5-7-dihydroxy-6-methoxy-2-phenylchromen-4-one and Memory-Disorders

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 GABAA receptor 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.

Topics: Acoustic Stimulation; Animals; Avoidance Learning; Flavonoids; Male; Memory Disorders; Mice; Mice, Inbred ICR; NAD(P)H Dehydrogenase (Quinone); Reflex, Startle; Sensory Gating; Treatment Outcome

Oroxylin A is a flavonoid that is found in the roots of Scutellaria baicalensis Georgi. The aim of this study was to characterize the effects of oroxylin A on the memory impairments and pathological changes induced by Abeta(25-35) peptide in mice. The ameliorating effect of oroxylin A on memory impairment was investigated using passive avoidance and Y-maze tasks and pathological changes were identified by immunostaining and western blotting. Abeta(25-35) peptide (5nmol) was administered by intracerebroventricular injection. In the acute treatment study, a single dose of oroxylin A (5mg/kg, p.o.) treated 1h before behavioral tests was found to significantly reverse Abeta(25-35)-induced cognitive impairments based on passive avoidance and Y-maze task findings (P<0.05). Moreover, these acute effects of oroxylin A were blocked by diazepam (1mg/kg, i.p.), a GABA(A)/benzodiazepine binding site agonist (P<0.05). On the other hand, our subchronic studies revealed that oroxylin A (1 or 5mg/kg/day, p.o.) for 7 days ameliorated the memory impairment induced by Abeta(25-35) peptide. Moreover, Abeta(25-35)-induced increases in GFAP (an astroglia marker) and OX-42 (a microglia marker), and increases in iNOS positive cells in the hippocampus were found to be attenuated by subchronic oroxylin A (1 or 5mg/kg/day, i.p., P<0.05). In addition, reductions in the immunoreactivity and protein level of ChAT (a cholinergic neuronal cell marker) in the CA3 hippocampal area induced by Abeta(25-35) peptide were also attenuated by oroxylin A. Furthermore, lipid peroxidation induced by Abeta(25-35) was also reduced by oroxylin A. These results suggest that the amelioration of Abeta(25-35) peptide-induced memory impairment by oroxylin A is mediated via the GABAergic neurotransmitter system after a single administration, or by reductions in Abeta(25-35) peptide-induced astrocyte and microglia activations, iNOS expression, lipid peroxidation, and increased cholinergic neurotransmission after subchronic administration.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Behavior, Animal; CD11b Antigen; Diazepam; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Exploratory Behavior; Flavonoids; Free Radical Scavengers; GABA Modulators; Glial Fibrillary Acidic Protein; Hippocampus; Lipid Peroxidation; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Peptide Fragments; Reaction Time

Oroxylin A is a flavonoid compound that is found in the root of Scutellaria baicalensis Georgi. The aim of this study was to determine the effects of oroxylin A on memory impairment induced by transient bilateral common carotid artery occlusion (2VO) in mice. The ameliorating effect of oroxylin A on memory impairment was investigated using a passive avoidance task, the Y-maze task, and the Morris water maze task in mice. Oroxylin A was found to significantly reverse 2VO-induced cognitive impairments in the passive avoidance and Y-maze tasks in a dose dependant manner (P<0.05). Moreover, oroxylin A (5 mg/kg, p.o.) shortened the escape-latency and prolonged swimming times in the target quadrant during the probe trial in the Morris water maze task (P<0.05). Histochemical and immunohistochemical studies showed that the number of Nissl bodies and OX-42 positive cells in the hippocampal CA1 and dentate gyrus regions were attenuated by oroxylin A. Moreover, phosphorylated cAMP response element-binding protein (CREB) and brain derived neurotrophic factor (BDNF) positive cell numbers were markedly increased in animals treated with oroxylin A than in untreated 2VO controls. These results suggest that oroxylin A dramatically attenuates the memory impairment induced by 2VO, and that this effect may be mediated by the neuroprotective effects of oroxylin A as supported oroxylin A induced reductions in activated microglia and increases in BDNF expression and CREB phosphorylation.

Topics: Animals; Avoidance Learning; Benzoxazines; Brain-Derived Neurotrophic Factor; Carotid Artery, Common; Carotid Stenosis; Cyclic AMP; Dose-Response Relationship, Drug; Flavonoids; Immunohistochemistry; Ischemic Attack, Transient; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Oxazines