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 GAC-3') against MAO-B, using qualitative and quantitative analyses as assessment measures. 2. Qualitative analysis using histochemical staining revealed that intracerebroventricular (ICV) administered antisense (100 picomoles twice daily x 3.5 days) eliminated all 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 expression in the rat striatum following ICV administration of the antisense sequence showed that 12-24 h after the last administration there was a dramatic reduction in MAO-B mRNA expression in the striatum. The reverse and scrambled sequences generated no change in MAO-B mRNA at 1 or 24 h after the last treatment. 4. Quantitative analysis using the MAO-B selective substrate 4-dimethylamino-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 dose of L-deprenyl. 5. Quantitative analysis of neurotransmitter levels 24 h after the last treatment suggested that the antisense sequence did not produce any significant changes in neurotransmitter levels. 6. Potential mechanisms for enhancing the antisense response and the speculated potential of an antisense against MAO-B for studying neurotoxicity, Parkinson's disease, and the aging process are also discussed.
Sprague
J E
JE
Department of Pharmaceutical & Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada 45810, USA. j-sprague@onu.edu
Worst
T J
TJ
Haynes
K
K
Mosler
C R
CR
Nichols
D E
DE
Kane
M D
MD
D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology*; D004298:Dopamine / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics* / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; D004298:Dopamine