Hippocampal zinc infusion delays the development of afterdischarges and seizures in a kindling model of epilepsy

Abstract

SUMMARY Purpose Zinc occurs in high concentration in synaptic vesicles of glutamatergic terminals including hippocampal mossy fibers. This vesicular zinc can be synaptically released during neuronal activity, including seizures. Zinc inhibits certain subtypes of N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid (GABA)A receptors. By blocking NMDA excitation or GABA inhibition, an excess of zinc may alter the excitability of hippocampal circuits, which contribute to the development of seizures. Methods Twenty-one adult Wistar rats were implanted under anesthesia with Alzet pumps releasing vehicle, 10 μM ZnCl2 or 1,000 μM ZnCl2, at a rate of 0.25 μl/h continuously into the hippocampal hilus for 4 weeks. Kindling was performed by daily awake commissural stimulation at 60 Hz and afterdischarges were recorded from a dentate gyrus electrode. Development of behavioral Racine seizure stages was recorded by a blinded investigator. Results The development of behavioral Racine seizure stages was delayed only in rats infused with 1,000 μM ZnCl2 (p < 0.02). With completion of kindling at stimulation number 20, all groups had reached the same maximum level of behavioral seizures. The expected increased progression of afterdischarge duration was inhibited by both 10 μM ZnCl2 and 1,000 μM ZnCl2 infusion compared to control animals (p < 0.01). At stimulation number 18, all groups had reached the same maximum duration of afterdischarges. Discussion We conclude that excess infused zinc delayed the development of behavioral seizures in a kindling model of epilepsy. These data support the hypothesis that zinc synaptically released during seizures may alter hippocampal excitability similar to zinc infused in our experiment.

Zinc and the aging brain

“…Zinc can also reduce oxidative stress associated with excitotoxicity through a variety of mechanisms including inhibition of the NMDAR and competition with copper for redox active binding sites on Ab (Cuajungco et al 2000;Oteiza 2012). Furthermore, infusion of zinc delays the development of seizures in a kindling model of epilepsy (Elsas et al 2009), and mice with ZnT3 and/or MT3 deficiency have increased susceptibility to kainic acid induced seizures and hippocampal damage (Cole et al 2000).…”

Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures

“…Indeed, genetic removal of synaptic Zn 2+ via ZnT3 deletion leads to enhanced susceptibility to epileptic seizures (Cole et al 1999; Cole et al 2000), and importantly, deficiencies in plasma Zn 2+ levels have been associated with human epileptic disorders (Goldberg et al 1982; Blasco-Ibanez et al 2004; Ganesh et al 2008; Farahani et al 2013; Seven et al 2013; Wojciak et al 2013; Saad et al 2014). Moreover, studies in kindling models of epilepsy suggest that seizure activity can be moderated via Zn 2+ administration (Elsas et al 2009; Baraka et al 2012). Nonetheless, the pathways linking synaptically released Zn 2+ to regulation of seizure activity are poorly understood.…”

Serum Zinc Level in Children With Febrile Convulsion

“…This element also facilitates the inhibitory effect of calcium on N-methyl-Daspartate receptors (NMDA) and by these effects prevents the stimulation of neuronal discharge [16]. High concen-tration zinc exists in the synaptic vesicles of glutamatergic neurons including the hippocampal mossy fiber which can be synaptically released during neural activity as in convulsion [17]. According to the important role of zinc in the nervous system, studies have shown that lack of zinc might have a role in pathogenesis of febrile seizures.…”