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

Abstract

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.

Zinc in the central nervous system: From molecules to behavior

“…Neuronal damage in these mice appeared almost identical to that observed in ZnT3 KO mice, a transgenic model in which free vesicular brain zinc is eliminated. These data imply that declines in free zinc during the first 24 h post-TBI are more damaging than excess levels of free zinc that have been observed in areas surrounding acute brain injury [71]. This observation has been confirmed in an in vitro model by Li et al [72].…”

ZnT3: a zinc transporter active in several organs

“…By contrast, specific knock-down of Znt3 in INS-1E by siRNA transfection leads to an increase in apoptosis as measured by DNA fragmentation (Petersen et al 2011). A possible protecting role of ZnT3 is demonstrated in mice exposed to a traumatic brain injury where Znt3 knock-out mice appear more vulnerable and reveal a significant higher number of apoptotic neurones compared to control mice (Doering et al 2010). …”

Vitamins and nutrients as primary treatments in experimental brain injury: Clinical implications for nutraceutical therapies

“…This free zinc then interferes with cell processes via oxidative mechanisms, mitochondrial interference and MAPK-related cell death pathways [109]. Because of this, removal of excess zinc, via chelation or targeted chemicals has been evaluated across several studies with a mixture of beneficial [62,178], null [29,60] and detrimental results [42]. …”