Inhibition of aconitase in astrocytes increases the sensitivity to chemical convulsants.
Although there is evidence that astrocytes support neuronal function, the contribution of astrocytes to seizure onset and termination is not known. To determine whether there are changes in seizure susceptibility or neuronal damage when the ability of astrocytes to generate ATP is reduced, 0.5 nmol of fluorocitrate (FC) was injected into the right ventricle. Injection of FC alone did not produce electrographic or behavioral seizures and did not stress or injure neurons or astrocytes, as measured with silver stain and immunohistochemistry for HSP32 or HSP72. However, in animals pretreated with FC, administration of kainic acid, at a dose that does not initiate seizures in control animals (7 mg/kg), caused wet dog shakes and neuronal damage in the hilus. Wet dog shakes did not cause any neuronal damage in control animals. If the dose of FC was increased to 0.75 nmol, then subsequent administration of the same dose of kainic acid (7 mg/kg) caused stage 3-5 seizures. Injection of FC also reduced the dose of pilocarpine needed to produce seizures. Given simultaneously with FC, isocitrate, which bypasses the biochemical inhibition of aconitase, blocked the effects of FC in both kainic acid and pilocarpine treated animals. The data demonstrate that inhibition of aconitase in astrocytes lowers the doses of both kainic acid and pilocarpine that will cause behavioral seizures and may increase neuronal vulnerability to seizures.
Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. xlian@bcm.tmc.edu
Xiao-Yuan
XY
Lian
Janet L
JL
Stringer
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002951:Citrates / Q000008:administration & dosage / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007523:Isocitrates / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced; D014746:Vimentin / Q000096:biosynthesis
D002951:Citrates; D003292:Convulsants; D004791:Enzyme Inhibitors; D007523:Isocitrates; D014746:Vimentin; D010862:Pilocarpine; C007744:fluorocitrate; D000255:Adenosine Triphosphate; C034219:isocitric acid; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D000154:Aconitate Hydratase; D007608:Kainic Acid