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Titolo:
Antinociceptive effects after intrathecal administration of phosphodiester-, 2 '-O-allyl-, and C-5-propyne-modified antisense oligodeoxynucleotides targeting the NMDAR1 subunit in mouse
Autore:
Rydh-Rinder, M; Berge, OG; Hokfelt, T;
Indirizzi:
AstraZeneca R&D, Sodertalje, Sweden AstraZeneca R&D Sodertalje SwedenAstraZeneca R&D, Sodertalje, Sweden Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden Karolinska InstStockholm Sweden S-17177 osci, S-17177 Stockholm, Sweden
Titolo Testata:
MOLECULAR BRAIN RESEARCH
fascicolo: 1-2, volume: 86, anno: 2001,
pagine: 23 - 33
SICI:
0169-328X(20010131)86:1-2<23:AEAIAO>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECEPTOR-CHANNEL SUBUNIT; D-ASPARTATE RECEPTORS; RAT SPINAL-CORD; MESSENGER-RNAS; PHOSPHOROTHIOATE OLIGONUCLEOTIDES; GLUTAMATE RECEPTORS; GENE INHIBITION; FORMALIN TEST; KETAMINE; ACID;
Keywords:
formalin test; pain modulation; spinal cord; excitatory amino acid antagonist;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
59
Recensione:
Indirizzi per estratti:
Indirizzo: Rydh-Rinder, M AstraZeneca R&D, Sodertalje, Sweden AstraZeneca R&D Sodertalje Sweden &D, Sodertalje, Sweden
Citazione:
M. Rydh-Rinder et al., "Antinociceptive effects after intrathecal administration of phosphodiester-, 2 '-O-allyl-, and C-5-propyne-modified antisense oligodeoxynucleotides targeting the NMDAR1 subunit in mouse", MOL BRAIN R, 86(1-2), 2001, pp. 23-33

Abstract

In the present study, we have compared the antinociceptive effect of threedifferent types of antisense oligodeoxynucleotides targeting the N-methyl-D-aspartate (NMDA) R1-subunit in mice. The probes were administrated intrathecally three times during a period of 5 days (1, 5 or 25 mug/injection), followed by evaluation using the formalin test. The antinociceptive effect was correlated to in vitro receptor binding in spinal cord sections. The tissue distribution was studied after a single injection of fluorescein-conjugated probes. The phosphodiester probe showed superficial tissue penetrationafter 30 min and disappeared within 2 h. The probe did however, significantly reduce both receptor binding in laminae I and II (by 36-44% compared tosaline) as well as pain behavior (32% compared to saline), without apparent side effects. The mismatched probe was ineffective at 25 pg, while some reductions in receptor binding and pain behavior were seen after 5 mug. The C-5-propyne-modified phosphorothioate probe showed pronounced tissue penetration and cellular uptake as soon as 30 min after injection which was stilldetectable after 24 h. Immediately after injection of the highest dose, long-lasting hind-limb paralysis was observed. Receptor binding was reduced but not in a dose-related manner. Pain behavior was significantly reduced by40% following 25 mug of antisense probe but not after lower doses or 25 mug of mismatched probe. The 2'-O-allyl-modified probe did not significantly reduce receptor binding or pain behavior. Thus, only the phosphodiester probe showed a significant correlation between reduction in pain behavior and receptor binding. These findings demonstrate that antisense technology is associated with specificity problems, but still could provide a valuable tool to study the role of different target proteins in the drug discovery process. (C) 2001 Elsevier Science B.V. All rights reserved.

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Documento generato il 30/11/20 alle ore 03:28:12