Enhanced Susceptibility to Spontaneous Seizures of Noda Epileptic Rats by Loss of Synaptic Zn2+

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.

Zinc: indications in brain disorders

“…Lavoie et al. reported that intracellular zinc chelators influence more neuronal excitability of the CA3 region of the hippocampus using a high [K + ] model of epilepsy for status epilepticus rather than extracellular zinc chelators.…”

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

“…(i) Clioquinol (5-chloro-7-iodo-quinolin-8-ol) is a halogenated 8-hydroxyquinoline (14). It was selected because it has been extensively used as a zinc chelator both in vitro and in vivo (15)(16)(17)(18)(19). Clioquinol (Fluca, 33931-100MG-R) was diluted to a 0.05 M stock solution in 100% dimethyl sulfoxide (DMSO).…”

“…(vii) N,N,N=,N=-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN) is a membrane-permeative zinc chelator that has also been used extensively in that role in vivo (18,19,32,33) and on A. fumigatus (25). TPEN (Life Technologies, T1210) was diluted to a 0.05 M stock solution in 100% DMSO.…”

Метаболізм Металів У Гіпокампі Та Роль Цинку В Патогенезі Епілептиформних Судом

“…Важливим аспектом фармакотерапії нейродегенеративних, цереброваскулярних та інших за-хворюваньЦНС,ветіологіїякихзначнурольвідіграютьстресіпорушенняметалолігандногогомео-стазуєнейропротекція,якарозглядаєтьсяякзахистнейронівприсудиннійпатологіїголовногомоз-ку.Однакнасьогоднівеликакількістьпроведенихклінічнихдослідженьстраждаютьнавідсутність задовільнихдоказівефективностідіїхелаторів,дляцьоготакожнеобхіднодослідитифізіологічні механізмиметалолігандногогомеостазу (Кудрин,Громова,2006;Zalups&Koropatnick,2010;Takeda et al, 2013).…”

“…Добревідомо,щонадлишковезвільненняцинкупідчаснейрональноїактивностіможепризво-дитидопорушеньзбудливостігіпокампу,утомучислівиникненнюсудомноїактивності (Elsas et al, 2009;Takeda et al,2013;Kazemi et al, 2016).…”