An evaluation of the neuroprotective effects of melatonin in an in vitro experimental model of age‐induced neuronal apoptosis

Abstract

The neuroprotective effects of melatonin in an experimental model of aging-induced apoptosis have been examined. Cerebellar granule neurons show characteristics of apoptosis after 17 days in culture (DV). The addition of melatonin to neuronal cell cultures (100-500 mum) resulted in neuroprotective and antiapoptotic effects, which were revealed by nuclear condensed cell counting. In a thorough analysis by Western-blot of the potential pathways responsible for melatonin's neuroprotective effects, we found an increase in the activation of prosurvival Akt. Subsequently GSK3beta inhibition and an increase in p-FOXO1 phosphorylation occurred. In this model of aging, apoptosis was associated with an elevated DNA damage, as demonstrated by an increase in the activation of ataxia telangiectasia muted (ATM). Subsequently, downstream targets such as p53 were activated. Furthermore, the process of DNA damage was coupled to an increase in the expression of certain proteins involved in cell cycle regulation; these were cyclin D and the proapoptotic transcription factor E2F-1. We conclude that the antiapoptotic effects of melatonin were mediated by two potential mechanisms: by increasing the activity of prosurvival pathways via Akt and by the prevention of DNA damage (via ATM inhibition) followed by the reduction of cell cycle re-entry.

Mitochondrial Superoxide Contributes to Blood Flow and Axonal Transport Deficits in the Tg2576 Mouse Model of Alzheimer's Disease

“…An alternative explanation is that mitochondrial ROS exert a direct effect on the signaling pathway leading to hyperphosphorylation of tau. For example, the glycogen synthase kinase 3 beta (GSK-3β), one of the major kinases modulating tau phosphorylation has been shown to be inhibited by antioxidant treatment [53], indicating that ROS activate the enzyme and result in increased phosphorylation of tau. Further experiments are required to clarify whether ROS affect tau phosphorylation directly or via their effect on blood flow.…”

Melatonin regulates the aging mouse hippocampal homeostasis via the sirtuin1-FOXO1 pathway

“…Our recent study showed that melatonin restored the impaired memory and attenuated the alteration of the amyloid precursor protein (APP) proteolytic processing enzyme (α- and β-secretases) expression in the hippocampus of aged mice (Mukda et al, 2016[40]). Melatonin preserved the relative protein levels of SIRT1 in the senescence-accelerated mice (SAMP8) (Cristofol et al, 2012[14]; Gutierrez-Cuesta et al, 2008[23]; Tajes Orduna et al, 2009[55]) and in the hippocampus of total sleep-deprived rats (Chang et al, 2009[12]). Age-related neuronal energy deficits contribute to the pathogenesis of several neurodegenerative disorders, such as Alzheimer's disease.…”

Differential effects of melatonin on amyloid-β peptide 25-35-induced mitochondrial dysfunction in hippocampal neurons at different stages of culture

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