Sirtuin1 (SIRT1) and forkhead box transcription factor O subfamily 1 (FOXO1) play vital roles in the maintenance of hippocampal neuronal homeostasis during aging. Our previous study showed that melatonin, a hormone mainly secreted by the pineal gland, restored the impaired memory of aged mice. Age-related neuronal energy deficits contribute to the pathogenesis of several neurodegenerative disorders. An attempt has been made to determine whether the effect of melatonin is mediated through the SIRT1-FOXO1 pathways. The present results showed that aged mice (22 months old) exhibited significantly downregulated SIRT1, FOXO1, and melatonin receptors MT1 and MT2 protein expression but upregulated tumor suppressor protein 53 (p53), acetyl-p53 protein (Ac-p53), mouse double minute 2 homolog (MDM2), Dickkopf-1 (DKK1) protein expression in mouse hippocampus compared with the young group. Melatonin treatment (10 mg/kg, daily in drinking water for 6 months) in aged mice significantly attenuated the age-induced downregulation of SIRT1, FOXO1, MT1 and MT2 protein expression and attenuated the age-induced increase in p53, ac-p53, MDM2, and DKK1 protein and mRNA expression. Melatonin decreased p53 and MDM2 expression, which led to a decrease in FOXO1 degradation. These present results suggest that melatonin may help the hippocampal neuronal homeostasis by increasing SIRT1, FOXO1 and melatonin receptors expression while decreasing DKK1 expression in the aging hippocampus. DKK1 can be induced by the accumulation of amyloid β (Aβ) which is the major hallmark of Alzheimer's disease.

Methamphetamine (METH), a highly addictive psychostimulant drug, is known to exert neurotoxic effects to the dopaminergic neural system. Long-term METH administration impairs brain functions such as cognition, learning and memory. Newly born neurons in the dentate gyrus of the hippocampus play an important role in spatial learning and memory. Previous in vitro studies have shown that METH inhibits cell proliferation and neurogenesis in the hippocampus. On the other hand, melatonin, a major indole secreted by the pineal gland, enhances neurogenesis in both the subventricular zone and dentate gyrus. In this study, adult C57BL/6 mice were used to study the beneficial effects of melatonin on METH-induced alterations in neurogenesis and post-synaptic proteins related to learning and memory functions in the hippocampus. The results showed that METH caused a decrease in neuronal phenotypes as determined by the expressions of nestin, doublecortin (DCX) and beta-III tubulin while causing an increase in glial fibrillary acidic protein (GFAP) expression. Moreover, METH inhibited mitogen-activated protein kinase (MAPK) signaling activity and altered expression of the N-methyl-d-aspartate (NMDA) receptor subunits NR2A and NR2B as well as calcium/calmodulin-dependent protein kinase II (CaMKII). These effects could be attenuated by melatonin pretreatment. In conclusion, melatonin prevented the METH-induced reduction in neurogenesis, increase in astrogliogenesis and alteration of NMDA receptor subunit expression. These findings may indicate the beneficial effects of melatonin on the impairment of learning and memory caused by METH.

Melatonin, secreted mainly by the pineal gland, plays roles in various physiological functions including protecting cell death. We showed in previous study that the proliferation and differentiation of precursor cells from the adult mouse subventricular zone (SVZ) can be modulated by melatonin via the MT1 melatonin receptor. Since melatonin and epidermal growth factor receptor (EGFR) share some signaling pathway components, we investigated whether melatonin can promote the proliferation of precursor cells from the adult mouse SVZ via the extracellular signal-regulated protein kinase /mitogen-activated protein kinase (ERK/MAPK) pathways in comparison with epidermal growth factor (EGF). Melatonin-induced ERK/MAPK pathways compared with EGF were measured by using in vitro and vivo models. We used neurosphere proliferation assay, immunocytochemistry, and immuno-blotting to analyze significant differences between melatonin and growth factor treatment. We also used specific antagonist and inhibitors to confirm the exactly signaling pathway including luzindole and U0126. We found that significant increase in proliferation was observed when two growth factors (EGF+bFGF) and melatonin were used simultaneously compared with EGF + bFGF or compared with melatonin alone. In addition, the present result suggested the synergistic effect occurred of melatonin and growth factors on the activating the ERK/MAPK pathway. This study exhibited that melatonin could act as a trophic factor, increasing proliferation in precursor cells mediated through the melatonin receptor coupled to ERK/MAPK signaling pathways. Understanding the mechanism by which melatonin regulates precursor cells may conduct to the development of novel strategies for neurodegenerative disease therapy.

Aging is often accompanied by a decline in cognitive function in conjunction with a variety of neurobiological changes, including neuroinflammation. Melatonin is a key endogenous indoleamine secreted by the pineal gland that plays a crucial role in the regulation of circadian rhythms, is a potent free radical scavenger, has anti-inflammatory activity and serves numerous other functions. However, the role of melatonin in sterile inflammation in the brain has not been fully investigated. In the present study, we investigated the neuroinflammation status in aged mouse brains. The results showed that the protein levels of integrin αM (CD11b), glial fibrillary acidic protein (GFAP), the major pro-inflammatory cytokines (interleukin-1 beta [IL-1β], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNF-α]) and phosphor-nuclear factor kappa B (pNFκB) were significantly increased, while N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and brain-derived neurotrophic factor (BDNF) were down-regulated in the hippocampus and prefrontal cortex (PFC) of 22-months-old (aged) mice compared with 2-months-old (young adult) mice. Melatonin was administered in the drinking water to a cohort of the aged mice at a dose of 10 mg/kg/day, beginning at an age of 16 months for 6 months. Our results revealed that melatonin significantly attenuated the alterations in these protein levels. The present study suggests an advantageous role for melatonin in anti-inflammation, and this may lead to the prevention of memory impairment in aging.

