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Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+ levels, we employed the Zn2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo. Our study highlights the importance of choosing "when", "where", and "how much" in the modulation of brain Zn2+ levels. Our findings confirm the importance of targeting Zn2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+ availability upon the early stages of development.

Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia.

BackgroundThe pathogenic road map leading to Alzheimer's disease (AD) is still not completely understood; however, a large body of studies in the last few years supports the idea that beside the classic hallmarks of the disease, namely the accumulation of amyloid-β (Aβ) and neurofibrillary tangles, other factors significantly contribute to the initiation and the progression of the disease. Among them, mitochondria failure, an unbalanced neuronal redox state, and the dyshomeostasis of endogenous metals like copper, iron, and zinc have all been reported to play an important role in exacerbating AD pathology. Given these factors, the endogenous peptide carnosine may be potentially beneficial in the treatment of AD because of its free-radical scavenger and metal chelating properties.MethodologyIn this study, we explored the effect of L-carnosine supplementation in the 3xTg-AD mouse, an animal model of AD that shows both Aβ- and tau-dependent pathology.Principal FindingsWe found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits.Conclusions and SignificanceOur data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD.

Overactivation of glutamate receptors and subsequent deregulation of the intraneuronal calcium ((Ca (2+))(1)) levels are critical components of the injurious pathways initiated by cerebral ischemia. Another hallmark of stroke is parenchymal acidosis, and we have previously shown that mild acidosis can act as a switch to decrease NMDAR-dependent neuronal loss while potentiating the neuronal loss mediated by AMPARs. Potentiation of AMPAR-mediated neuronal death in an acidotic environment was originally associated only with (Ca2+), dyshomeostasis, as assessed by Ca2+ imaging; however, intracellular dyshomeostasis of another divalent cation, Zn2+, has recently emerged as another important co-factor in ischemic neuronal injury. Rises in(Zn2+)1 greatly contribute to the fluorescent changes of Ca2+-sensitive fluorescent probes, which also have great affinity for Zn2+. We therefore revisited our original findings (Mcdonald et al., 1998) and investigated if AMPAR-mediated fura-2 signals we observed could also be partially due to (Zn2+)(1) increases.Fura-2 loaded neuronal cultures were exposed to the AMPAR agonist, kainate, in a physiological buffer at pH 7.4 and then washed either at pH 7.4 or pH 6.2. A delayed recovery of fura-2 signals was observed at both pHs. Interestingly this impaired recovery phase was found to be sensitive to chelation of intracellular Zn2+. Experiments with the Zn2+ sensitive (and Ca(2+ -)insensitive) fluorescent probe FluoZin-3 confirmed the idea that AMPAR activation increases (Zn2+), a phenomenon that is potentiated by mild acidosis. Additionally, our results show that selective Ca 2+ imaging mandates the use of intracellular heavy metal chelators to avoid confounding effects of endogenous metals such as Zn2+.

Forecasting seizure risk aims to detect proictal states in which seizures would be more likely to occur. Classical seizure prediction models are trained over long‐term electroencephalographic (EEG) recordings to detect specific preictal changes for each seizure, independently of those induced by shifts in states of vigilance. A daily single measure—during a vigilance‐controlled period—to estimate the risk of upcoming seizure(s) would be more convenient. Here, we evaluated whether intracranial EEG connectivity (phase‐locking value), estimated from daily vigilance‐controlled resting‐state recordings, could allow distinguishing interictal (no seizure) from preictal (seizure within the next 24 h) states. We also assessed its relevance for daily forecasts of seizure risk using machine learning models. Connectivity in the theta band was found to provide the best prediction performances (area under the curve ≥.7 in 80% of patients), with accurate daily and prospective probabilistic forecasts (mean Brier score and Brier skill score of.13 and.72, respectively). More efficient ambulatory clinical application could be considered using mobile EEG or chronic implanted devices. [ABSTRACT FROM AUTHOR]

Abstract: Zn2+ is co-released at glutamatergic synapses throughout the central nervous system and acts as a neuromodulator for glutamatergic neurotransmission, as a key modulator of NMDA receptor functioning. Zn2+ is also implicated in the neurotoxicity associated with several models of acute brain injury and neurodegeneration. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the spinal cord and cortex. In this study, we have investigated the modulatory role exerted by Zn2+ in NMDA-mediated neurotoxicity in either near-pure or mixed cortical cultured neurons obtained from either mice over-expressing the G93A mutant form of Cu/Zn superoxide dismutase (SOD1) human gene, a gene linked to familial ALS, or wild type (WT) mice. To that aim, SOD1G93A or WT cultures were exposed to either NMDA by itself or to Zn2+ prior to a toxic challenge with NMDA, and neuronal loss evaluated 24 h later. While we failed to observe any significant difference between NMDA and Zn2+/NMDA-mediated toxicity in mixed SOD1G93A or WT cortical cultures, different vulnerability to these toxic paradigms was found in near-pure neuronal cultures. In the WT near-pure neuronal cultures, a brief exposure to sublethal concentrations of Zn2+-enhanced NMDA receptor-mediated cell death, an effect that was far more pronounced in the SOD1G93A cultures. This increased excitotoxicity in SOD1G93A near-pure neuronal cultures appears to be mediated by a significant increase in NMDA-dependent rises of intraneuronal Ca2+ levels as well as enhanced production of cytosolic reactive oxygen species, while the injurious process seems to be unrelated to activation of nNOS or ERK1/2 pathways. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’. [Copyright &y& Elsevier]

Abstract: The membrane permeant alkylating agent N-ethylmaleimide (NEM) regulates numerous biological processes by reacting with thiol groups. Among other actions, NEM influences the cytosolic concentration of free Ca2+ ([Ca2+]i). Depending on the cell type and the concentration used, NEM can promote the release of Ca2+, affect its extrusion, stimulate or block its entry. However, most of these findings were obtained in experiments that employed fluorescent Ca2+ probes and one major disadvantage of such experimental setting derives from the lack of specificity of the probes as all the so-called “Ca2+-sensitive” indicators also bind metals like Zn2+ or Mn2+ with higher affinities than Ca2+. In this study, we examined the effects of NEM on the [Ca2+]i homeostasis of murine cortical neurons. We performed live-cell Ca2+ and Zn2+ imaging experiments using the fluorescent probes Fluo-4, FluoZin-3 and RhodZin-3 and found that NEM does not affect the neuronal [Ca2+]i homeostasis but specifically increases the cytosolic and mitochondrial concentration of free Zn2+([Zn2+]i). In addition, NEM triggers some neuronal loss that is prevented by anti-oxidants such as N-acetylcysteine or glutathione. NEM-induced toxicity is dependent on changes in [Zn2+]i levels as chelation of the cation with the cell-permeable heavy metal chelator, N,N,N′N′-tetrakis(−)[2-pyridylmethyl]-ethylenediamine (TPEN), promotes neuroprotection of cortical neurons exposed to NEM. Our data indicate that NEM affects [Zn2+]i but not [Ca2+]i homeostasis and shed new light on the physiological actions of this alkylating agent on central nervous system neurons. [Copyright &y& Elsevier]