Hippocampal zinc infusion delays the development of afterdischarges and seizures in a kindling model of epilepsy.
OBJECTIVE
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 gamma-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 microM ZnCl(2) or 1,000 microM ZnCl(2), at a rate of 0.25 microl/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 microM ZnCl(2) (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 microM ZnCl(2) and 1,000 microM ZnCl(2) infusion compared to control animals (p < 0.01). At stimulation number 18, all groups had reached the same maximum duration of afterdischarges.


CONCLUSIONS
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.
Elsas
Siegward-M
SM
Department of Neurology, University of California Los Angeles, Los Angeles, California, USA. elsas@ohsu.edu
Hazany
Saman
S
Gregory
William L
WL
Mody
Istvan
I
D000704:Analysis of Variance; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D002712:Chlorides / Q000008:administration & dosage*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D004558:Electric Stimulation; D005029:Ethylenediamines / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects*; D007696:Kindling, Neurologic / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects*; D012640:Seizures / Q000473:pathology* / Q000503:physiopathology*; D018709:Statistics, Nonparametric; D013997:Time Factors; D017967:Zinc Compounds / Q000008:administration & dosage*
D002614:Chelating Agents; D002712:Chlorides; D005029:Ethylenediamines; D017967:Zinc Compounds; C016837:zinc chloride; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine