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.
Highlights
Zinc is found in every cell of our body and is required for processes as diverse as gene expression, DNA synthesis, enzymatic catalysis, hormonal storage, tissue repair, neurotransmission and memory [1,2]
Cell Death/FluoroJade B Neurons Neuronal counting of FJB positive neurons and statistical analysis show that the zinc transporter 3 protein (ZnT3)-KO mice have significantly more dead or dying neurons evaluated after 24 hours after Traumatic brain injury (TBI) (Figure 1E, F)
The finding that TBI exposed neurons of ZnT3-KO mice accumulate zinc ions in their somata and reveal significantly more damaged neurons by the FluoroJade B staining suggests that zinc ions, in complete contrast to what has been suggested until now, have protective qualities to the TBI aftermath
Summary
Zinc is found in every cell of our body and is required for processes as diverse as gene expression, DNA synthesis, enzymatic catalysis, hormonal storage, tissue repair, neurotransmission and memory [1,2]. In 1996 it was suggested that the zinc transporter 3 protein (ZnT3) was responsible for transport of zinc ions into the synaptic vesicles of the ZEN terminals [22]. ZnT3-KO mice lack the ZnT3 protein and these animals are completely void of zinc ions in their ZEN terminals This finding is supported by the fact that the total zinc levels in the hippocampus and the neocortex have been reported to be reduced by 20% [23,25]. In harmony with former observations based on a temporary chemical binding of the vesicular zinc pool [26,27] or a reduced level of vesicular zinc following an adrenally induced loss of zinc ions [28] no major physiological and behavioural changes were found in studies comparing the ZnT3 mouse to the WT littermate. The present study aims at scrutinizing this hypothesis using ZnT3-KO mice and WT controls, i.e. mice with and without vesicular zinc
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