Kainic acid-induced seizures and brain damage in the rat: role of calcium homeostasis.
Seizure activity induced by kainic acid (KA) and subsequent neuronal death are thought to be associated with an increase in cytoplasmic free calcium ([Ca2+]i) and can be prevented by N-methyl-D-aspartate (NMDA) antagonists. In addition to influx through receptor operated Ca2+ channels the increase in [Ca2+]i may be the result of an increased influx through voltage-operated calcium channels and/or release from intracellular deposits. It was therefore investigated whether compounds other than NMDA antagonists with known actions on the intracellular Ca2+ homeostasis had any protective effect against KA-induced neuronal death. Voltage-operated calcium channels in the cell membrane were blocked with the L-type ion channel antagonist, Nimodipine (1.0 mg/kg), and release of Ca2+ from internal stores was prevented with Dantrolene (10 mg/kg). Animals from two control groups injected with kainate (8 mg/kg) exhibited a survival rate of 67 and 53%, respectively. Countings of neurons in dorsal hippocampus showed subtotal or total loss in the CA1 and CA3 subregions. There were no significant differences concerning seizure and survival rates in the groups injected with kainate and treated with Dantrolene or Nimodipine and the control groups. The group treated with Dantrolene showed no neuropathological changes in the hippocampal CA3 region and only slight changes in the Ca1 region, while the neuron loss in the Nimodipine group did not differ from that of its control group. The results emphasize the importance of Dantrolene-sensitive Ca2+ release from intracellular stores for the development of seizure-induced neuronal death.
Berg
M
M
PharmaBiotec Research Center, University of Copenhagen, Denmark.
Bruhn
T
T
Frandsen
A
A
Schousboe
A
A
Diemer
N H
NH
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001927:Brain Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D015640:Ion Channel Gating / Q000187:drug effects; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D009553:Nimodipine / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism
D015220:Calcium Channels; D009553:Nimodipine; D003620:Dantrolene; D007608:Kainic Acid; D002118:Calcium