Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury

Suh, Sang Won; Chen, Jefferson; Motamedi, Massoud; Bell, Brent A.; Listiak, Kathy; Pons, Neus F.; Danscher, Gorm; Frederickson, Christopher J.

doi:10.1016/s0006-8993(99)02095-8

Cited by 272 publications

(195 citation statements)

References 38 publications

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“…Upon stimulation, vesicular zinc ions are released (Assaf and Chung 1984;Charton et al 1985;Aniksztejn et al 1987) and may enter the postsynaptic neurons via ionotropic glutamate receptors and calcium channels (Sensi et al 1997;Choi and Koh 1998;Weiss and Sensi 2000). This translocation of chelatable zinc ions from presynaptic terminals to postsynaptic neurons has been proposed to play an important role in the selective neuronal death resulting from ischemia, status epilepticus and trauma Tonder et al 1990;Koh et al 1996;Suh et al 2000; except for Cole et al 2000). Consistent with our in vitro observation that zinc ions promote the assembly of the PSD, after transient cerebral ischemia, a condition that lead to the accumulation of chelatable zinc in neurons (Tonder et al 1990;Koh et al 1996), the PSDs of hippocampal neurons became significantly thicker (Hu et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Structural role of zinc ions bound to postsynaptic densities

Jan

Chen

Tsai

et al. 2002

Journal of Neurochemistry

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Postsynaptic densities (PSDs) isolated from porcine cerebral cortices are large aggregates consisting of more than 30 different proteins. Inductively coupled plasma-mass spectrometric analyses revealed that isolated PSDs contained zinc at a concentration of 4.1 nmol per mg protein. Treatment with 8 M urea lead to dissociation of the PSDs into small components and, concomitantly, depletion of most of their bound zinc. After removal of the urea by dialysis, urea-dissociated PSD proteins did not reassemble into aggregates by themselves. Adding ZnCl 2 to urea-treated PSD samples resulted in the assembly of urea-dissociated proteins into large aggregates with morphology and protein composition closely resembling those of the original PSDs. Mg 2+ , Ca 2+ , Co 2+ , Cd 2+ , Cu 2+ , Mn 2+ , Fe 3+ , K + and Na + ions at higher concentrations also induced the aggregation of urea-dissociated PSD protein. The structures of the K + -, Na + -, Mg 2+ -and Ca 2+ -induced aggregates were distinct from that of the original PSDs. Our results indicate that the structure of the PSD could be disassembled and reassembled under in vitro conditions. They further suggest that Zn 2+ ions, by binding to certain zincbinding proteins, play an important role in the formation and maintenance of the structure of the PSD.

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Section: Discussionmentioning

confidence: 99%

Structural role of zinc ions bound to postsynaptic densities

Jan

Chen

Tsai

et al. 2002

Journal of Neurochemistry

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“…130,136 Treatment with zinc chelators has been shown to reduce neuronal death in animal models of cerebral ischemia, trauma, hypoglycemia, and neurodegenerative disorders. [137][138][139][140][141][142] These effects may be due in part to suppression of zinc-mediated microglial activation. Zinc has been shown to induce activation of microglia in culture and in brain, and injection of the zinc chelator CaEDTA prevents ischemia-induced microglial activation.…”

Section: Zincmentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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“…The scalp and temporalis muscles were reflected and a 3.0 mm diameter burr hole was drilled through the skull 3.0 mm lateral to the midline and 4.0 mm caudal to bregma. Traumatic brain injury was performed using a weight drop model (Clark et al, 1994;Suh et al, 2000a). With this method, brief displacement and deformation of brain is induced by dropping a weight through a guide tube such that the weight hits a blunt steel impactor resting on the dura.…”

Section: Weight Drop Traumatic Brain Injurymentioning

confidence: 99%

“…N-(6-Methoxy-8-Quinolyl)-Para-Toluenesulfonamide Fluorescence for Zinc Staining Temperature-dependent Zn 2 þ translocation was assessed in 10 mm sections that were stained with TSQ. Staining was performed as previously described (Frederickson et al, 1987;Suh et al, 2000a). Briefly, the frozen, unfixed brains were sectioned coronally in a À141C cryostat, thawed on gelatin-coated slides and dried by gentle air flow.…”

Section: Autometallographic Zinc Stainingmentioning

confidence: 99%

“…Evidence implicating Zn 2 þ as an important contributing cause of excitotoxic neuronal injury has accumulated over the last 15 years (Frederickson et al, 1989;Koh et al, 1996;Suh et al, 2000aSuh et al, , 2004Tonder et al, 1990). These data raise the possibility that the release of, and postsynaptic accumulation of, toxic amounts of Zn 2 þ might also be strongly temperature-dependent, thus contributing to the overall temperature sensitivity of the excitotoxic process (Suh et al, 2000b;Tsuchiya et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Neurotoxic Zinc Translocation into Hippocampal Neurons is Inhibited by Hypothermia and is Aggravated by Hyperthermia after Traumatic Brain Injury in Rats

Suh

Frederickson

Danscher

2005

J Cereb Blood Flow Metab

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Hypothermia reduces excitotoxic neuronal damage after seizures, cerebral ischemia and traumatic brain injury (TBI), while hyperthermia exacerbates damage from these insults. Presynaptic release of ionic zinc (Zn 2 þ ), translocation and accumulation of Zn 2 þ ions in postsynaptic neurons are important mechanisms of excitotoxic neuronal injury. We hypothesized that temperature-dependent modulation of excitotoxicity is mediated in part by temperature-dependent changes in the synaptic release and translocation of Zn 2 þ . In the present studies, we used autometallographic (AMG) and fluorescent imaging of N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining to quantify the influence of temperature on translocation of Zn 2 þ into hippocampal neurons in adult rats after weight drop-induced TBI. The central finding was that TBI-induced Zn 2 þ translocation is strongly influenced by brain temperature. Vesicular Zn 2 þ release was detected by AMG staining 1 h after TBI. At 301C, hippocampus showed almost no evidence of vesicular Zn 2 þ release from presynaptic terminals; at 36.51C, the hippocampus showed around 20% to 30% presynaptic vesicular Zn 2 þ release; and at 391C vesicular Zn 2 þ release was significantly greater (40% to 60%) than at 36.51C. At 6 h after TBI, intracellular Zn 2 þ accumulation was detected by the TSQ staining method, which showed that Zn 2 þ translocation also paralleled the vesicular Zn 2 þ release. Neuronal injury, assessed by counting eosinophilic neurons, also paralleled the translocation of Zn 2 þ , being minimal at 301C and maximal at 391C. We conclude that pathological Zn 2 þ translocation in brain after TBI is temperature-dependent and that hypothermic neuronal protection might be mediated in part by reduced Zn 2 þ translocation.

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Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury

Cited by 272 publications

References 38 publications

Structural role of zinc ions bound to postsynaptic densities

Structural role of zinc ions bound to postsynaptic densities

Microglial Activation in Stroke: Therapeutic Targets

Neurotoxic Zinc Translocation into Hippocampal Neurons is Inhibited by Hypothermia and is Aggravated by Hyperthermia after Traumatic Brain Injury in Rats

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