Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain.
The present study was directed at evaluating the possible involvement of protein synthesis in excitotoxin-induced neuronal damage and prolonged expression of the proto-oncogene, c-fos. Kainic acid-induced seizure activity elicited varying degrees of neuronal damage and cell loss in selectively vulnerable regions of the adult rat limbic system. Pretreatment with cycloheximide, a protein synthesis inhibitor, did not alter behavioral seizure characteristics, but markedly attenuated damage to susceptible neuronal populations. A prolonged increase in c-fos mRNA was observed by in situ hybridization up to 16 h after the onset of seizures in regions exhibiting neuronal death. Pretreatment with cycloheximide did not affect the transient induction of c-fos observed in numerous structures, but significantly reduced the prolonged expression of c-fos mRNA in kainate-vulnerable regions. Despite producing massive seizure activity, systemic kainic acid administration during the early postnatal period did not induce any neuronal death, and did not result in prolonged c-fos expression in any brain structures. The developmental onset of selective neuronal vulnerability coincided with that of prolonged c-fos expression in susceptible neuronal populations. In adult rats, seizure activity induced by pentylenetetrazole did not produce neuronal damage nor did it produce prolonged c-fos expression. These results not only demonstrate that kainate-induced neurotoxicity and the prolonged expression of c-fos are both prevented by cycloheximide, but also strengthen idea that prolonged c-fos expression is a marker of neuronal death.
Schreiber
S S
SS
Department of Neurology, University of Southern California, School of Medicine, Los Angeles 90033.
Tocco
G
G
Najm
I
I
Thompson
R F
RF
Baudry
M
M
D000375:Aging / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009928:Organ Specificity; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D013462:Sulfur Radioisotopes
D012333:RNA, Messenger; D013462:Sulfur Radioisotopes; D003513:Cycloheximide; D007608:Kainic Acid