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Abstract: We examined the expression of SIRT1 in several experimental paradigms of human pathologies. We used a neuroblastoma cell line (B65), neuronal primary cultures (hippocampus and cerebellar granule cells) and in vivo approaches in rat and senescence murine models (SAM). Cell cultures and rats were treated with several well-know neurotoxins, i.e. rotenone, MPP+, kainate and 3-nitropropionic acid. Subsequently, SIRT1 expression was compared in these different paradigms of neurotoxicity. The pattern of expression of SIRT1 in proliferating cell cultures (B65) was different to that in quiescent cell cultures. In the murine model of senescence (senescence-accelerated mice prone, SAMP8), SIRT1 expression progressively decreased, while in the control strain (senescence-accelerated mice resistant, SAMR1) it increased. Finally, we studied human samples of Parkinson''s disease (PD), dementia with Lewy bodies (DLB) and Huntington''s diseases (HD). SIRT1 expression decreased dramatically in HD, but there were no significant changes in Parkinson-related illnesses. In conclusion, SIRT1 expression may be a good sensor of toxic neuronal processes. [Copyright &y& Elsevier]

Abstract: Lithium reduced striatal neurodegeneration induced in rats by 3-nitropropionic acid inhibiting calpain activation. Lithium prevented an increase in cdk5 activity, as shown by the levels of the co-activator p35. Myocite enhancer factor 2 (MEF2), a downstream substrate for cdk5 with pro-survival activity, showed increased phosphorylation. In primary cultures of neurons treated with 3-NP, lithium also reduced protease activity mediated by calpain, cdk5 activation and cellular death. These observations indicate that lithium has a neuroprotective effect. Lithium treatment also reduced the intracellular increase in calcium induced by 3-NP. The finding that lithium mediates the modulation of the calpain/cdk5 pathway further supports its use in the treatment of neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: An active lifestyle involving regular exercise reduces the deleterious effects of the aging process. At the cerebral level, both synaptic plasticity and neurogenesis are modulated by exercise, although the molecular mechanisms underlying these effects are not clearly understood. In the mature nervous system, the canonical Wnt (Wnt/β-catenin) signaling pathway is implicated in neuroprotection and synaptic plasticity. Here, we examined whether the Wnt pathway could be modulated in adult male rat hippocampus by long-term moderate exercise (treadmill running) or enrichment (handling/environmental stimulation). Sedentary animals showed higher protein levels of the Wnt antagonist, Dkk-1, the lowest levels being found in the exercised group. Although there was no evidence of any changes in activation of the LRP6 receptor, the total levels of LRP6 were higher in exercised and enriched animals. Analysis of some of the components implicated in the phosphorylation of β-catenin, which leads ultimately to its proteasomal degradation, revealed higher levels and activation of Axin1 and GSK-3α/β respectively in sedentary animals. However neither different phosphorylated forms nor total β-catenin protein levels differed between the experimental groups. Higher protein levels of Axin2 and the antiapoptotic protein, Bcl-2, were found with exercise and handling, whereas the proapototic, Bax, was unaffected. Thus, our results suggest activation of the Wnt pathway not only with moderate exercise, but also with the handling of the animals. [Copyright &y& Elsevier]

Abstract: The protein deacetylase, sirtuin 1, is suggested as a master regulator of exercise-induced beneficial effects. Sirtuin 1 modulates mitochondrial biogenesis, primarily via its ability to deacetylate and activate proliferator-activated receptor-γ coactivator-1α (PGC-1α), interacting with AMPK kinase. Redox cell status can also influence this regulatory axis and together they form an important convergence point in hormesis during the aging process. Here, we tested whether treadmill training (36weeks), as a paradigm of long-term moderate exercise, modifies the AMPK–sirtuin 1–PGC-1α axis and redox balance in rat gastrocnemius muscle, liver and heart. Physical activity induced increases in sirtuin 1 protein levels in all the aged rat tissues studied, as well as total PGC-1α levels. However, no changes in AMPK activation or significant differences in mitochondrial biogenesis (by measuring electron transport chain protein content) were found after exercise training. Parallel to these changes, we observed an improvement of oxidative stress defenses, mainly in muscle, with modification of the antioxidant enzyme machinery resulting in a reduction in lipid peroxidation and protein carbonylation. Thus, we demonstrate that moderate long-term exercise promotes tissue adaptations, increasing muscle, liver and heart sirtuin 1 protein content and activity and increasing PGC-1α protein expression. However, AMPK activation or mitochondrial biogenesis is not modified, but it cannot be discarded that its participation in the adaptive mechanism which prevents the development of the deleterious effects of age. [Copyright &y& Elsevier]