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1.
J Pharmacol Exp Ther ; 366(1): 58-65, 2018 07.
Article in English | MEDLINE | ID: mdl-29674331

ABSTRACT

GABAA receptors containing α5 subunits (GABAAα5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABAAα5-deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABAAα5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABAAα5 NAM that improves hippocampal functions. ONO-8590580 [1-(cyclopropylmethyl)-5-fluoro-4-methyl-N-[5-(1-methyl-1H-imidazol-4-yl)-2-pyridinyl]-1H-benzimidazol-6-amine] binds to the benzodiazepine binding sites on recombinant human α5-containing GABAA receptors with a Ki of 7.9 nM, and showed functionally selective GABAAα5 NAM activity for GABA-induced Cl- channel activity with a maximum 44.4% inhibition and an EC50 of 1.1 nM. In rat hippocampal slices, tetanus-induced long-term potentiation of CA1 synapse response was significantly augmented in the presence of 300 nM ONO-8590580. Orally administered ONO-8590580 (1-20 mg/kg) dose-dependently occupied hippocampal GABAAα5 in a range of 40%-90% at 1 hour after intake. In the rat passive avoidance test, ONO-8590580 (3-20 mg/kg, by mouth) significantly prevented (+)-MK-801 hydrogen maleate (MK-801)-induced memory deficit. In addition, ONO-8590580 (20 mg/kg, p.o.) was also effective in improving the cognitive deficit induced by scopolamine and MK-801 in the rat eight-arm radial maze test with equal or greater activity than 0.5 mg/kg donepezil. No anxiogenic-like or proconvulsant effect was associated with ONO-8590580 at 20 mg/kg p.o. in the elevated plus maze test or pentylenetetrazole-induced seizure test, respectively. In sum, ONO-8590580 is a novel GABAAα5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.


Subject(s)
Cognition/drug effects , Imidazoles/pharmacology , Long-Term Potentiation/drug effects , Pyridines/pharmacology , Receptors, GABA-A/metabolism , Allosteric Regulation/drug effects , Animals , Avoidance Learning/drug effects , HEK293 Cells , Hippocampus/drug effects , Hippocampus/physiology , Humans , Imidazoles/therapeutic use , Male , Maze Learning/drug effects , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley
2.
Biol Pharm Bull ; 26(6): 896-8, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12808309

ABSTRACT

Unsei-in, a traditional medicine, is prescribed against pruritic cutaneous diseases, but the mechanisms of antipruritic action are still unknown. In the present study, we examined the antipruritic effects of Unsei-in in mice. Single administration of Unsei-in did not inhibit substance P-induced itch-associated response (scratching) in mice. However, repeated treatment with Unsei-in for 7 d significantly inhibited substance P-induced scratching. The same repeated treatment with Unsei-in suppressed the expression of NK(1) tachykinin receptors in the skin. These results suggest that Unsei-in inhibits substance P-associated itching and that the inhibition is at least partly due to the suppression of the expression of NK(1) tachykinin receptors in the skin.


Subject(s)
Antipruritics/therapeutic use , Drugs, Chinese Herbal/therapeutic use , Pruritus/drug therapy , Receptors, Neurokinin-1/biosynthesis , Skin/metabolism , Administration, Oral , Animals , Antipruritics/administration & dosage , Disease Models, Animal , Down-Regulation , Drugs, Chinese Herbal/administration & dosage , Injections, Intradermal , Male , Mice , Mice, Inbred ICR , Pruritus/chemically induced , Pruritus/metabolism , Skin/drug effects , Substance P/toxicity
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