Neurosignals 

About: Neurosignals is an academic journal published by Karger Publishers. The journal publishes majorly in the area(s): Melatonin & Signal transduction. It has an ISSN identifier of 1424-862X. It is also open access. Over the lifetime, 600 publications have been published receiving 23635 citations. The journal is also known as: Neuro-Signals & Neurosignals.

Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity

Abstract: Microglial-neuronal interactions are essential for brain physiopathology. In this framework, recent data have changed the concept of microglia from essentially macrophagic cells to crucial elements in maintaining neuronal homeostasis and function through the release of neuroprotective molecules. Using proteomic analysis, here we identify copper-zinc superoxide dismutase (SOD1) as a protein produced and released by cultured rat primary microglia. Evidence for a neuroprotective role of microglia-derived SOD1 resulted from experiments in which primary cerebellar granule neurons (CGNs) were exposed to the dopaminergic toxin 6-hydroxydopamine (6-OHDA). Microglial conditioned medium, in which SOD1 had accumulated, protected CGNs from degeneration, and neuroprotection was abrogated by SOD1 inhibitors. These effects were replicated when exogenous SOD1 was added to a nonconditioned medium. SOD1 neuroprotective action was mediated by increased cell calcium from an external source. Further experiments demonstrated the specificity of SOD1 neuroprotection against 6-OHDA compared to other types of neurotoxic challenges. SOD1, constitutively produced and released by microglia through a lysosomal secretory pathway, is identified here for the first time as an essential component of neuroprotection mediated by microglia. This novel information is relevant to stimulating further studies of microglia-mediated neuroprotection in in vivo models of neurodegenerative diseases.

Significance of melatonin in antioxidative defense system: reactions and products.

Abstract: Melatonin is a potent endogenous free radical scavenger, actions that are independent of its many receptor-mediated effects In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant Melatonin has been reported to scavenge hydrogen peroxide (H2O2), hydroxyl radical (HO·), nitric oxide (NO·), peroxynitrite anion (ONOO–), hypochlorous acid (HOCl), singlet oxygen (1O2), superoxide anion (O2–·) and peroxyl radical (LOO·), although the validity of its ability to scavenge O2–· and LOO· is debatable Regardless of the radicals scavenged, melatonin prevents oxidative damage at the level of cells, tissues, organs and organisms The antioxidative mechanisms of melatonin seem different from classical antioxidants such as vitamin C, vitamin E and glutathione As electron donors, classical antioxidants undergo redox cycling; thus, they have the potential to promote oxidation as well as prevent it Melatonin, as an electron-rich molecule, may interact with free radicals via an additive reaction to form several stable end-products which are excreted in the urine Melatonin does not undergo redox cycling and, thus, does not promote oxidation as shown under a variety of experimental conditions From this point of view, melatonin can be considered a suicidal or terminal antioxidant which distinguishes it from the opportunistic antioxidants Interestingly, the ability of melatonin to scavenge free radicals is not in a ratio of mole to mole Indeed, one melatonin molecule scavenges two HO· Also, its secondary and tertiary metabolites, for example, N1-acetyl-N2-formyl-5-methoxykynuramine, N-acetyl-5-methoxykynuramine and 6-hydroxymelatonin, which are believed to be generated when melatonin interacts with free radicals, are also regarded as effective free radical scavengers The continuous free radical scavenging potential of the original molecule (melatonin) and its metabolites may be defined as a scavenging cascade reaction Melatonin also synergizes with vitamin C, vitamin E and glutathione in the scavenging of free radicals Melatonin has been detected in vegetables, fruits and a variety of herbs In some plants, especially in flowers and seeds (the reproductive organs which are most vulnerable to oxidative insults), melatonin concentrations are several orders of magnitude higher than measured in the blood of vertebrates Melatonin in plants not only provides an alternative exogenous source of melatonin for herbivores but also suggests that melatonin may be an important antioxidant in plants which protects them from a hostile environment that includes extreme heat, cold and pollution, all of which generate free radicals

Curcumin requires tumor necrosis factor α signaling to alleviate cognitive impairment elicited by lipopolysaccharide.

Abstract: A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

Anorexigenic and Orexigenic Hormone Modulation of Mammalian Target of Rapamycin Complex 1 Activity and the Regulation of Hypothalamic Agouti-Related Protein mRNA Expression

Abstract: Activation of mammalian target of rapamycin 1 (mTORC1) by nutrients, insulin and leptin leads to appetite suppression (anorexia). Contrastingly, increased AMP-activated protein kinase (AMPK) activity by ghrelin promotes appetite (orexia). However, the interplay between these mechanisms remains poorly defined. The relationship between the anorexigenic hormones, insulin and leptin, and the orexigenic hormone, ghrelin, on mTORC1 signalling was examined using S6 kinase phosphorylation as a marker for changes in mTORC1 activity in mouse hypothalamic GT1-7 cells. Additionally, the contribution of AMPK and mTORC1 signalling in relation to insulin-, leptin- and ghrelin-driven alterations to mouse hypothalamic agouti-related protein (AgRP) mRNA levels was examined. Insulin and leptin increase mTORC1 activity in a phosphoinositide-3-kinase (PI3K)- and protein kinase B (PKB)-dependent manner, compared to vehicle controls, whereas increasing AMPK activity inhibits mTORC1 activity and blocks the actions of the anorexigenic hormones. Ghrelin mediates an AMPK-dependent decrease in mTORC1 activity and increases hypothalamic AgRP mRNA levels, the latter effect being prevented by insulin in an mTORC1-dependent manner. In conclusion, mTORC1 acts as an integration node in hypothalamic neurons for hormone-derived PI3K and AMPK signalling and mediates at least part of the assimilated output of anorexigenic and orexigenic hormone actions in the hypothalamus.

Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson's disease.

Abstract: Excessive misfolded proteins and/or dysfunctional mitochondria, which may cause energy deficiency, have been implicated in the etiopathogenesis of Parkinson's disease (PD). Enhanced clearance of misfolded proteins or injured mitochondria via autophagy has been reported to have neuroprotective roles in PD models. The fact that resveratrol is a known compound with multiple beneficial effects similar to those associated with energy metabolism led us to explore whether neuroprotective effects of resveratrol are related to its role in autophagy regulation. We tested whether modulation of mammalian silent information regulator 2 (SIRT1) and/or metabolic energy sensor AMP-activated protein kinase (AMPK) are involved in autophagy induction by resveratrol, leading to neuronal survival. Our results showed that resveratrol protected against rotenone-induced apoptosis in SH-SY5Y cells and enhanced degradation of α-synucleins in α-synuclein-expressing PC12 cell lines via autophagy induction. We found that suppression of AMPK and/or SIRT1 caused decrease of protein level of LC3-II, indicating that AMPK and/or SIRT1 are required in resveratrol-mediated autophagy induction. Moreover, suppression of AMPK caused inhibition of SIRT1 activity and attenuated protective effects of resveratrol on rotenone-induced apoptosis, further suggesting that AMPK-SIRT1-autophagy pathway plays an important role in the neuroprotection by resveratrol on PD cellular models.