Evaluation of potential pro‐survival pathways regulated by melatonin in a murine senescence model

Abstract

We examined the effect of melatonin on pro-survival processes in three groups of mice. Untreated senescence-accelerated mice (SAMP8), melatonin-treated SAMP8 and untreated senescence-accelerated resistant mice (SAMR1) of 10 months old were studied. Melatonin (10 mg/kg) or vehicle (ethanol at 0.066%) was supplied in the drinking water from the end of the first month until the end of the ninth month of life. Differences in the Akt/Erk1-2 pathway and downstream targets were examined and no significant changes were observed, except for beta-catenin. However, sirtuin 1 expression was significantly lower in SAMP8 than in SAMR1. In addition, acetylated p53 and NFkappaB expression were lower in SAMP8 than in SAMR1. These changes were prevented by melatonin. Moreover, the concentration/expression of alpha-secretase was lower and that of amyloid beta aggregates (Abeta) was higher in untreated SAMP8 than in SAMR1. Likewise, the levels of Bid were higher, whereas Bcl-2(XL) levels were lower in SAMP8 than in SAMR1. Melatonin reduced all these changes. We conclude that melatonin improves pro-survival signals and reduces pro-death signals in age-related impairments of neural processes.

Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8

“…Moreover, decreased SIRT1 expression has been found in patients with AD, and this decrease correlates with tau and Aβ levels (Julien et al 2009). Modulation of ADAM10 expression by SIRT1 has also been demonstrated (Gutierrez-Cuesta et al 2008;Donmez et al 2010). In our experimental paradigm, we found that resveratrol reduces the Aβ burden in treated SAMP8 brain concomitantly with increases in ADAM10 expression.…”

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

“…Accordingly, a decrease of SIRT1 expression with age in SAMP8 has been found [97] that correlate with a decrease in tau phosphorylation and with an increase in ADAM10 [58].…”

“…SAMP8 shows spontaneous overproduction of soluble Aβ in the hippocampus [26] and cortex [58]. Evidence strongly suggests that an increase in soluble Aβ contributes to cognitive decline in aged SAMP8.…”

“…Tau hyperphosphorylation in SAMP8 is mediated by AD-related mechanisms, such as increases in Cdk5 expression [55]. Moreover, treatments such as melatonin [57,58] and lithium chloride [59] that reduce Cdk5 and GSK3β activation and activation of the cdk5/p35 pathway at its cleavage to cdk5/p25, which are all key players in AD-related hyperphosphorylation of tau during aging and neurodegenerative diseases [4,60], lead to a reduction in tau hyperphosphorylation when administered to SAMP8.…”

Melatonin and ubiquitin: what’s the connection?

“…Hardeland and colleagues [74] interpret this as evidence that mitochondrial biogenesis is stimulated by melatonin. Deacetylation of PGC-1a apparently depends on the SIrt1 protein, a protein that is upregulated by melatonin [75]; it is also upregulated by estradiol, apparently via the ubiquitin-proteasome system [76]. It is predicted that melatonin and the ubiquitin-proteasome system interact in regulating mitochondrial biogenesis and in inducing the expression of rOS-detoxifying enzymes.…”