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Titolo:
MODIFICATION OF PHOSPHOROTHIOATE OLIGONUCLEOTIDES YIELDS POTENT ANALOGS WITH MINIMAL TOXICITY FOR ANTISENSE EXPERIMENTS IN THE CNS
Autore:
HO SP; LIVANOV V; ZHANG W; LI JH; LESHER T;
Indirizzi:
DUPONT PHARMACEUT RES LABS,EXPT STN,CNS DEPT,POB 80400 WILMINGTON DE 19880
Titolo Testata:
Molecular brain research
fascicolo: 1, volume: 62, anno: 1998,
pagine: 1 - 11
SICI:
0169-328X(1998)62:1<1:MOPOYP>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
H-3 LABELED OLIGONUCLEOTIDES; GENE-EXPRESSION; ADMINISTERED OLIGODEOXYNUCLEOTIDES; MESSENGER-RNA; PROTEIN-BINDING; RAT-BRAIN; IN-VIVO; RECEPTOR; STABILITY; BIODISTRIBUTION;
Keywords:
ANTISENSE OLIGONUCLEOTIDES; PHOSPHOROTHIOATES; CORTICOTROPIN RELEASING FACTOR TYPE-2 RECEPTOR; RIBONUCLEASE H;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
57
Recensione:
Indirizzi per estratti:
Citazione:
S.P. Ho et al., "MODIFICATION OF PHOSPHOROTHIOATE OLIGONUCLEOTIDES YIELDS POTENT ANALOGS WITH MINIMAL TOXICITY FOR ANTISENSE EXPERIMENTS IN THE CNS", Molecular brain research, 62(1), 1998, pp. 1-11

Abstract

There is increasing evidence that phosphorothioate oligonucleotides infused into the brain can cause a host of undesired side effects whichcompromise the antisense experiment. In studies on the corticotropin releasing factor type-2 receptor, several phosphorothioate oligonucleotides administered intraventricularly produced significant weight lossin rats. Four different phosphodiester and phosphorothioate oligonucleotide analogs were examined to identify molecules which could eliminate these side effects while maintaining good potency for antisense inhibition. Of these, chimeric oligonucleotides consisting of a mixed phosphodiester-phosphorothioate backbone, and having 2-methoxyribonucleotide modifications in 60% of the oligonucleotide were the most optimal. Rats treated with these chimeric oligonucleotides gained weight at rates identical to that of saline-treated controls. In addition, the antisense oligonucleotide but not the mismatch control sequence reduced corticotropin releasing factor type-2 receptor binding of (125)iodo-sauvagine in the lateral septum by 40-60% after 5 daily injections. Increasing the dosing period to 9 days reduced receptor binding by 78%. Reductions in protein binding were accompanied by comparable reductions in the in situ hybridization signal of the corticotropin releasing factor type-2 receptor mRNA. However, when an oligonucleotide analog incapable of supporting ribonuclease H activity was used, neither protein nor RNA binding levels were changed compared to saline-treated controls. These results suggest that ribonuclease H or enzymes with similar activity are critical to the antisense inhibition observed in the lateral septum. (C) 1998 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/09/20 alle ore 07:36:52