ANTISENSE OLIGODEOXYRIBONUCLEOTIDES - STABILITY AND DISTRIBUTION AFTER INTRACEREBRAL INJECTION INTO RAT-BRAIN

As a prerequisite for blocking specific gene expression in the brain, the pharmacokinetics of two radiolabelled analogs of antisense oligode oxyribonucleotides (unmodified O-ODN and nuclease resistant phosphorot hioate S-ODN) were examined by infusion into the base-lateral nucleus of amygdala. Both ODN analogs were found to penetrate at restricted di stances into the brain tissue. Rapidly after injection, O-ODN was almo st completely degraded, while S-ODN remained intact up to 24 h followi ng administration as examined by gel electrophoresis of nucleic acids recovered from the injection site. The tissue clearance of the radioac tivity delivered in a form of O-ODN and S-ODN was also different, the former characterised by much better tissue retention. Microscopic stud ies suggested that S-ODN can apparently penetrate across the cell memb rane and accumulate both in the cytoplasm in the cell nucleus. In situ hybridisation histochemistry experiments (antisense probe to injected ODN) revealed that injected S-ODN was present in a form available for annealing with the complementary strand. Our results provide a basic description of the distribution, retention, and stability of antisense oligonucleotides injected into brain tissue.