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The Journal of Neuroscience, February 15, 1999, 19(4):1335-1344

Suppression of Postischemic Hippocampal Nerve Growth Factor Expression by a c-fos Antisense Oligodeoxynucleotide

Jian-Kun Cui¹, Chung Y. Hsu², and Philip K. Liu¹

¹ Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, and ² Department of Neurology, Washington University, St. Louis, Missouri 63110-1093

We examined the uptake and distribution of an antisense phosphorothioated oligodeoxynucleotide (s-ODN) to c-fos, rncfosr₁₁₅, infused into the left cerebral ventricle of male Long-Evans rats and the effect of this s-ODN on subsequent Fos, NGF, neurotrophin-3 (NT-3), and actin expression. To establish the uptake and turnover of s-ODN in the brain, we studied the copurification of the immunoreactivity of biotin with biotinylated s-ODN that was recovered from different regions of the brain. A time-dependent diffusion and the localization of s-ODN were further demonstrated by labeling the 3'-OH terminus of s-ODN in situ with digoxigenin-dUTP using terminal transferase and detection using anti-digoxigenin IgG-FITC. Cellular uptake of the s-ODN was evident in both the hippocampal and cortical regions, consistent with a gradient originating at the ventricular surface. Degradation of the s-ODN was observed beginning 48 hr after delivery. The effectiveness of c-fos antisense s-ODN was demonstrated by its suppression of postischemic Fos expression, which was accompanied by an inhibition of ischemia-induced NGF mRNA expression in the dentate gyrus. Infusion of saline, the sense s-ODN, or a mismatch antisense s-ODN did not suppress Fos expression. That this effect of c-fos antisense s-ODN was specific to NGF was demonstrated by its lack of effect on the postischemic expression of the NT-3 and -actin genes. Our results demonstrate that c-fos antisense s-ODN blocks selected downstream events and support the contention that postischemic Fos regulates the subsequent expression of the NGF gene and that Fos expression may have a functional component in neuroregeneration after focal cerebral ischemia-reperfusion.

Key words: antisense DNA; experimental cerebral ischemia; c-fos; drug target validation; gene regulation; gene function analysis; immediate early genes; intracerebroventricular delivery; neurotrophin; NGF; oligodeoxynucleotide; transfection; stroke

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1941335-10$05.00/0

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