The leaves of Aster glehni Fr. Schm. (Asteraceae) have been used to treat insomnia in Korea. Insomnia is a common adverse effect of therapeutic agents for Alzheimer's disease (AD), and the control of sleep disturbance may prevent dementia. We hypothesized that the leaves of A. glehni can attenuate cognitive dysfunctions observed in AD. We observed the ameliorating effects of the ethanolic extract of leaves of A. glehni (AG-D) on memory dysfunction through the Morris water maze test, the passive avoidance test, and the Y-maze test. We performed acetylcholinesterase (AChE) activity assay and Western blotting to determine the mechanism of action of AG-D. AG-D significantly attenuated memory dysfunction observed in the above behavior studies and inhibited the activity of AChE. AG-D also increased the levels of phosphorylation extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase 3β (GSK-3β) and the expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampi. These results suggest that AG-D ameliorates memory impairments by AChE inhibition and activation of ERK-CREB-BDNF and PI3K-Akt-GSK-3β signaling pathways. Taken together, this study suggests that AG-D could be used as a potential treatment for cognitive dysfunction.

Bee pollen consists of floral pollen mixed with bee secretions and nectar. It has been considered as a functional food and has different kinds of biologically active ingredients, such as flavonoids, polyphenols, phytosterols and minerals. However, its function in cognition has yet been investigated. In the present study, we investigated the ameliorating effect of bee pollen against scopolamine-caused cognitive impairment through the passive avoidance test, the Y-maze test and the Morris water maze test. In addition, Western blotting was employed to verify the effects of bee pollen on memory-related signaling molecules in the hippocampus. Bee pollen extract (100 or 300 mg/kg, per os (p.o.)) obviously reversed scopolamine-caused cognitive impairment in the passive avoidance test, ameliorated spontaneous alternation versus the scopolamine-treated group in the Y-maze test and prolonged swimming time in the target zone in the Morris water maze test. In addition, the phosphorylation levels of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β), and the expression levels of brain-derived neurotrophic factor (BDNF) and tissue plasminogen activator (tPA) in the hippocampi, were increased in response to the treatment with bee pollen extract (100 or 300 mg/kg, p.o.). These results indicated that bee pollen ameliorates cognitive impairment induced by cholinergic blockade through the enhancing conversion of proBDNF to mature BDNF by tPA, probably, through the ERK-CREB pathway or Akt-GSK-3β signaling pathway and would be a useful agent for the treatment of cognitive dysfunction.

Many works have been performed to understand the mechanisms of the formation and persistence of memory. However, it is not fully understood whether the decay of long-term memory can be modulated by the activation of dopamine D-1 receptor. A Barnes maze task was employed to measure long-term spatial memory. We observed that the spatial memory acquired through 3 trials per session for 4 days had begun to fade out by the 14th day and had completely disappeared by 21 days after the first probe test. The intraperitoneal administration of SKF 38393 (a dopamine D-1 receptor agonist) for 7 days beginning on the 14th day after the first probe test prevented natural memory forgetting, and the intraperitoneal administration of SCH 23390 (a dopamine D-1 receptor antagonist) prevented this memory persistence. In the Western blotting, the administration of SKF 38393 increased the phosphorylation levels of PKA, ERK1/2, CaMKII, and CREB in the hippocampus. In addition, such increased levels were decreased by the corresponding antagonist (SCH 23390). Moreover, the inhibition of PKA could completely reverse the preservation of spatial memory induced by dopamine D1 receptor activation. These results suggest that the activation of the dopamine D-1 receptor plays a critical role in the persistence of long-term spatial memory through the PKA signaling pathway.

