Melatonin Attenuates Memory Impairment, Amyloid-β Accumulation, and Neurodegeneration in a Rat Model of Sporadic Alzheimer’s Disease

Abstract

Melatonin is a multifunctional molecule and plays a crucial role in the regulation of circadian rhythms. The role of melatonin in the protection of the central nervous system is well documented. Therefore, melatonin was proposed as a possible therapeutic agent for reducing the severity of Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by cognitive decline and memory dysfunction. Recently, we showed beneficial neuroprotective effects of prophylactic supplementation with melatonin in a suitable model of sporadic AD: OXYS rats, which exhibit disturbances in melatonin secretion. In the present study, we demonstrated that melatonin administration, when started at the age of active progression of AD-like pathology, decreased the amyloid-β1 - 42 and amyloid-β1 - 40 levels in the hippocampus and amyloid-β1 - 42 levels in the frontal cortex of OXYS rats. Furthermore, oral administration of melatonin slowed down degenerative alterations in hippocampal neurons of OXYS rats. The most noticeable improvement was observed in the CA1 region of the hippocampus. Melatonin administration prevented the decrease in the mitochondria-occupied portion of the neuronal volume and improved the ultrastructure of mitochondria in the neurons of the CA1 region. Additionally, melatonin treatment of OXYS rats slowed down an increase in anxiety and deterioration of reference memory. Thus, melatonin administration could alleviate the burden of AD and may be considered a promising pharmaceutical treatment of the disease.

An antioxidant specifically targeting mitochondria delays progression of Alzheimer’s disease-like pathology

“…We can assume that the effects of SkQ1 are due to a direct antioxidant effect [64] as well as the ability to suppress mitochondrial production of ROS, and thereby to enhance the fatty-acid-driven mild decoupling of oxidation and phosphorylation [65]. We can also speculate that the effects of SkQ1, like those of another powerful neuroprotector, melatonin [31; 66], which are considered in recent years as a mitochondria-targeted antioxidant, are mediated by improved coordination of cellular signaling pathways responsible for tissue homeostasis [67]. In any case, this hypothesis is supported by the improved structural and functional state of mitochondria (and neurons on the whole) in SkQ1-treated OXYS rats as well as downregulation of amyloid-β and of tau protein hyperphosphorylation, recovery of synaptic processes and as a consequence, restoration of cognitive functions.…”

Melatonin for Sleep Disorders in Patients with Neurodegenerative Diseases

“…In vitro, beta-amyloid toxicity and aggregation are decreased by melatonin [48][49][50][51]. In animal AD models, melatonin reduces the neurotoxicity and deposition of beta-amyloid, decreases oxidative stress, increases survival time, and protects against cognitive decline [52][53][54][55][56][57][58]. Melatonin decreases proinflammatory cytokines in rats injected with beta-amyloid [59].…”

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

“…Moreover, it is proved to be neuroprotective in HD and stroke models AD and HD [114] Melatonin Improves the ultrastructure of mitochondria in the neurons of the CA1 region and prevents the decrease in the mitochondria-occupied portion of the neuronal volume in AD AD [115] Mori Fructus (ME) Decreases mitochondria depolarization, Cyt c release from mitochondria and caspase-3 activation induced by Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) toxicity in the mouse hippocampus AD [116] Erythropoietin (EPO) Alleviates the Aβ-induced mitochondrial dysfunction and apoptosis in brain AD [117] Linagliptin…”