenstein

et al. 2016

Pharmacological Research

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The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains γ-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenously administered melatonin. Both meta-analyses and consensus agreements give support to the therapeutic use of melatonin in sleep disorders. This action is attributed to MT1 and MT2 melatoninergic receptors localized in the SCN, as well as in other brain areas. This review discusses available data on the efficacy of melatonin to curtail chronic BZD/Z drug use in insomnia patients. A major advantage is that melatonin has a very safe profile, it is usually remarkably well tolerated and, in some studies, it has been administered to patients at very large doses and for long periods of time, without any potentiality of abuse. Further studies on this application of melatonin are warranted.

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Melatonin Therapy in Patients with Alzheimer’s Disease

Cited by 62 publications

References 203 publications

Monoaminergic neuropathology in Alzheimer’s disease

Monoaminergic neuropathology in Alzheimer’s disease

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease

Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse

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