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The ameliorating effects of 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one, an oroxylin A derivative, against memory impairment and sensorimotor gating deficit in mice

Author:
Liu, Xiaotong, Hong, Sung In, Park, Se Jin, dela Peña, June Bryan, Che, Haiyan, Yoon, Seo Young, Kim, Dong Hyun, Kim, Jong Min, Cai, Mudan, Risbrough, Victoria, Geyer, Mark A., Shin, Chan Young, Cheong, Jae Hoon, Park, Haeil, Lew, Jae Hwan, Ryu, Jong Hoon
Source:
Archives of pharmacal research 2013 v.36 no.7 pp. 854-863
ISSN:
0253-6269
Subject:
acoustics, agonists, antagonists, cognition, gamma-aminobutyric acid, in vitro studies, memory, mice, models, schizophrenia, scopolamine
Abstract:
We previously reported that oroxylin A, a γ-aminobutyric acid A (GABAA) receptor antagonist, ameliorates drugs-induced memory impairments. We synthesized several oroxylin A derivatives in efforts to find a substance that has pro-cognitive effects as well as improves sensorimotor gating. The aim of the present study is to investigate the effect of a novel oroxylin A derivative, 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one (DMPC), on pharmacological models of schizophrenia, which exhibit memory impairment and sensorimotor gating deficit. Memory impairment was induced by scopolamine, a muscarinic receptor antagonist, or MK-801, an N-methyl-D-aspartate receptor antagonist. Sensorimotor gating deficits were induced by MK-801 and measured by prepulse inhibition (PPI) of the acoustic startle response task. DMPC treatment (20 mg/kg) significantly attenuated scopolamine- or MK-801-induced memory impairment and it even enhanced cognitive performance of normal animals. Furthermore, DMPC significantly ameliorated MK-801-induced PPI deficits in the acoustic startle response task. In an in vitro study, DMPC (20 μM) inhibited intracellular Cl⁻influx induced by muscimol, a selective GABAAreceptor agonist. These results suggest that DMPC would be a potential candidate for alleviating cognitive dysfunction and sensorimotor gating deficits in schizophrenia, and that its effects may be mediated, in part, via blockade of the GABAergic neurotransmitter system.
Agid:
224429