Increase in hippocampal cell death after treatment with kainate in zinc deficiency
Introduction
Dietary zinc deficiency not only retards the growth of humans and animals, but also affects brain function (Golub et al., 1995, Penland, 2000, Sandstead et al., 2000, Takeda, 2000). Approximately, 50% of the world population does not get adequate zinc (Brown et al., 2001). Ten percent of the North American population consumes less than half the recommended daily allowance for zinc (King et al., 2000).
Zinc is a component of over 300 proteins, such as DNA-binding proteins with zinc fingers and is important for the function of many enzymes and other proteins, including some unique to the brain and important to neurotransmission (Prohaska, 1987, Ebadi, 1991, Vallee and Falchuk, 1993). Dietary zinc deficiency affects zinc homeostasis in the brain (Takeda, 2001); zinc concentration in the presynaptic vesicle and extracelullar zinc concentration are decreased in 8-week-old rats fed a zinc-deficient diet for 4 weeks (Takeda et al., 2003a), in which susceptibility to kainate-induced seizures is more enhanced than in the control rats (Takeda et al., 2003b). The enhanced susceptibility to epileptic seizures is also observed in zinc-deficient EL mice (Fukahori and Itoh, 1990) and kindled cats (Sterman et al., 1986). The in vivo microdialysis experiment demonstrated an enhanced release of glutamate associated with a decrease in GABA concentrations as a possible mechanism for the enhanced susceptibility to kainate-induced seizures in zinc deficiency (Takeda et al., 2003b).
To evaluate kainate-induced excitotoxicity in zinc deficiency, in the present study, the relationship between kainate-induced seizures and hippocampal cell death was examined in control and zinc-deficient mice, which showed the same seizure severity scores. The observation of hippocampal cell death is important to evidence the vulnerability to glutamate excitotoxicity in zinc deficiency. In the hippocampal CA3 of zinc-deficient mice, furthermore, extracellular zinc and intracellular calcium levels were checked using their indicators.
Section snippets
Diets and chemicals
Control (44 mg Zn/kg) and zinc-deficient (2.7 mg Zn/kg) diets were purchased from Oriental Yeast Co. Ltd. (Yokohama, Japan). ZnAF-2, a membrane-impermeable zinc indicator, was kindly supplied from Daiichi Pure Chemicals Co., Ltd. (Tokyo, Japan). Fura-2 AM, a membrane-permeable calcium indicator, was purchased from Molecular Probes, Inc. (Eugene, OR).
Experimental animals
Male ddY mice (both 3-week-old) were purchased from Japan SLC (Hamamatsu, Japan). They were housed under the standard laboratory conditions (23 ± 1 °C,
Results
When 4-week-old mice were fed a zinc-deficient diet for 4 weeks, zinc concentration in the liver and serum was significantly decreased, while zinc concentration in the whole brain was not decreased (Fig. 1). However, zinc concentration in the hippocampus was significantly decreased by the zinc deficiency. Kainate was injected into the control and zinc-deficient mice and seizure severity of each mouse was semi-quantified according the seizure score scale of Racine (1972) and Sperk et al. (1985).
Discussion
Zinc homeostasis in the brain is altered by dietary zinc deficiency (Takeda, 2001) and its alteration may be associated with the etiology and manifestation of epileptic seizures (Sterman et al., 1988). When susceptibility to kainate-induced seizures was examined in 8-week-old mice and rats fed the zinc-deficient diet for 4 weeks, kainate-induced seizures were enhanced by dietary zinc deficiency (Takeda et al., 2003b). Furthermore, the mechanism of the enhanced seizure susceptibility was studied
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