Effect of diethyldithiocarbamate (DEDTC) on sulphide silver stained boutons reversible blocking of Timm's sulphide silver stain for “heavy” metals in DEDTC treated rats (Light Microscopy)

Danscher, Gorm; Haug, Finn‐Mogens Šmejda; Fredens, Kjeld

doi:10.1007/bf00234478

Cited by 91 publications

(35 citation statements)

References 34 publications

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“…Previous studies have shown that Zn 2 þ translocation is strongly associated with neuronal injury after TBI (Suh et al, 2000a). Although the presence of chelatable Zn 2 þ in brain has been recognized for decades (Timm, 1958;(Danscher et al, 1973(Danscher et al, , 1975Haug, 1975), the potential role of Zn 2 þ in excitotoxic injury has only been appreciated for slightly more than a decade (Frederickson et al, 1988). Zinc-containing neurons are most densely present in brain regions that are highly vulnerable to ischemic and traumatic damage, that is, in the neocortex, hippocampus and the amygdaloid nuclei.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…To ensure that the NeoTimm method demonstrates only zinc ions, the amount of sodium sulfide molecules has to match the amount of zinc ions in the tissues. The right amount has been defined as the highest level of sulfide ions that does not cause staining of sections from an animal exposed to 1000 mg/kg body weight of the zinc chelator diethyldithiocarbamate (DEDTC) 1 hr before perfusion (Danscher et al 1973;Danscher 1981). In vivo chelation with the red chelator dithizone likewise results in a lack of Timm staining (Danscher et al 1985b).…”

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confidence: 99%

Zinc-specific Autometallographic In Vivo Selenium Methods: Tracing of Zinc-enriched (ZEN) Terminals, ZEN Pathways, and Pools of Zinc Ions in a Multitude of Other ZEN Cells

Danscher

Stoltenberg

2005

J Histochem Cytochem.

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106

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S U M M A R YIn vivo-applied sodium selenide or sodium selenite causes the appearance of zinc-selenium nanocrystals in places where free or loosely bound zinc ions are present. These nanocrystals can in turn be silver enhanced by autometallographic (AMG) development. The selenium method was introduced in 1982 as a tool for zinc-ion tracing, e.g., in vesicular compartments such as synaptic vesicles of zinc-enriched (ZEN) terminals in the central nervous system, and for visualization of zinc ions in ZEN secretory vesicles of, e.g., somatotrophic cells in the pituitary, zymogene granules in pancreatic acinar cells, beta-cells of the islets of Langerhans, Paneth cells of the crypts of Lieberkühn, secretory cells of the tubuloacinar glands of prostate, epithelium of parts of ductus epididymidis, and osteoblasts. If sodium selenide/selenite is injected into brain, spinal cord, spinal nerves containing sympathetic axons, or intraperitoneally, retrograde axonal transport of zinc-selenium nanocrystals takes place in ZEN neurons, resulting in accumulation of zinc-selenium nanocrystals in lysosomes of the neuronal somata. The technique is, therefore, also a highly specific tool for tracing ZEN pathways. The present review includes an update of the 1982 paper and presents evidence that only zinc ions are traced with the AMG selenium techniques if the protocols are followed to the letter. T he presence of zinc ions in a subpopulation of synaptic vesicles of a rather numerous group of glutaminergic neurons in the brain and GABAergic, glutaminergic, and possibly glycinergic neurons in the spinal cord and cerebellum, the so-called zinc-enriched (ZEN) neurons, is well established (Slomianka 1992;

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“…1 DEDTC is the active metabolite of disulfiram (Antabus), a drug used in the treatment of alcoholism (45). Disulfiram and DEDTC have complex biochemical effects (34). In the present context it is of interest that DEDTC is a chelating agent (34).…”

Section: Resultsmentioning

confidence: 97%

“…Disulfiram and DEDTC have complex biochemical effects (34). In the present context it is of interest that DEDTC is a chelating agent (34). Moreover, it has been shown that DEDTC in vivo can inactivate the copper enzyme dopamine /8-hydroxylase, which converts dopamine to noradrenaline (46).…”

Section: Resultsmentioning

confidence: 99%

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Modulation of cholecystokinin concentrations in the rat hippocampus by chelation of heavy metals.

Stengaard‐Pedersen¹,

Larsson²,

Fredens³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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Previously, we have reported that enkephalins, cholecystokinin, and heavy metals show roughly parallel distributional patterns in the hippocampus. A substantial body of evidence indicates that cholecystokinin-octapeptide (CCK-8) and enkephalins act as neurotransmnitters. A CCK-8 degrading enzyme was recently detected in brain synaptosomes. Its activity depended on free thiol groups and the presence of a heavy metal. Since the heavy metal-containing neuropil is closely related to CCK-immunoreactive nerve terminals, we have investigated the effect of metal chelation on CCK conmponents in the rat hippocampus. In vivo treatment of rats with a single dose of the chelating agent diethyldithiocarbamate caused a reversible chelation of heavy metals in the hippocampus. This effect was paralleled by a 3-fold increase in hippocampal content of CCK-8 and a smaller increase in the intermediate forms of CCK (CCK-58, CCK-39, CCK-33). Diethyldithiocarbamate also decreased the spontaneous motility and aggressiveness of the rats. These data show reversible changes of neuronal CCK processing by a drug, and hence they provide additional evidence that CCK is involved in the regulation of neuronal activities.Heavy metals occur in distinct layers of the rat hippocampus, associated with the terminal fields of certain neuronal systems, including the mossy fibers (1, 2). In the mossy fibers, there is ample evidence that most of the detectable metal is zinc (3, 4), which is located in the mossy fiber boutons (5, 6). Otherwise, the exact localization of specific metals is unknown (7).The role of zinc and other heavy metals in specific nerve terminals of the hippocampus is unknown. Recently, we have shown that both enkephalin-like molecules and heavy metals (mainly zinc) occur in the mossy fibers of rodents (8, 9). Subsequently, we have shown that zinc and other metal ions can down-regulate the binding capacity of opioid receptors (10, 11). These observations, together with the fact that endogenous opioid peptides excite hippocampal pyramidal cells via binding to opioid receptors (12), indicate that zinc, and possibly other neuronal metals, may regulate the binding capacity of opioid receptors (10, 11). The close relationship between enkephalin and zinc in the mossy fiber system may reflect that zinc is a cofactor for the recently discovered enkephalin degrading enzyme "enkephalinase" (13)(14)(15)(16).Also, cholecystokinin (CCK) nerve terminals occur closely associated with the heavy metal-containing neuropil in the rat hippocampus (8, 17). Thus, CCK immunoreactivity is located in the terminal areas of the medial perforant path and the temporo-ammonic tracts from the medial entorhinal cortex, as well as in the terminal area of the commissural-associational path of area dentata. CCK-containing cell bodies occur in all layers of the rat hippocampus, but'mostly in the stratum pyramidale, the mossy fiber zone, and the stratum radiatum (8, 17). The COOH-terminal octapeptide of 'CCK (CCK-8) appears to be a putative transmitter (18-30) wi...

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Effect of diethyldithiocarbamate (DEDTC) on sulphide silver stained boutons reversible blocking of Timm's sulphide silver stain for “heavy” metals in DEDTC treated rats (Light Microscopy)

Cited by 91 publications

References 34 publications

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

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

Zinc-specific Autometallographic In Vivo Selenium Methods: Tracing of Zinc-enriched (ZEN) Terminals, ZEN Pathways, and Pools of Zinc Ions in a Multitude of Other ZEN Cells

Modulation of cholecystokinin concentrations in the rat hippocampus by chelation of heavy metals.

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