Is zinc the link between compromises of brain perfusion (excitotoxicity) and Alzheimer's disease? (original) (raw)
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Zinc and Excitotoxic Brain Injury: A New Model
2004
It has been nearly 15 years since the suggestion that synaptically released Zn2+ might contribute to excitotoxic brain injury after seizures, stroke, and brain trauma. In the original "zinc-translocation" model, it was proposed that synaptically released Zn2+ ions penetrated postsynaptic neurons, causing injury. According to the model, chelating zinc in the cleft was predicted to be neuroprotective. This proved to be true: zinc chelators have proved to be remarkably potent at reducing excitotoxic neuronal injury in many paradigms. Promising new zinc-based therapies for stroke, head trauma, and epileptic brain injury are under development. However, new evidence suggests that the original translocation model was incomplete. As many as three sources of toxic zinc ions may contribute to excitotoxicity: presynaptic vesicles, postsynaptic zinc-sequestering proteins, and (more speculatively) mitochondrial pools. The authors present a new model of zinc currents and zinc toxicity that offers expanded opportunities for zinc-selective therapeutic chelation interventions.
Zinc: new clues to diverse roles in brain ischemia
Trends in Pharmacological Sciences, 2011
Cerebral ischemia is a leading cause of morbidity and mortality, reflecting the extraordinary sensitivity of the brain to a brief loss of blood flow. A significant goal has been to identify neuronal injury pathways that are selectively activated following stroke and may be amenable to drug therapy. An important advance was made close to a quarter century ago, when Ca 2+ overload was implicated as a critical link between glutamate excitotoxicity and ischemic neurodegeneration. However, early hope for effective therapies faded to frustration, as glutamate-targetted trials repeatedly failed to demonstrate efficacy in humans. In a review in 2000 in this journal, we described new evidence linking a related cation, zinc (Zn 2+), to neuronal injury, emphasizing sources and mechanisms of Zn 2+ toxicity. The current review highlights progress over the last decade, emphasizing mechanisms through which Zn 2+ ions, from multiple sources, participate together with Ca 2+ in different stages of ischemic injury cascades.
The role of zinc in cerebral ischemia
Molecular medicine (Cambridge, Mass.)
Ischemic stroke is one of the most pervasive life-threatening neurological conditions for which there currently exists limited therapeutic intervention beyond prevention. As calcium-focused neuroprotective strategies have met with limited clinical success, it is imperative that alternative therapeutic targets be considered in the attempt to antagonize ischemic-mediated injury. As such, zinc, which is able to function both as a signaling mediator and neurotoxin, has been implicated in cerebral ischemia. While zinc was first purported to have a role in cerebral ischemia nearly twenty years ago, our understanding of how zinc mediates ischemic injury is still in its relative infancy. Within this review, we examine some of the studies by which zinc has exerted either neuroprotective or neurotoxic effects during global and focal cerebral ischemia.
Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model
Journal of Immunology Research, 2016
Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p.) for 14 days before common carotid artery occlusion (CCAO) in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and...
Effect of zinc in ischemic brain injury in an embolic model of stroke in rats
Neuroscience Letters, 2004
Zinc is prevalent in the mammalian central nervous system and its role in ischemic brain injury is still controversial. In the present study, the effect of zinc in ischemic brain injury was examined in an embolic model of stroke in rats. Furthermore, the effect of zinc in combination with bicuculline, a GABAa antagonist, was also examined in the ischemic injury. Treatment with zinc or zinc plus bicuculline increased infarct volume significantly and also worsened neurological deficits. Moreover, treatment with zinc plus bicuculline also enhanced ischemic brain edema. These results thus support the hypothesis that administration of zinc i.p. worsens the outcome of ischemic brain injury in the embolic model of stroke in rats. q
Neuroscience Letters, 2008
Increases of synaptically released zinc and intracellular accumulation of zinc in hippocampal neurons after traumatic or ischemic brain injury is neurotoxic and chelation of zinc has been shown to reduce neurodegeneration. Although our previous studies showed that zinc chelation in traumatically braininjured rats correlated with an increase in whole-brain expression of several neuroprotective genes and reduced numbers of apoptotic neurons, the effect on functional outcome has not been determined, and the question of whether this treatment may actually be clinically relevant has not been answered. In the present study, we show that treatment of TBI rats with the zinc chelator calcium EDTA reduces the numbers of injured, Fluoro-Jade-positive neurons in the rat hippocampus 24 hours after injury but does not improve neurobehavioral outcome (spatial memory deficits) two weeks post-injury. Our data suggest that zinc chelation, despite providing short-term histological neuroprotection, fails to improve long-term functional outcome, perhaps because long-term disruptions in homeostatic levels of zinc adversely influence hippocampus-dependent spatial memory.
Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury
Brain Research, 2000
Prior evidence indicates that synaptically-released zinc enters postsynaptic neurons in toxic excess during ischemia and seizures. In addition, prevention of this zinc translocation has been shown to be neuroprotective in both ischemia and seizures. Here we show evidence that the same translocation of zinc from presynaptic boutons into postsynaptic neurons occurs after mechanical injury to the Ž . brain. Specifically, using a rat model of traumatic brain injury, we show that trauma is associated with i loss of zinc from presynaptic Ž . Ž . boutons ii appearance of zinc in injured neurons, and iii neuroprotection by intraventricular administration of a zinc chelator just prior to brain impact. The possible use of zinc chelators for neuroprotection after head trauma is considered. q
Is the zinc neuroprotective effect caused by prevention of intracellular zinc accumulation?
Advances in clinical and experimental medicine : official organ Wroclaw Medical University
Zinc plays an important role in the functioning of all cells, including neurons. The precise mechanisms responsible for its neurotoxic and neuroprotective effects remain unclear despite extensive investigations. Similar Zn(+2) effects can also be observed in cells outside the nervous system, and their lower sensitivity to hypoxia prolongs the cytotoxic effect of excess zinc. The evident dualism of zinc's effects depends primarily on the energetic state of the particular cell and the efficacy of ion pumps; on genetically conditioned mechanisms regulating Zn efflux from cells and Zn sequestration inside the cell; and on the concentration of extracellular free Zn.
Zinc contributes to acute cerebral ischemia-induced blood-brain barrier disruption
Neurobiology of disease, 2016
Zinc ions are stored in synaptic vesicles and cerebral ischemia triggers their release from the terminals of neurons. Zinc accumulation in neurons has been shown to play an important role in neuronal death following ischemia. However, almost nothing is known about whether zinc is involved in ischemia-induced blood-brain barrier (BBB) disruption. Herein, we investigated the contribution of zinc to ischemia-induced acute BBB disruption and the possible molecular mechanisms using both cellular and animal models of cerebral ischemia. Zinc greatly increased BBB permeability and exacerbated the loss of tight junction proteins (Occludin and Claudin-5) in the endothelial monolayer under oxygen glucose deprivation conditions. In cerebral ischemic rats, a dramatically elevated level of zinc accumulation in microvessels themselves was observed in isolated microvessels and in situ, showing the direct interaction of zinc on ischemic microvessels. Treatment with a specific zinc chelator N,N,N'...