Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A

Abstract

We have reported recently that inhibition of protein phosphatase (PP)-2A and PP-1 by calyculin A, a specific inhibitor of PP-2A and PP-1, induced Alzheimer-like hyperphosphorylation of tau and spatial memory retention impairment. In this study, we tested the in vivo effects of melatonin on these Alzheimer-like changes. We found that administration of melatonin intraperitoneally for 9 consecutive days before injection of calyculin A could prevent calyculin A-induced synaptophysin loss, memory retention deficits, as well as hyperphosphorylation of tau and neurofilaments. Furthermore, melatonin partially reversed the phosphorylation of the catalytic subunit of PP-2A at Tyrosine 307 (Y307), a crucial site negatively regulating the activity of PP-2A, and reduced the levels of malondialdehyde, a marker of oxidative stress, induced by calyculin A. These results suggest that melatonin could serve as a potential therapeutic agent for preventing Alzheimer-like pathological changes and behavioral abnormality via modulating the activity of PP-2A and oxidative stress.

Does Melatonin Ameliorate Neurological Changes Associated With Alzheimer’s Disease in Ovariectomized Rat Model?

“…Melatonin stabilizes membranes against free radicals and can resist the rigidity of the biological membranes caused by Al [32]. Moreover, Yang et al [6] reported that melatonin effectively reduces lipid peroxidation induced by Al in Alzheimer's patients. Melatonin is a potent antioxidant that protects DNA, lipids and proteins from free radical damage [33].…”

“…While, treatment of Al-intoxicated Ovx rats with melatonin revealed almost normal structure of the hippocampus with few dark neurons remaining in the cortex. Yang et al [6] reported that melatonin effectively reduces lipid peroxidation and ameliorates Alzheimer-like pathological changes.…”

“…It can directly act as free radical scavenger and indirectly induce the expression of some genes linked to the antioxidant defense system [5]. Melatonin could serve as a promising modulator for Alzheimer-like pathological changes and behavioral abnormalities [6].…”

Subthreshold Concentrations of Melatonin and Galantamine Improves Pathological AD-Hallmarks in Hippocampal Organotypic Cultures

“…In fact, a recent report by Wade et al show that the addition of melatonin to an acetylcholinesterase inhibitor, with or without memantine treatment, has positive effects on cognitive function and sleep maintenance in mild to moderate AD patients compared to placebo [47]. There are also several studies that support the potential role of melatonin as an effective adjuvant in AD management [19,20].…”

“…Furthermore, melatonin has low toxicity and is able to reduce the side effects and increase the efficacy of other drugs [18], being proposed as an effective adjuvant in AD management [19,20]. Additionally, previous data from our group have shown that sub-effective concentrations of melatonin combined with galantamine offer a synergic neuroprotective effect in an in vitro model of oxidative stress [12].…”