Beta-amyloid (Aβ) peptide is the pathological hallmark of Alzheimer's disease (AD). Interestingly, Aβ is normally synthesized in the brain of healthy people; however, during advanced aging, the level of Aβ peptides increases. As a result, the aggregation of Aβ peptides leads to trafficking problems, synaptic loss, inflammation, and cell death. Melatonin, the hormone primarily synthesized and secreted from the pineal gland, is decreased with progressing age, particularly in Alzheimer's disease patients. The loss of melatonin levels and the abnormal accumulation of some proteins, such as Aβ peptides in the brains of AD patients are considered important factors in the initiation of the cognitive symptoms of dementia. A previous study in mice reported that increased brain melatonin levels remarkably diminished the potentially toxic Aβ peptide levels. The present study showed that aged mice significantly impaired spatial memory in the Morris Water Maze task. We also showed that α-, β-, and γ-secretases, which are type-I membrane protein proteases responsible for Aβ production, showed alterations in both mRNA and protein expression in the hippocampus of aged mice. The long-term administration of melatonin, mice had shorter escape latencies and remained in the target quadrant longer compared to the aged group. Melatonin attenuated the reduction of α-secretase and inhibited the increase of β- and γ-secretases. Moreover, melatonin attenuated the upregulation of pNFkB and the reduction of sirtuin1 in the hippocampus of aged mice. These results suggested that melatonin protected against Aβ peptide production in aged mice. Hence, melatonin loss in aging could be recompensed through dietary supplementation as a beneficial therapeutic strategy for AD prevention and progression.

Chronic stress or prolonged exposure to high levels of glucocorticoid induces neuropathological alterations, such as dendritic atrophy of hippocampal or cortical neurons. The chronic administration of high doses of dexamethasone (DEX), a synthetic glucocorticoid receptor agonist, impairs long-term memory and motor coordination, reduces body weight and induces mortality in mice. DEX is typically administered clinically for a prolonged period. Therefore, we are interested in studying the mechanism by which chronic DEX administration affects cognitive function. In this study, we attempted to explore whether chronic DEX administration alters the process of memory formation and to determine the mechanism underlying the detrimental effect of DEX. The results showed that mice treated with DEX for 21 consecutive days had significantly impaired spatial memory in the Morris Water Maze task. Mice treated with DEX had prolonged water maze performance latencies and spent less time in the target quadrant compared to the control group. Furthermore, DEX reduced brain-derived neurotrophic factor (BDNF), N-methyl-d-aspartate (NMDA) receptor subunit (NR2A/B), calcium/calmodulin-dependent protein kinase II (CaMKII) in both the prefrontal cortex and hippocampus and synaptophysin in the prefrontal cortex. We also investigated whether melatonin, a hormone synthesized in the pineal gland, could protect against DEX-induced changes in spatial memory and synaptic plasticity. The results showed that mice pretreated with melatonin prior to the DEX treatment had shorter escape latencies and remained in the target quadrant longer compared to the group only treated with DEX. Melatonin significantly prevented a DEX-induced reduction in the expression of NR2A/B, BDNF, CaMKII and synaptophysin. The results from the present study demonstrate that melatonin pretreatment prevents cognitive impairment caused by DEX. However, the precise mechanism by which melatonin affects cognitive function requires further investigation.

Glucocorticoids play various physiological functions via the glucocorticoid receptor (GR). Glucocorticoid is associated with the pathophysiology of depression. Dexamethasone (DEX), a synthetic GR agonist, has a greater affinity for GR than the mineralocorticoid receptor (MR) in the hippocampus of pigs and may mimic the effects of GR possession. DEX decreases neurogenesis and induces damage to hippocampal neurons that is associated with depressive-like behavior. Melatonin, a hormone mainly synthesized in the pineal gland, is a potent free radical scavenger and antioxidant. Melatonin alters noradrenergic transmission in depressed patients. It may be interesting to further explore the mechanism of melatonin that is associated with the role of stress as a key factor to precipitate depression and as a factor altering neurogenesis. In this study, we assessed the capability of melatonin to protect the hippocampus of mouse brains to counteract the effects of chronic DEX treatment for 21 days on depressive-like behavior and neurogenesis. Our results revealed that chronic administration of DEX induced depressive-like behavior and that this could be reversed by pretreatment with melatonin. Moreover, the number of 5-bromo-2-deoxyuridine (BrdU)-immunopositive cells and doublecortin (DCX; the neuronal-specific marker) protein levels were significantly reduced in the DEX-treated mice. Pretreatment with melatonin was found to renew BrdU and DCX expression in the dentate gyrus. Furthermore, pretreatment with melatonin prevented DEX-induced reductions in GR and an extracellular-signal-regulated kinase (ERK1/2) in the hippocampal area. Melatonin may protect hippocampal neurons from damage and reverse neurogenesis after chronic DEX by activating brain-derived neurotrophic (BDNF) and ERK1/2 cascades. These results revealed that melatonin pretreatment prevented the reduction of cell proliferation, immature neuron precursor cells, and GR and ERK1/2 expression. This finding indicates that melatonin attenuates the DEX-induced depressive-like behavior, supporting the notion that melatonin possesses anti-stress and neurogenic actions.