Abstract
Zinc homeostasis in the brain is associated with the etiology and manifestation of epileptic seizures. Adult Noda epileptic rats (NER, >12-week-old) exhibit spontaneously generalized tonic-clonic convulsion about once a day. To pursue the involvement of synaptic Zn2+ signal in susceptibility to spontaneous seizures, in the present study, the effect of zinc chelators on epileptogenesis was examined using adult NER. Clioquinol (CQ) and TPEN are lipophilic zinc chelotors, transported into the brain and reduce the levels of synaptic Zn2+. The incidence of tonic-clonic convulsion was markedly increased after i.p. injection of CQ (30–100 mg/kg) and TPEN (1 mg/kg). The basal levels of extracellular Zn2+ measured by ZnAF-2 were decreased before tonic-clonic convulsion was induced with zinc chelators. The hippocampal electroencephalograms during CQ (30 mg/kg)-induced convulsions were similar to those during sound-induced convulsions in NER reported previously. Exocytosis of hippocampal mossy fibers, which was measured with FM4-64, was significantly increased in hippocampal slices from CQ-injected NER that did not show tonic-clonic convulsion yet. These results indicate that the abnormal excitability of mossy fibers is induced prior to epileptic seizures by injection of zinc chelators into NER. The incidence of tonic-clonic convulsion induced with CQ (30 mg/kg) was significantly reduced by co-injection with aminooxyacetic acid (5–10 mg/kg), an anticonvulsant drug enhancing GABAergic activity, which did not affect locomotor activity. The present paper demonstrates that the abnormal excitability in the brain, especially in mossy fibers, which is potentially associated with the insufficient GABAergic neuron activity, may be a factor to reduce the threshold for epileptogenesis in NER.
Highlights
Zinc homeostasis in the brain is associated with the etiology and manifestation of epileptic seizures [1,2]
In the amygdala rapid kindling model, on the other hand, DEDTC decreased the duration of both behavioral seizures and electrical afterdischarges, and decreased the electroencephalogram spike frequency, without changing the progression of behavioral seizure severity, suggesting that synaptic Zn2+ has a facilitatory role during kindling progression [31]
The incidence of tonic-clonic convulsion was markedly increased in NER after i.p. injection of CQ (30 mg/kg) and Tetrakis-(2-pyridylmethyl) ethylendediamine (TPEN) (1 mg/kg), which did not induce any convulsion in the control rats (Wistar strain)
Summary
Zinc homeostasis in the brain is associated with the etiology and manifestation of epileptic seizures [1,2]. The three synapses in the hippocampus are stained by Timm’s sulfide-silver method [3], which detects vesicular zinc to serve as a signal factor (Zn2+ signal). Because synaptic Zn2+ serves as a negative feedback factor against glutamate release in the hippocampus [9,10], it is likely that synaptic Zn2+ levels is involved in pathophysiology of epileptic seizures [11,12,13]. The increase in extracellular glutamate in the hippocampus may trigger spontaneous seizures in patients with complex partial epilepsy [15]. Intracellular Zn2+ signal increases through Zn2+ influx and Zn2+ release from the internal stores after seizures and can be involved in neurodegeneration [16,17]
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