Melatonin induces neural SOD2 expression independent of the NF‐kappaB pathway and improves the mitochondrial population and function in old mice

Abstract

Aging is commonly defined as a physiological phenomenon associated with morphological and functional deleterious changes in which oxidative stress has a fundamental impact; therefore, readjusting the oxidative balance should have beneficial effects. In our study, we tested the antioxidant melatonin in old mouse brains and showed positive effects at the cellular and mitochondrial levels. Melatonin attenuated β-amyloid protein expression and α-synuclein deposits in the brain compared to aged group. Furthermore, oxidative stress was increased by aging and induced the nuclear translocation of nuclear factor-kappa B (NF-κB), which was suppressed by melatonin treatment. The antioxidant mitochondrial expression, superoxide dismutase 2 (SOD2), was increased in both control and melatonin-treated old mice, despite the different activation states of the NF-κB pathway. The NF-κB pathway was activated in the old mice, which may be explained by this group's response to the increased oxidative insult; this insult was inhibited in melatonin-treated animals, showing this group an increase in active mitochondria population that was not observed in old group. We also report that melatonin is capable of restoring the mitochondrial potential of age-damaged neurons. In conclusion, melatonin's beneficial effects on brain aging are linked to the increase in mitochondrial membrane potential and SOD2 expression, which probably reduces the mitochondrial contribution to the oxidative stress imbalance.

Gene regulation by melatonin linked to epigenetic phenomena

“…These changes were prevented by melatonin administration in a concentration-dependent manner. Garcia-Macia et al (2011) reported that melatonin induces neural SOD2 (mitochondrial MnSOD) expression independent of the NF-κB pathway in the brain tissues of old mice which also implies Nrf2 induction by melatonin.…”

Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle

“…The endogenous mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) is upregulated by treatments that improve insulin sensitivity (18,25,46) and may be playing a role in the regulation of insulin action. However, interventional studies are needed to explore this possibility.…”

Neuroimmunomodulation in unipolar depression: a focus on chronobiology and chronotherapeutics

“…Numerous biological pathways and molecular mechanisms that appear to be involved in the bi-directional cross-talk. Further, given the immunomodulatory effects of ADs and CTs (Bondy et al 2010;Garcia-Macia et al 2011;Min et al 2011;Racagni et al 2011;Ramirez-Rodriguez et al 2011), their associated effects on circadian rhythms Hickie and Rogers 2011), we suggest that these therapeutic agents may exert some of their chronobiological effects via immune mediation. This paper has provided an overview of the biological pathways which may mediate the bidirectional cross-talk between the immune and circadian systems.…”

“…IL-1b, TNF-a) and oxidative stress in the striatum, cortex, HC and hypothalamus (Shen et al 2007;Tyagi et al 2010). Other studies have shown melatonin suppresses NF-jB production and reduces oxidative stress in the CNS (Bondy et al 2010;Garcia-Macia et al 2011). In the same LPS model of immune challenge, melatonin attenuated chemokine expression (i.e.…”

“…However, some classical ADs, including selective serotonin reuptake inhibitors (SSRIs) and noradrenaline reuptake inhibitors (NRIs), may disrupt circadian processes, hence having a detrimental effect on sleep-wake cycles (Krystal 2010;Antonioli et al 2012). A newer CT, agomelatine, effective in the treatment of depression Hickie and Rogers 2011), may also exert beneficial neuroimmunomodulatory and pro-neuroplastic effects (Bondy et al 2010;Garcia-Macia et al 2011;Min et al 2011;Racagni et al 2011;RamirezRodriguez et al 2011). As circadian dysfunction is shown to create a neuroinflammatory state in the CNS (Imeri and Opp 2009) and some CTs and ADs (i.e.…”