Effects of Sun ginseng on memory enhancement and hippocampal neurogenesis.

Panax ginseng C.A. Meyer has been used in traditional herb prescriptions for thousands of years. A heat-processing method has been used to increase the efficacy of ginseng, yielding what is known as red ginseng. In addition, recently, a slightly modified heat-processing method was applied to ginseng, to obtain a new type of processed ginseng with increased biological activity; this new form of ginseng is referred to as Sun ginseng (SG). The aim of this study was to investigate the effect of SG on memory enhancement and neurogenesis in the hippocampal dentate gyrus (DG) region. The subchronic administration of SG (for 14 days) significantly increased the latency time in the passive avoidance task relative to the administration of the vehicle control (P < 0.05). Western blotting revealed that the levels of phosphorylated extracellular signal-regulated kinase (pERK) and phosphorylated protein kinase B (pAkt) were significantly increased in hippocampal tissue after 14 days of SG administration (P < 0.05). Doublecortin and 5-bromo-2-deoxyuridine immunostaining revealed that SG significantly enhanced the neuronal cell proliferation and the survival of immature neurons in the subgranular zone of the hippocampal DG region. These results suggest that SG has memory-enhancing activities and that these effects are mediated, in part, by the increase in the levels of pERK and pAkt and by the increases in cell proliferation and cell survival.

Neuroprotective effect of sinapic acid in a mouse model of amyloid ß(1-42) 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 ß (Aß)(1-42) protein-induced Alzheimer's disease (AD) were investigated. Mice received a bilateral injection of Aß(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 Aß(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 Aß(1-42) protein. SA significantly attenuated memory impairment in the passive avoidance task. These results suggest that SA ameliorated Aß(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.

The memory ameliorating effects of INM-176, an ethanolic extract of Angelica gigas, against scopolamine- or Aß(1-42)-induced cognitive dysfunction in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's 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 ß(1-42) (Aß(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 Aß(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 Aß(1-42) protein. INM-176 inhibited acetylcholinesterase activity in the hippocampal tissue in vitro and ex vivo. In addition, INM-176 attenuated the Aß(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 Aß(1-42) protein-induced memory impairment are mediated, in part, via acetylcholinesterase inhibition and neuroprotective activities.

GSK-3ß activity in the hippocampus is required for memory retrieval.

Several molecules were recently found to be important for the memory retrieval process in the hippocampus; however, the mechanisms underlying the memory retrieval remain poorly understood. GSK-3ß has been implicated in the control of synaptic plasticity and memory formation. Here, we investigated the relationship between hippocampal GSK-3ß activity and memory retrieval using behavioral and Western blotting methods. We found that GSK-3ß was activated in the hippocampus after a retention session in the passive avoidance task. An intrahippocampal injection of the GSK-3ß inhibitor, SB 216763, before the retention session blocked memory retrieval (but not reconsolidation) without affecting locomotor activity. These results suggest that GSK-3ß activation would be essential for memory retrieval in the hippocampus.

The neuroprotective effect of eupatilin against ischemia/reperfusion-induced delayed neuronal damage in mice.

Eupatilin, a pharmacologically active flavone derived from the Artemisia plant species, has been reported to have anti-oxidant, anti-inflammatory, anti-allergic, and anti-tumor activities. In the present study, we investigated whether eupatilin exhibits neuroprotective activities against ischemia/reperfusion-induced delayed neuronal injury in mice. Transient global cerebral ischemia was induced in mice by bilateral common carotid artery occlusion (BCCAO) for 15 min followed by reperfusion for 4 days. Eupatilin (1, 3, or 10 mg/kg, p.o.) was administered immediately after the reperfusion. Histochemical studies showed that eupatilin (10 mg/kg) increased the number of viable cells detected by Nissl staining and decreased the number of degenerating neuronal cells detected by Fluoro-Jade B staining in the hippocampal CA1 region. Western blotting indicated that eupatilin further increased the level of Akt phosphorylation at 8h after BCCAO. Furthermore, wortmannin, a phosphatidylinositol 3-kinase inhibitor, attenuated the eupatilin-induced increase of Akt phosphorylation. In addition, wortmannin completely reversed the eupatilin-induced neuroprotective effects observed at 4 days after reperfusion. These findings suggest that eupatilin is a promising therapeutic agent against global cerebral ischemia-induced neuronal damage and that its neuroprotective effects may be mediated in part by increased Akt phosphorylation.

The ameliorating effects of stigmasterol on scopolamine-induced memory impairments in mice.

Stigmasterol, a kind of phytosterol, is present in small amounts in various foods. In the present study, we investigated the effects of stigmasterol on scopolamine-induced memory impairments using the passive avoidance and the Morris water maze tasks in mice. In addition, changes in memory-related molecules, including extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were examined following the administration of stigmasterol. Scopolamine-induced memory impairments were significantly attenuated by the administration of stigmasterol (10mg/kg) in the passive avoidance task. In the Morris water maze task, the escape latencies were significantly decreased in the stigmasterol-treated group compared to the scopolamine-treated group during the training phase. The swimming times within the target zone during the probe trial were significantly increased as compared to scopolamine-treated mice. Furthermore, the ameliorating effect of stigmasterol on scopolamine-induced memory dysfunction was blocked by a sub-effective dose of dizocilpine (MK-801), an NMDA receptor antagonist, and tamoxifen, an estrogen receptor antagonist, in the passive avoidance task. In addition, the expression levels of phosphorylated ERK and CREB in the hippocampus were significantly increased by stigmasterol, which was blocked by tamoxifen or MK-801 with scopolamine. These results suggest that stigmasterol-induced cognitive ameliorative effects are mediated by the enhancement of cholinergic neurotransmission system via the activation of estrogen or NMDA receptors.

The memory-enhancing effects of Kami-ondam-tang in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Kami-ondam-tang (KOT), a traditional Chinese medicine, has been used to treat mental and neuropsychiatric disorders, including dementia. This study aimed to investigate the effects of KOT on cognition and the mechanisms underlying these effects in mice. MATERIALS AND METHODS: Using the passive avoidance task, we investigated the effect of sub-chronic administration of KOT on the cognition of mice. We also examined the expressions of protein kinase B (Akt), cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and doublecortin (DCX) in the hippocampal CA1 and dentate gyrus regions using immunohistochemistry and western blotting. RESULTS: The administration of KOT (50mg/kg/day, p.o.) for 14 days significantly increased step-through latency in the passive avoidance task compared with vehicle-treated controls. Furthermore, KOT administration (50mg/kg/day, p.o.) significantly increased the expressions of phosphorylated Akt, phosphorylated CREB and BDNF in the hippocampal CA1 and dentate gyrus. In addition, KOT administration resulted in a significant increase in the number of DCX-immunopositive cells in the dentate gyrus. CONCLUSIONS: These results suggest that KOT enhances cognitive performance through the upregulation of Akt-CREB-BDNF signaling and neurogenesis.