Hyung Eun Lee

Neuroprotective effects of salvianolic acid B on an Aβ25-35 peptide-induced mouse model of Alzheimer's disease.

Salvianolic acid B (SalB) is a polyphenolic compound found in Salvia miltiorrhiza Bunge that has several anti-oxidative and anti-inflammatory effects. In the present study, we investigated whether SalB has neuroprotective effects in an amyloid β (Aβ) peptide-induced Alzheimers disease mouse model. Mice were injected with Aβ25-35 peptide intracerebroventricularly and were subsequently administered SalB once daily for 7 days. Subchronic SalB administration (10mg/kg) significantly ameliorated the Aβ25-35 peptide-induced memory impairment in the passive avoidance task (P<0.05). SalB treatment also reduced the number of activated microglia and astrocytes that were observed during the inflammatory reaction after the administration of the Aβ25-35 peptide. Moreover, SalB markedly reduced inducible nitric oxide synthase and cyclooxygenase-2 expression levels and thiobarbituric acid reactive substances, which were increased by the administration of the Aβ25-35 peptide. Furthermore, SalB administration significantly rescued the Aβ25-35 peptide-induced decrease of choline acetyltransferase and brain-derived neurotrophic factor protein levels. These results suggest that SalB exerts neuroprotective activity via anti-inflammatory and anti-oxidative effects and that SalB may be a potential candidate for Alzheimers disease therapy.

Neuroprotective effect of sinapic acid in a mouse model of amyloid β1–42 protein-induced Alzheimer's disease

Sinapic acid (SA) is a phenylpropanoid compound with anti-inflammatory and neuroprotective activities. The neuroprotective effects of SA in a mouse model of amyloid β (Aβ)(1-42) protein-induced Alzheimers disease (AD) were investigated. Mice received a bilateral injection of Aβ(1-42) protein into the hippocampus to verify the efficacy of SA. Mice were treated with SA (10mg/kg/day, p.o.) for 7days beginning immediately after Aβ(1-42) protein injection, and an acquisition trial of the passive avoidance task was conducted 1h after the last administration of SA. Retention trial was conducted 24h after the acquisition trial, and mice were sacrificed for immunohistochemistry immediately after the retention trial. SA rescued neuronal cell death in the hippocampal CA1 region and also attenuated the increase of iNOS expression, glial cell activations and nitrotyrosine expressions induced by Aβ(1-42) protein. SA significantly attenuated memory impairment in the passive avoidance task. These results suggest that SA ameliorated Aβ(1-42) protein-related pathology including neuronal cell death and cognitive dysfunction via its anti-oxidative and anti-inflammatory activities, and may be an efficacious treatment for AD.

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 Alzheimers disease.

The memory ameliorating effects of INM-176, an ethanolic extract of Angelica gigas, against scopolamine- or Aβ1–42-induced cognitive dysfunction in mice

ETHNOPHARMACOLOGICAL RELEVANCE Alzheimers disease is a neurodegenerative disorder associated with cognitive impairment and cholinergic neuronal death. INM-176 is a standardized ethanolic extract of Angelica gigas Nakai that has been traditionally used in herbal medicine in China, Japan, and Korea to treat anemia or as a sedative. We investigated whether INM-176 exhibits anti-amnesic effects. MATERIALS AND METHODS Memory impairment was induced by scopolamine, a cholinergic muscarinic receptor antagonist, or amyloid β(1-42) (Aβ(1-42)) protein. Anti-amnesic effects of INM-176 were measured by the passive avoidance and the Morris water maze tasks in mice. We also examined the effect of INM-176 on the acetylcholinesterase activity, as well as Aβ(1-42) protein-induced astrogliosis or cholinergic neuronal loss in the brain. RESULTS Scopolamine-induced cognitive dysfunction was significantly attenuated by a single or sub-chronic administration of INM-176 in the passive avoidance and the Morris water maze tasks. A single or sub-chronic administration of INM-176 also ameliorated memory impairments induced by Aβ(1-42) protein. INM-176 inhibited acetylcholinesterase activity in the hippocampal tissue in vitro and ex vivo. In addition, INM-176 attenuated the Aβ(1-42) protein-induced astrocyte activation in the hippocampus as well as cholinergic neuronal damage in the CA3 region of the hippocampus and the nucleus basalis of Meynert. CONCLUSION These results suggest that the memory ameliorating effects of INM-176 on scopolamine- or Aβ(1-42) protein-induced memory impairment are mediated, in part, via acetylcholinesterase inhibition and neuroprotective activities.

