The application of antisense oligonucleotide technology to the brain: Some pitfalls
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1. Amphetamine-induced c-fos andegr-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.
Key wordsc-fos egr-1 antisense oligodeoxynucleotides (ODNs) amygdala kindling immediate-early genes ODN-induced toxicity
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- Chiasson, B. J., and Robertson, H. A. (1994). Toxicity following in vivo infusion of antisense oligonucleotide: Role of the inter-infusion interval.Soc. Neurosci. Abstr. (in press).Google Scholar
- Chiasson, B. J., Hooper, M. L., and Robertson, H. A. (1992a). Amphetamine induced rotational behavior in non-lesioned rats: A role for c-fos expression in the striatum.Soc. Neurosci. Abstr. 18562.Google Scholar
- Chiasson, B. J., Hooper, M. L., Murphy, P. R., and Robertson, H. A. (1992b). Antisense oligonucleotide eliminatesin vivo expression of c-fos in mammalian brain.Eur. J. Mol. Pharmacol. 227451–453.Google Scholar
- Chiasson, B. J., Dennison, Z., and Robertson, H. A. (1995). Amygdala kindling and immediate-early genesMol. Brain. Res. (in press).Google Scholar
- Gao, W.-Y., Hand, F.-S., Storm, C., Egan, W., and Cheng, Y.-C. (1991). Phosphorothioate oligonucleotides are inhibitors of human DNA polymerases and RNase H: Implications for antisense technology.Mol. Pharmacol. 41223–229.Google Scholar
- Hooper, M. L., Chiasson, B. J., and Robertson, H. A. (1994). Infusion into the brain of an antisense oligonucleotide to the immediate-early gene c-fos suppresses production of Fos and produces a beharioral effect.Neurosci. 63917–924.Google Scholar
- Koelle, C. G., and Friedenwald, J. S. (1949). A histochemical method for localizing cholinesterase activity.Proc. Soc. Exp. Biol. Med. 70617–622.Google Scholar
- Kreig, A. M. (1993). Uptake and efficacy of phosphodiester and modified antisense oligonucleotides in primary cell cultures.Clin. Chem. 39 710–712.Google Scholar
- Krieg, A. M., Tonkinson, J., Matson, S., Zhao, Q., Saxon, M., Zhang, L.-M., Bhanja, U., Yakubov, L., and Stein, C. A. (1993). Modification of antisense phosphodiester oligodeoxynucleotides by a 5′ cholesteryl moiety increases cellular association and improves efficacy.Proc. Natl. Acad. Sci. USA 901048–1052.PubMedGoogle Scholar
- Lewis, P. R. (1961). The effect of varying the conditions in the Koelle method.Biblthca. Anat. Vol. 2, Karger, Basel, pp. 11–20.Google Scholar
- Perez, J. R., Li, Y., Stein, C. A., Majumder, S., van Oorschot, A., and Narayanan, R. (1994). Sequence-independent induction of Sp 1 transcription factor activity by phosphorothioate oligonucleotides.Proc. Natl. Acad. Sci. USA 915959–5961.Google Scholar
- Ungerstedt, U. (1971). Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system.Acta. Physiol Scand. (Suppl.) 36769–93.Google Scholar