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Since there were no significant differences between the injured and uninjured sides of the hippocampus or the cortex, data were pooled, and a comparison was made between sham-treated rats and rats that received TBI. Both sham and moderate parasagittal fluid percussion caused an overall decrease in total MT + T levels ( Figure 7 ). At 30 minutes, total MT + T concentrations became significantly higher (p Figure 8 ).

During the acute phase after sham or TBI ( 0.05), individual time points (hippocampus: 0.5 hours; cortex: 2 and 4 hours) differ significantly in sham- and TBI-injured animals when analyzed by Student’s t-test (p 2+ concentration in astrocytes, with persistent alterations in calcium-mediated signal transduction (Rzigalinski et al. It enhanced both NMDA- and AMPA-mediated ion currents, but the mechanisms for the enhancement differed: RSI reduced the Mg 2+ blockade of the NMDA receptor (Zhang et al. 1996), but it desensitized the AMPA receptor (Goforth et al. Oxidative stress is one of the major consequences of RSI (Arundine et al. To date, the effects of RSI on cellular zinc ions have not been reported. Our results demonstrate intracellular zinc ion fluctuations within the physiological range (0.4 – 1.4 nM, Figure 2 ) of zinc ion concentrations in undifferentiated PC12 cells (Li and Maret 2009) as a consequence of sub-lethal RSI, and an NO-mediated increase of zinc ions. exerting a pro-oxidant effect, the increased zinc ion concentrations had a pro-antioxidant effect because levels of ROS were higher when cellular zinc ion concentrations were lowered with a cell-permeable chelating agent ( Figure 5 ). Zinc ions may protect cells from oxidative damage by binding to thiols and preventing their oxidation, and/or by activating metal response element (MRE)-binding transcription factor-1 (MTF-1) and antioxidant response element (ARE)-binding transcription factors, such as Nrf2 (Maret 2006;Cortese et al.

In zinc ion-mediated ischemic preconditioning, sub-lethal increases in zinc ion concentrations induced activated caspase 3 to levels that do not induce apoptosis but are sufficient to promote the cleavage of poly(ADP-ribose) polymerase 1 (PARP1), thereby blocking the downstream damaging effects of this enzyme (Lee et al. At twenty-four hours after mechanical injury, the cellular zinc ion concentrations were below normal baseline values (0.9 nM), suggesting that PC12 cells develop a cellular “zinc ion deficiency”. We observed recently that serum starvation leads to a low threshold of 0.4 nM cellular zinc ion in PC12 cells (Li and Maret 2009). Prolonged incubation in serum-starved medium will induce apoptosis, which can be prevented by addition of zinc ions (Adamo et al. The deficit of zinc ions after sub-lethal RSI therefore can be detrimental for cellular functions because free zinc ions are a metabolically active pool of zinc in cellular regulation and signaling (Maret and Li 2009). Such a “zinc ion deficiency” refers to the inability of the cell to control this pool of zinc and is different from a deficiency of total cellular zinc. The intracellular zinc ion concentration measured by FluoZin-3 AM is the total zinc ion concentration in the cytoplasm. This method does not provide any information about the source of the zinc ions released after injury. Although cell and tissue culture models permit mechanistic studies of pathways contributing to cell death and tissue degeneration, validation of the in vitro findings in animal models is required to formulate interventions for preventing and treating brain injuries. In the CA3 and the dentate gyrus regions of the hippocampus, TBI causes selective neuronal loss that may be associated with learning and memory deficits in both experimental animals (Hamm et al. 1994;Dietrich and Allen 1998) and humans (McAllister 1992;Kesner and Hopkins 2006). The hippocampus and the cerebral cortex also are regions that stain most intensely for histochemically reactive zinc ions. Staining of rat brain sections with TSQ (Suh et al. 2004) 24 hours after brain injury demonstrated that zinc ions accumulate in degenerating hippocampal and cortical neurons. Although the presence of free zinc ions can be demonstrated histochemically, an effective method to quantify them in animal tissues does not exist. However, MT levels and MT metal loads can be employed as indicators of free zinc ion concentrations (Yang et al. Using metallothionein as a reporter molecule, our results demonstrated transient increases in cellular free zinc ion concentrations monitored as increased MT/T ratios in the hippocampus and cortex of adult male sham or moderately injured Sprague-Dawley rats four hours after TBI. Increases in intracellular zinc ions were also observed in sham-operated rats, suggesting that anesthesia and/or surgical stress alone increased zinc ion concentrations in the same brain regions. Compared to sham operation, a difference was not detected in TBI at a significance level of 0.05 when the data were analyzed by two-way ANOVA. The observed initial increase in intracellular zinc ion concentrations followed by a decrease several hours after TBI is consistent with the results from rapid stretch-injured PC12 cells. The biphasic changes in zinc ion concentrations demarcate two phases with potentially different and opposite functions of zinc ions during progression of the injury. Thus, time is a critical parameter when investigating the functions of zinc ions in brain injuries. In addition, similar patterns of changing MT/T ratios after sham and TBI where observed in the hippocampus and the cortex.

However, the individual time points at the acute phase of injury when TBI showed a significantly higher MT/T ratio compared to sham are different in the hippocampus and the cortex. The overall decrease in the total concentrations of MT and T and in the MT/T ratio suggest that a zinc ion deficiency develops over a longer period after TBI, which is also apparent for the rapidly stretch-injured PC12 cells.

MT and T levels and their ratios provide a surrogate of direct measurements of zinc ion concentrations, which at present cannot be determined directly in animal tissues. It is possible that during tissue homogenization, with the breakdown of the barrier between intracellular and extracellular compartments, extracellular zinc ions contribute to a change in the MT/T ratio. Therefore, observed changes in MT/T ratios may be due to fluctuations of zinc ions intracellularly and/or extracellularly. However, with the possible exception of zinc ions released from presynaptic zinc-rich vesicles, the contribution from extracellular zinc ions on the MT/T ratios must be small given the very low extracellularly available zinc ion concentration and the low ratio of interstitial/cytoplasmic fluid.


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