Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury

Hellmich, Helen L.; Eidson, Kristine A.; Cowart, Jeremy; Crookshanks, Jeanna M.; Boone, Deborah Kennedy; Shah, Syed Qaiser; Uchida, Tatsuo; DeWitt, Douglas S.; Prough, Donald S.

doi:10.1016/j.neulet.2008.05.068

Cited by 24 publications

(20 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other studies have implied that vesicular zinc 1) is not the causative agent of neuronal damage [29], [47], [48], 2) that it excerpts a protective effect [49], and 3) that zinc chelation provides a short-term neuroprotection (evaluated histologically), but fails to improve long-term functional outcome [50].…”

Section: Discussionmentioning

confidence: 99%

Chemical Blocking of Zinc Ions in CNS Increases Neuronal Damage Following Traumatic Brain Injury (TBI) in Mice

et al. 2010

View full text Add to dashboard Cite

BackgroundTraumatic brain injury (TBI) is one of the leading causes of disability and death among young people. Although much is already known about secondary brain damage the full range of brain tissue responses to TBI remains to be elucidated. A population of neurons located in cerebral areas associated with higher cognitive functions harbours a vesicular zinc pool co-localized with glutamate. This zinc enriched pool of synaptic vesicles has been hypothesized to take part in the injurious signalling cascade that follows pathological conditions such as seizures, ischemia and traumatic brain injury. Pathological release of excess zinc ions from pre-synaptic vesicles has been suggested to mediate cell damage/death to postsynaptic neurons.Methodology/Principal FindingsIn order to substantiate the influence of vesicular zinc ions on TBI, we designed a study in which damage and zinc movements were analysed in several different ways. Twenty-four hours after TBI ZnT3-KO mice (mice without vesicular zinc) were compared to littermate Wild Type (WT) mice (mice with vesicular zinc) with regard to histopathology. Furthermore, in order to evaluate a possible neuro-protective dimension of chemical blocking of vesicular zinc, we treated lesioned mice with either DEDTC or selenite. Our study revealed that chemical blocking of vesicular zinc ions, either by chelation with DEDTC or accumulation in zinc-selenium nanocrystals, worsened the effects on the aftermath of TBI in the WT mice by increasing the number of necrotic and apoptotic cells within the first 24 hours after TBI, when compared to those of chemically untreated WT mice.Conclusion/SignificanceZnT3-KO mice revealed more damage after TBI compared to WT controls. Following treatment with DEDTC or selenium an increase in the number of both dead and apoptotic cells were seen in the controls within the first 24 hours after TBI while the degree of damage in the ZnT3-KO mice remained largely unchanged. Further analyses revealed that the damage development in the two mouse strains was almost identical after either zinc chelation or zinc complexion therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Chemical Blocking of Zinc Ions in CNS Increases Neuronal Damage Following Traumatic Brain Injury (TBI) in Mice

et al. 2010

View full text Add to dashboard Cite

show abstract

“…18 Furthermore, published reports show that zinc chelation did not result in improved spatial learning in injured rats. 19 …”

Section: Discussionmentioning

confidence: 99%

Use of Zinc as a Treatment for Traumatic Brain Injury in the Rat

Cope

Morris

Scrimgeour

et al. 2012

Neurorehabil Neural Repair

View full text Add to dashboard Cite

Background While treatments for the behavioral deficits associated with traumatic brain injury (TBI) are currently limited, animal models suggest that zinc supplementation may increase resilience to TBI. Objective This work tests the hypothesis that zinc supplementation after TBI can be used as treatment to improve behavioral outcomes such as anxiety, depression, and learning and memory. Methods TBI was induced by controlled cortical impact to the medial frontal cortex. After TBI, rats were fed either a zinc adequate (ZA, 30 ppm) or zinc supplemented (ZS, 180 ppm) diet. Additional rats in each dietary group (ZA or ZS) were given a single intraperitoneal (ip) injection of zinc (30 mg/kg) 1 hour following injury. Results Brain injury resulted in significant increases in anxiety-like and depression-like behaviors as well as impairments in learning and memory. None of the zinc treatments (dietary or ip zinc) improved TBI-induced anxiety. The 2-bottle saccharin preference test for anhedonia revealed that dietary ZS also did not improve depression-like behaviors. However, dietary ZS combined with an early ip zinc injection significantly reduced anhedonia (P < .001). Dietary supplementation after injury, but not zinc injection, significantly improved (P < .05) cognitive behavior as measured by the time spent finding the hidden platform in the Morris water maze test compared with injured rats fed a ZA diet. Conclusions These data suggest that zinc supplementation may be an effective treatment option for improving behavioral deficits such as cognitive impairment and depression following TBI.

show abstract

“…Previous investigations demonstrated changes in gene expression after traumatic injury (Dash et al, 2004;Hayes et al, 1995;Hellmich et al, 2005Hellmich et al, ,2008Shimamura et al, 2004Shimamura et al, ,2005. Mechanical injury (Morrison et al, 2000) or other types of trauma, including ischemia or seizures, can lead to disruption of calcium homeostasis that can produce alterations in gene expression (Bazan et al, 1995;West et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Cerebrovascular Connexin Expression: Effects of Traumatic Brain Injury

Avila

Sell

Hawkins

et al. 2011

Journal of Neurotrauma

Self Cite

View full text Add to dashboard Cite

Traumatic brain injury (TBI) results in dysfunction of the cerebrovasculature. Gap junctions coordinate vasomotor responses and evidence suggests that they are involved in cerebrovascular dysfunction after TBI. Gap junctions are comprised of connexin proteins (Cxs), of which Cx37, Cx40, Cx43, and Cx45 are expressed in vascular tissue. This study tests the hypothesis that TBI alters Cx mRNA and protein expression in cerebral vascular smooth muscle and endothelial cells. Anesthetized (1.5% isoflurane) male Sprague-Dawley rats received sham or fluid-percussion TBI. Two, 6, and 24 h after, cerebral arteries were harvested, fresh-frozen for RNA isolation, or homogenized for Western blot analysis. Cerebral vascular endothelial and smooth muscle cells were selected from frozen sections using laser capture microdissection. RNA was quantified by ribonuclease protection assay. The mRNA for all four Cx genes showed greater expression in the smooth muscle layer compared to the endothelial layer. Smooth muscle Cx43 mRNA expression was reduced 2 h and endothelial Cx45 mRNA expression was reduced 24 h after injury. Western blot analysis revealed that Cx40 protein expression increased, while Cx45 protein expression decreased 24 h after injury. These studies revealed significant changes in the mRNA and protein expression of specific vascular Cxs after TBI. This is the first demonstration of cell type-related differential expression of Cx mRNA in cerebral arteries, and is a first step in evaluating the effects of TBI on gap junction communication in the cerebrovasculature.

show abstract

Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury

Cited by 24 publications

References 36 publications

Chemical Blocking of Zinc Ions in CNS Increases Neuronal Damage Following Traumatic Brain Injury (TBI) in Mice

Chemical Blocking of Zinc Ions in CNS Increases Neuronal Damage Following Traumatic Brain Injury (TBI) in Mice

Use of Zinc as a Treatment for Traumatic Brain Injury in the Rat

Cerebrovascular Connexin Expression: Effects of Traumatic Brain Injury

Contact Info

Product

Resources

About