Amyrin attenuates scopolamine-induced cognitive impairment in mice.

Alzheimer's disease, a neurodegenerative disorder, is characterized by progressive cognitive impairment associated with the disruption of cholinergic neurotransmission. The aim of the present study was to evaluate the effect of α- or ß-amyrin, a type of pentacyclic triterpene, on the cognitive impairment induced by scopolamine, a muscarinic acetylcholine receptor antagonist. To measure the abilities of various types of learning and memory, we conducted step-through passive avoidance task. Scopolamine induced deficits in learning and memory processes in mice, which were antagonized by a single administration of α-amyrin (2 or 4 mg/kg) or ß-amyrin (4 mg/kg), respectively. Additionally, in vitro analysis revealed that acetylcholinesterase activity was inhibited by ß-amyrin, but not by α-amyrin. Furthermore, Western blot analysis revealed that the expression levels of phosphorylated extracellular signal-regulated kinase 1/2 (pERK) and phosphorylated glycogen synthase kinase-3ß (pGSK-3ß) were significantly enhanced by a single administration of α- and ß-amyrin in the hippocampus. Finally, the memory ameliorating effects of α- or ß-amyrin on the scopolamine-induced cognitive impairments were significantly blocked by ERK inhibitor U0126. The present study suggests that α- and ß-amyrin may ameliorate the cognitive impairment induced by hypocholinergic neurotransmission via the activation of ERK as well as GSK-3ß signaling.

The effects of atomoxetine and methylphenidate on the prepulse inhibition of the acoustic startle response in mice.

Atomoxetine (ATM) and methylphenidate (MPD) have been used for the treatment of attention deficit hyperactivity disorder (ADHD). ATM is a selective norepinephrine reuptake inhibitor, whereas MPD is a psychostimulant and acts as a norepinephrine and dopamine reuptake inhibitor. In the present study, we investigated the effects of ATM (1, 3 or 10mg/kg) and MPD (5, 10 or 20mg/kg) on pharmacological mouse models of sensorimotor gating measured by prepulse inhibition (PPI) using the acoustic startle response test. MK-801, a non-competitive N-methyl-d-aspartate receptor antagonist, or apomorphine, a non-competitive dopamine receptor agonist, was used to induce PPI deficits. ATM (3 or 10mg/kg, s.c.) significantly attenuated the MK-801-, but not apomorphine-, induced PPI deficits. In contrast to ATM, MPD did not reverse the PPI deficits induced by either MK-801 or apomorphine. Immunostaining revealed that the number of c-Fos-immunopositive cells was increased in the nucleus accumbens following MK-801 treatment, and this was reversed by the administration of ATM (3mg/kg), but not MPD (10mg/kg). However, neither ATM nor MPD reversed the increased number of c-Fos-immunopositive cells in the nucleus accumbens following apomorphine treatment. These results suggest that the attenuating effect of ATM on the increased c-Fos immunoreactivity in the nucleus accumbens induced by MK-801 may be attributed to the PPI deficit-ameliorating effects of ATM and that ATM would be useful to treat sensorimotor gating-related disorders by improving the patient's attention span or cognitive function.

Spicatoside A enhances memory consolidation through the brain-derived neurotrophic factor in mice.

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in memory consolidation. Previously, we found that the increased mature BDNF (mBDNF) levels in the hippocampal region at a specific time window after the acquisition trial are required for memory consolidation. In the present study, we investigated whether spicatoside A enhances memory consolidation, and whether its effects on memory consolidation are related to hippocampal mBDNF levels. Spicatoside A (2.5, 5, 10 or 20mg/kg) enhanced memory consolidation in a dose-dependent manner, and enhanced memory consolidation was also observed when spicatoside A was administered 1h after the acquisition trial. Concurrently, when spicatoside A was administered immediately or 1h after the acquisition trial, hippocampal mBDNF levels were similar or significantly increased at 9h after the acquisition trial compared to levels at 6h. These results suggest that increased mBDNF levels in the hippocampal region at 9h after the acquisition trial might play a pivotal role in memory consolidation and that spicatoside A might enhance memory consolidation by increasing hippocampal mBDNF levels.

Anxiolytic-like effect of danshensu [(3-(3,4-dihydroxyphenyl)-lactic acid)] in mice.

AIMS: Danshensu [3-(3,4-dihydroxyphenyl)-lactic acid], a phenylpropanoid compound isolated from Prunella vulgaris var. lilacina, is a well-known antioxidant. Although its antioxidant activity and cardioprotective effect have been reported, the pharmacological properties of danshensu in the central nervous system remain unclear. We investigated whether danshensu exerts anxiolytic-like activity in mice. MAIN METHODS: We conducted monoamine oxidase A (MAO-A) inhibition assay on danshensu in vitro, and behavioral tests including the elevated plus-maze test (EPM), the hole-board test, the rotarod test and the open field test were employed. KEY FINDINGS: We found that danshensu significantly inhibited the activity of MAO-A in vitro. The administration of danshensu (3 or 10mg/kg) produced a significant anxiolytic-like effect in the EPM and hole-board test. In addition, no changes in the spontaneous locomotor activity and no myorelaxant effects were observed compared to the control group; these effects were confirmed with the open field test and the rotarod test. Moreover, the anxiolytic-like properties of danshensu were antagonized by a dopamine D1 receptor antagonist (SCH 23390) but not by a 5-HT1A receptor antagonist (WAY 100635) or an α1-adrenergic receptor antagonist (prazosin). SIGNIFICANCE: These results indicate that danshensu exerts its anxiolytic-like properties, in part, through dopaminergic neurotransmitter signaling.

