The application of antisense oligonucleotide technology to the brain: some pitfalls.
1. Amphetamine-induced c-fos and egr-1 expression in the striatum was used as a model in which to study the effects of antisense oligodeoxynucleotides (ODNs) directed at c-fos. Using direct infusions of ODNs into the striata of animals we have demonstrated that c-fos antisense ODNs retain most of their biological activity with 2- or 3-base substitutions. The c-fos antisense and mismatch ODNs attenuated Fos immunoreactivity but had little effect on Egr-1 immunoreactivity. 2. In another group of studies examining the role of c-fos in amygdala kindling, we have demonstrated that ODNs cause neurotoxic damage following repeated daily infusions into the amygdala. The damage observed was greatly diminished when the time interval between infusions was extended.
Chiasson
B J
BJ
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Armstrong
J N
JN
Hooper
M L
ML
Murphy
P R
PR
Robertson
H A
HA
D000679:Amygdala / Q000187:drug effects*; D000818:Animals; D001483:Base Sequence; D001923:Brain Chemistry / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D003913:Dextroamphetamine / Q000494:pharmacology; D051766:Early Growth Response Protein 1; D017781:Genes, Immediate-Early / Q000187:drug effects; D016762:Genes, fos; D005911:Gliosis / Q000139:chemically induced; D017874:Immediate-Early Proteins; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000633:toxicity; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D013873:Thionucleotides; D014157:Transcription Factors; D003913:Dextroamphetamine