Understanding the mechanisms underlying the natural decay of long-term memory can help us find means of extending the duration of long-term memory. However, the neurobiological processes involved in the decay of long-term memory are poorly understood. In the present study, we examined the effect of acute and chronic treatment of fluoxetine on natural decay of long-term memory and the possible mechanism. Late administration of fluoxetine prolonged the persistence of long-term memory in mice, as demonstrated by object location recognition and Barnes maze tests. Fluoxetine altered Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling in the hippocampus. Late short- and long-term pharmacological inhibition of GSK-3β mimicked the effect of fluoxetine on memory persistence. Pharmacological inhibition of Akt blocked the effect of fluoxetine on memory persistence. Finally, late infusion of fluoxetine increased hippocampal long-term potentiation (LTP) and pharmacological inhibition of GSK-3β blocked the natural decline in LTP. These results demonstrate that GSK-3β might be a key molecule in memory decay process, and fluoxetine extends the period of long-term memory maintenance via Akt/GSK-3β signaling.

Ethnopharmacological relevance: The seeds of Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F Chow (Rhamnaceae) and the roots of Codonopsis lanceolata (Siedbold & Zucc.) Benth. & Hook. f ex Trautv. (Campanulaceae), contained in the DHP1402, have long been used for treating dementia or hypomnesia as folk medicine. Aim of the study: It has been reported that Z jujuba var. spinosa and C. lanceolata are effective in improving cognitive function, but via different mechanisms. Therefore, in the present study, we evaluated the synergistic effects of Z. jujuba var. spinosa and C. lanceolata on scopolamine-induced memory impairment. Materials and methods: Scopolamine, a cholinergic muscarinic receptor antagonist, was used to induce cognitive dysfunction. We employed several behavioral tasks to estimate the synergistic effect of the seeds of Z. jujuba var. spinosa and the roots of C. lanceolata. In addition, we introduced the Western blotting, the antagonism passive avoidance task to investigate a synergistic effect of an herbal formulation. Results: Synergistic effects of a combination of Z. jujuba var. spinosa and C. lanceolata at a 5:1 ratio [(w/w), DHP1402] were observed against cognitive dysfunction in the passive avoidance and Y-maze tasks. DHP1402 also ameliorated memory deficits in a dose-dependent manner in these behavioral tasks, as well as in the Morris water maze task. According to the Western blot results, the phosphorylation levels of protein kinase A (PKA), extracellular signal-regulated kinase (ERIC) and cAMP response element-binding protein (CREB) in the hippo campus were also increased in a synergistic manner after the administration of DHP1402. In addition, we found that the effects of DHP1402 on cognitive function were mediated by N-methyl-D-aspartate (NMDA) receptor signalling, based on the antagonism studies. Furthermore, we found that DHP1402 has inhibitory activity against acetylcholinesterase (AChE). Conclusion: DHP1402 attenuates cholinergic blockade-induced cognitive dysfunction through NMDA receptor modulation, PKA-ERK-CREB pathway activation, and AChE inhibition. Therefore, DHP1402 could be a candidate for alleviating cognitive dysfunction.

The stem of Opuntia ficus-indica var. saboten is edible and has been used as a medicinal herb on Jeju Island in Korea. We previously reported that the butanolic extract of O. ficus-indica var. saboten exerts the enhancement of long-term memory in mice. However, the antiamnesic effects of O. ficus-indica var. saboten and its mode of action has not been clearly elucidated. In the present study, we explored the effects of the ethanolic extract of stems of O. ficus-indica var. saboten (EOFS) on cognitive performance in mouse and attempted to delineate its mechanism of action. We used the passive avoidance, Y-maze, and novel object recognition tests to assess its effects on cognitive functions in scopolamine-induced memory-impaired mice. We observed that EOFS (100, 200, and 400mg/kg) ameliorated scopolamine-induced cognitive dysfunction. We also explored its mechanism of action by conducting an acetylcholinesterase (AChE) activity assay using the mouse whole brain and Western blot using the mouse hippocampal tissue. Western blot analysis and the ex vivo study revealed that EOFS increased the levels of phosphorylated extracellular signal-regulated kinase and cAMP response element-binding protein (CREB) and the levels of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. It also inhibited AChE activity in the brain. Our findings suggest that EOFS would be useful for the treatment of cholinergic blockade-induced cognitive dysfunction.