Ameliorating effect of spinosin, a C-glycoside flavonoid, on scopolamine-induced memory impairment in mice.

Spinosin is a C-glycoside flavonoid isolated from the seeds of Zizyphus jujuba var. spinosa. This study investigated the effect of spinosin on cholinergic blockade-induced memory impairment in mice. Behavioral tests were conducted using the passive avoidance, Y-maze, and Morris water maze tasks to evaluate the memory-ameliorating effect of spinosin. Spinosin (10 or 20mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairment in these behavioral tasks with a prolonged latency time in the passive avoidance task, an increased percentage of spontaneous alternation in the Y-maze task and a lengthened swimming time in target quadrant in the Morris water maze task. In addition, a single administration of spinosin in normal naïve mice also enhanced the latency time in the passive avoidance task. To identify the mechanism of the memory-ameliorating effect of spinosin, receptor antagonism analysis and Western blotting were performed. The ameliorating effect of spinosin on scopolamine-induced memory impairment was significantly antagonized by a sub-effective dose (0.5mg/kg, i.p.) of 8-hydroxy-2-(di-N-propylamino)tetralin, a 5-HT1A receptor agonist. In addition, spinosin significantly increased the expression levels of phosphorylated extracellular signal-regulated kinases and cAMP response element-binding proteins in the hippocampus. Taken together, these results indicate that the memory-ameliorating effect of spinosin may be, in part, due to the serotonergic neurotransmitter system, and that spinosin may be useful for the treatment of cognitive dysfunction in diseases such as Alzheimer's disease.

Effects of allantoin on cognitive function and hippocampal neurogenesis.

Allantoin is contained in Nelumbo nucifera (lotus) and a well-known cosmetic ingredient reported to have anti-oxidative and anti-inflammatory activities. In the present study, we investigated whether allantoin affects cognitive function in mice. The subchronic administration of allantoin (1, 3 or 10 mg/kg, for 7 days) significantly increased the latency time measured during the passive avoidance task in scopolamine-induced cholinergic blockade and normal naïve mice. Allantoin treatment (3 or 10 mg/kg, for 7 days) also increased the expression levels of phosphorylated phosphatidylinositide 3-kinase (PI3K), phosphorylated protein kinase B (Akt) and phosphorylated glycogen synthase kinase-3ß (GSK-3ß). Doublecortin and 5-bromo-2-deoxyuridine immunostaining revealed that allantoin significantly increased the neuronal cell proliferation of immature neurons in the hippocampal dentate gyrus region. In conclusion, allantoin has memory-enhancing effects, and these effects may be partly mediated by the PI3K-Akt-GSK-3ß signal pathway. These findings suggest that allantoin has therapeutic potential for the cognitive dysfunctions observed in Alzheimer's disease.

Kami-ondam-tang, a traditional herbal prescription, attenuates the prepulse inhibition deficits and cognitive impairments induced by MK-801 in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Kami-ondam-tang (KODT) has been used to treat neuropsychiatric disorders, including neurosis and insomnia, in traditional herbal medicine. However, the mechanisms of this drug have not been well characterized in the treatment of schizophrenia-like behaviors. AIM OF THE STUDY: We investigated whether schizophrenia-like behaviors induced by MK-801, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, could be attenuated by KODT. MATERIALS AND METHODS: Acute systemic administration of MK-801 was used to establish an animal model of schizophrenia. The effects of KODT on the MK-801-induced prepulse inhibition (PPI) deficits, hyperlocomotion, social withdrawal, and cognitive impairment were assessed. We also examined the changes in the expression levels of Akt and extracellular signal-regulated kinase (ERK) after the administration of KODT with MK-801 in the cortical and hippocampal tissues. RESULTS: The acoustic startle response test showed that the acoustic startle enhancement and PPI deficits induced by MK-801 were attenuated by KODT. Moreover, KODT ameliorated social and objective recognition impairments that were induced by MK-801 in the social novelty preference test and the novel object recognition test. In addition, the upregulation of phosphorylated Akt or phosphorylated ERK expression induced by MK-801 was blocked by KODT in the cortex. However, MK-801-induced hyperlocomotion was not affected by KODT in the open field test. CONCLUSION: These findings suggest that KODT attenuates MK-801-induced PPI disruption, social interaction deficits, and cognitive impairments, possibly, by regulating of cortical Akt and ERK signaling.