Ethanolic Extract of the Seed of Zizyphus jujuba var. spinosa Ameliorates Cognitive Impairment Induced by Cholinergic Blockade in Mice

In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activity. The ameliorating effect of EEZS on scopolamine-induced memory impairment was significantly reversed by a sub-effective dose of MK-801 (0.0125 mg/kg, s.c.). In addition, single administration of EEZS in normal naïve mouse enhanced latency time in the passive avoidance task. Western blot analysis was employed to confirm the mechanism of memory-ameliorating effect of EEZS. Administration of EEZS (200 mg/kg) increased the level of memory-related signaling molecules, including phosphorylation of extracellular signal-regulated kinase or cAMP response element-binding protein in the hippocampal region. Also, the time-dependent expression level of brain-derived neurotrophic factor by the administration of EEZS was markedly increased from 3 to 9 h. These results suggest that EEZS has memory-ameliorating effect on scopolamine-induced cognitive impairment, which is mediated by the enhancement of the cholinergic neurotransmitter system, in part, via NMDA receptor signaling, and that EEZS would be useful agent against cognitive dysfunction such as Alzheimer’s disease.

Oleanolic acid attenuates MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a severe neuropsychiatric disorder that is characterized by core psychiatric symptoms, including positive, negative, and cognitive symptoms. Current treatments for schizophrenia have an effect on positive symptoms but have a limited efficacy on negative or cognitive symptoms. Oleanolic acid is a plant-derived pentacyclic terpenoid that is known to exhibit anti-oxidative and anti-inflammatory activities. Here, we investigated the effects of oleanolic acid on schizophrenia-like behaviors in mice elicited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. A single administration of oleanolic acid blocked MK-801-induced hyperlocomotion in the open field test. In the acoustic startle response test, oleanolic acid itself did not have any effects on the acoustic startle response or prepulse inhibition (PPI) level, whereas the MK-801-induced PPI deficit was ameliorated by oleanolic acid. In the novel object recognition test, the attention and recognition memory impairments induced by MK-801 were reversed by a single administration of oleanolic acid. Additionally, oleanolic acid normalized the MK-801-induced alterations of signaling molecules including phosphorylation levels of Akt and GSK-3β in the frontal cortex. These results suggest that oleanolic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, and cognitive impairments.

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-3β (GSK-3β). 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-3β signal pathway. These findings suggest that allantoin has therapeutic potential for the cognitive dysfunctions observed in Alzheimers disease.

Spinosin, a C-glycoside flavonoid, enhances cognitive performance and adult hippocampal neurogenesis in mice.

Adult neurogenesis has received much attention due to its potential role in neurological or psychiatric disorders such as Alzheimers disease. In the present study, we examined whether spinosin, a C-glycoside flavonoid from the seeds of Zizyphus jujuba var. spinosa, affects cognitive performance and adult hippocampal neurogenesis in normal naïve mice. The subchronic administration of spinosin (5mg/kg) for 14days significantly increased the latency time in the passive avoidance task. Doublecortin and 5-bromo-2-deoxyuridine immunostaining revealed that the subchronic administration of spinosin (5mg/kg) significantly increased the proliferation and survival of neuronal cells and the number of immature neurons in the hippocampal dentate gyrus region. In addition, we observed an increase in the percentage of BrdU-incorporated cells co-localized with NeuN, a mature neuronal marker, which indicated that spinosin stimulates the differentiation of newly generated cells into mature neurons. Also, the subchronic treatment with spinosin (5mg/kg) increased the expression levels of phosphorylated extracellular-regulated kinase (ERK), phosphorylated cAMP response element-binding protein (CREB) and mature brain-derived neurotrophic factor (mBDNF) in the hippocampus. These findings demonstrate that spinosin has the potential for therapeutic use in treating the cognitive dysfunction observed in neurological or psychiatric disorders by up-regulating adult hippocampal neurogenesis or activating of the ERK-CREB-BDNF signaling pathway.

Oleanolic acid ameliorates cognitive dysfunction caused by cholinergic blockade via TrkB-dependent BDNF signaling.

&NA; 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. HighlightsOleanolic acid activated the ERK1/2‐CREB‐BDNF pathway in the hippocampus via TrkB activation.Scopolamine‐induced memory dysfunction was ameliorated by oleanolic acid treatment.Oleanolic acid evoked the long‐term potentiation in a dose‐dependent manner.Oleanolic acid would be a potential therapeutic agent for the cognitive problem.

Nodakenin Enhances Cognitive Function and Adult Hippocampal Neurogenesis in Mice

In our previous study, we demonstrated that nodakenin, a coumarin compound isolated from Angelica decursiva, ameliorates learning and memory impairments induced by scopolamine. In the present study, we investigated the effects of nodakenin on the cognitive function in the normal naïve mice in a passive avoidance task, and the results showed that nodakenin significantly increased the latency time in normal naïve mice. In addition, sub-chronic administration of nodakenin increased the number of 5-bromo-2-deoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus (DG) region. The percentage of BrdU and NeuN (neuronal cell marker)-immunopositive cells was also significantly increased by the nodakenin administration. Western blotting results showed that the expression levels of phosphorylated protein kinase B (Akt) and phosphorylated glycogen synthase kinase-3β (GSK-3β) were significantly increased in hippocampal tissue by sub-chronic nodakenin administration. These findings suggest that the sub-chronic administration of nodakenin enhances adult hippocampal neurogenesis in the DG region via Akt–GSK-3β signaling and this increase may be associated with nodakenin’s positive effect on cognitive processing.