Acanthopanax koreanum Nakai (Araliaceae) is one of the most widely cultivated medicinal plants in Jeju Island, Korea, and the roots and stem bark of A. koreanum have been traditionally used as a tonic agent for general weakness. However, the use of A. koreanum for general weakness observed in the elderly, including those with declined cognitive function, has not been intensively investigated. This study was performed to investigate the effect of the ethanol extract of A. koreanum (EEAK) on cholinergic blockade‐induced memory impairment in mice. To evaluate the ameliorating effects of EEAK against scopolamine‐induced memory impairment, mice were orally administered EEAK (25, 50, 100, or 200 mg/kg), and several behavioral tasks, including a passive avoidance task, the Y‐maze, and a novel object recognition task, were employed. Besides, western blot analysis was conducted to examine whether EEAK affected memory‐associated signaling molecules, such as protein kinase B (Akt), Ca2+/calmodulin‐dependent protein kinase II (CaMKII), and cAMP response element‐binding protein (CREB). The administration of EEAK (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine‐induced cognitive impairment in the passive avoidance task, the Y‐maze, and the novel object recognition task. The phosphorylation levels of both Akt and CaMKII were significantly increased by approximately two‐fold compared with the control group because of the administration of EEAK (100 or 200 mg/kg) (p < 0.05). Moreover, the phosphorylation level of CREB was also significantly increased compared with the control group by the administration of EEAK (200 mg/kg) (p < 0.05). The present study suggests that EEAK ameliorates the cognitive dysfunction induced by the cholinergic blockade, in part, via several memory‐associated signaling molecules and may hold therapeutic potential against cognitive dysfunction, such as that presented in neurodegenerative diseases, for example, Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.

In the present study, we investigated whether 1-palmitoyl-2-linoleoyl-3-acetylglycerol (PLAG), a component of antlers of Cervus nippon Temminck, would have memory-ameliorating properties against cholinergic blockade-induced memory impairment in mice. In the passive avoidance task to investigate the effects of PLAG on long-term memory, PLAG (10mg/kg, p.o.) administration ameliorated scopolamine-induced memory impairment. PLAG also reversed the impairments of working memory in the Y-maze task and spatial memory as shown in the Morris water maze. To identify the mechanism of the memory-ameliorating effect of PLAG, acetylcholinesterase (AChE) inhibition assay and the Western blot analysis were conducted. In the AChE inhibition assay, PLAG inhibited the AChE activity in mice and PLAG increased the expression levels of phosphorylated CaMKII, ERK, and CREB in the hippocampus. Additionally, long-term potentiation (LTP) of synaptic strength occurred by PLAG treatment in the hippocampal cultures. Overall, the present study suggests that PLAG reversed memory deficits in an animal model and that it affects biochemical pathways related to learning and memory.

Oleanolic acid is a naturally occurring triterpenoid and is widely present in food and medicinal plants. To examine the effect of oleanolic acid on memory deficits, we employed a cholinergic blockade-induced cognitive deficit mouse model. A single administration of oleanolic acid significantly increased the latency on the passive avoidance task and affected the alternation behavior on the Y-maze task and the exploration time on the novel object recognition task, indicating that oleanolic acid reverses the cognitive impairment induced by scopolamine. In accordance with previous reports, oleanolic acid enhanced extracellular-signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Interestingly, ameliorating effect of oleanolic acid on scopolamine-induced memory impairment was abolished by N2-(2-{[(2-oxoazepan-3-yl)amino]carbonyl}phenyl)benzo[b]thiophene-2-carboxamide (ANA-12), a potent and specific inhibitor of tropomyosin receptor kinase B (TrkB), in the passive avoidance task. Similarly, oleanolic acid significantly evoked long-term potentiation in a dose-dependent manner, which was diminished by ANA-12 treatment as shown in the electrophysiology study. Together, these results imply that oleanolic acid ameliorates scopolamine-induced memory impairment by modulating the BDNF-ERK1/2-CREB pathway through TrkB activation in mice, suggesting that oleanolic acid would be a potential therapeutic agent for the treatment of cognitive deficits.

Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments.