The pharmacodynamic characterization of an antisense oligonucleotide against monoamine oxidase-B (MAO-B) in rat brain striatal tissue

1. The aim of our work was to pharmacodynamically characterize an antisense oligonucleotide sequence (5'-GCC AAA CTT TTG CAT GAG-3') against MAO-B, us ing qualitative and quantitative analyses as assessment measures. 2. Qualitative analysis using histochemical staining revealed that intracer ebroventricular (ICV) administered antisense (100 picomoles twice daily x 3 .5 days) eliminated an visibly detectable histochemical staining for MAO-B throughout the striatum 1, 12, and 24 h after the last antisense treatment. 3. Qualitative analysis using RT-PCR of the time course of MAO-B mRNA expre ssion in the rat striatum following ICV administration of the antisense seq uence showed that 12-24 h after the last administration there was a dramati c reduction in MAO-B mRNA expression in the striatum. The reverse and scram bled sequences generated no change in MAO-B mRNA at 1 or 24 h after the las t treatment. 4. Quantitative analysis using the MAO-B selective substrate 4-dimethylamin o-phenethylamine (DMAPEA) showed that the antisense sequence reduced MAO-B activity by more than 40%, which was comparable to a single 2 mg/kg, ip dos e of L-deprenyl. 5. Quantitative analysis of neurotransmitter levels 24 h after the last tre atment suggested that the antisense sequence did not produce any significan t changes in neurotransmitter levels. 6. Potential mechanisms for enhancing the antisense response and the specul ated potential of an antisense against MAO-B for studying neurotoxicity, Pa rkinson's disease, and the aging process are also discussed.