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Cassiae semen, a commonly consumed tea and medicinal food, has been shown to have multiple therapeutic actions related to the prevention of dementia and ischemia. In this study, we investigated the effects of extract of Cassiae semen (COE) against neurotoxicities in in vitro and in vivo Parkinson's disease (PD) models. In PC12 cells, COE attenuated the cell damage induced by 100 microM 6-hydroxydopamine (6-OHDA) stress in MTT assay, and it inhibited the overproduction of reactive oxygen species, glutathione depletion, mitochondrial membrane depolarization and caspase-3 activation at 0.1-10 microg/ml. In addition, COE showed radical scavenging activity in the DPPH and ABTS assays. In mesencephalic dopaminergic (DA) culture, COE protected DA cells against 10 microM 6-OHDA- and 10 microM 1-methyl-4-phenylpyridine-induced toxicities at 0.1-1 microg/ml. We also evaluated the effect of COE in a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the pole test, COE (50mg/kg, 15 days)+MPTP (30 mg/kg, 5 days)-treated group had decreased T-turn and T-LA which were longer in MPTP group. Moreover, COE significantly protected DA neuronal degeneration induced by MPTP in the substantia nigra and striatum of these mice. These results demonstrate that COE can prevent DA neurons against the toxicities involved in PD.

Excitotoxin induces neurodegeneration via glutamatergic activation or oxidative stress, which means that the blockade of glutamate receptors and the scavenging of free radicals are potential therapeutic targets in neurodegenerative diseases. Sinapic acid (SA) has a GABA A receptor agonistic property and free radical scavenging activity. We investigated the neuroprotective effects of SA on kainic acid (KA)-induced hippocampal brain damage in mice. SA (10 mg/kg) by oral administration has an anticonvulsant effect on KA-induced seizure-like behavior. Moreover, SA (10 mg/kg) significantly attenuated KA-induced neuronal cell death in the CA1 and CA3 hippocampal regions when administered as late as 6 h after KA. In addition, flumazenil, a GABA A antagonist, blocked the effect of SA administered immediately after KA but not the effect of SA administered 6 h after KA. This late protective effect of SA was accompanied by reduced levels of reactive gliosis, inducible nitric oxide synthase expression, and nitrotyrosine formation in the hippocampus. In the passive avoidance task, KA-induced memory impairments were ameliorated by SA. These results suggest that the potential therapeutic effect of SA is due to its attenuation of KA-induced neuronal damage in the brain via its anti-convulsive activity through GABA A receptor activation and radical scavenging activity.

Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and its flowers are used to treat inflammation in traditional Chinese medicine. In the present study, we studied the effects of the ethanolic extract of the flower of P. vulgaris var. lilacina (EEPV) on drug-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. EEPV (25 or 50 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (P

The fruit of Euphoria longan (Lour.) Steud. (Sapindaceae) is sweet and edible. Dried Euphoria longan fruit is prescribed as a tonic and for the treatment of forgetfulness, insomnia, or palpitations caused by fright in traditional Chinese medicine. The effects of aqueous extract of Euphoria longan fruit (ELE) on learning and memory and their underlying mechanisms were investigated.Aqueous extract of Euphoria longan fruit (ELE) was administered to ICR mice for 14 days. Piracetam was used as a positive control for its known memory-enhancing effects. Memory performances were assessed using the passive avoidance task. The expressions of phosphorylated extracellular signal-regulated kinase (pERK) 1/2, phosphorylated cAMP response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), doublecortin (DCX) and the incorporation of 5-bromo-2-deoxyuridine (BrdU) in hippocampal dentate gyrus and CA1 regions were investigated using immunohistochemical methods.The step-through latency in the ELE-treated group was significantly increased compared with that in the vehicle-treated controls (P0.05) in the passive avoidance task. Piracetam-treated group also showed enhanced cognitive performaces in the passive avoidance task. Immunohistochemical studies revealed that the number of cells immunopositive for BDNF, pCREB, or pERK 1/2 was significantly increased in the hippocampal dentate gyrus and CA1 regions after ELE treatment for 14 days (P0.05). DCX and BrdU immunostaining also revealed that ELE significantly enhanced immature neuronal survival, but not neuronal cell proliferation in the subgranular zone of the dentate gyrus.The present results suggest that subchronic administration of aqueous extract of Euphoria longan fruit enhances learning and memory, and that its beneficial effects are mediated, in part, by BDNF expression and immature neuronal survival.

The aim of this study was to investigate what kind of stress vitamin C could alleviate. Experiments were performed using male ICR mice. Vitamin C (1, 5, 25, and 100 mg/kg) was administered orally daily for 7 days without stress and then were given for 5 days with electroshock (ES) or restraint stress (RS). After loading final stress, we recorded stress-related behaviors and measured the levels of blood corticosterone. Vitamin C supplementation (25 and 100 mg/kg) partially blocked stress-related behaviors such as freezing, smelling, burrowing, facewashing, and grooming. It decreased also staying time in closed arms. Stress responses induced by ES but not immobility were also significantly alleviated by vitamin C. Vitamin C (25 and 100 mg/kg) decreased corticosterone level increased by ES. Swimming time in cold water (8±2°C) was not changed by vitamin C, but crossing frequency in the electric field was increased by vitamin C (25 mg/kg). These results suggest that vitamin C supplementation can prevent damages or diseases induced by stress, especially psychological stress.

－ Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor involved in neuronal differentiation, plasticity, survival and regeneration. BDNF draws massive attention mainly due to the potential as a therapeutic target in neurological diseases such as depression and Alzheimer’s disease. In a primary screening for the natural compounds enhancing BDNF release from cultured rat primary cortical neuron, we found that compounds such as baicalein, tanshinone IIa, cinnamic acid, epiberberine, genistein and wogonin among many others increased BDNF release. All the compounds at 0.1 μM of concentration barely showed stimulatory effect on BDNF induction, however, their combination (mixture 1; baicalein, tanshinone IIa and cinnamic acid, mixture 2; epiberberine, genistein and wogonin) showed synergistic increase in BDNF release as well as mRNA and protein expression. The level of BDNF expression was comparable to the maximum BDNF stimulation attainable by a positive control oroxylin A (20 μM) without cell toxicity as determined by MTT analysis. Both mixtures synergistically increased the phosphorylation of extracellular signal-regulated kinase (ERK) as well as cAMP response element binding protein (CREB), an immediate and essential regulator of BDNF expression. Similar to these results, mixture of these compounds synergistically inhibited the up-regulation of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide treatments in rat primary astrocytes. These results suggest that the combinatorial treatment of natural compounds in lower concentration might be a useful strategy to obtain sufficient BDNF stimulation in neurological disease condition such as depression, while minimizing potential side effects and toxicity of higher concentration of a single compound.Keywords: BDNF, Cortical neuron, CREB, ERK, Synergism

Background and purpose: The intracellular signalling kinase, extracellular signal-regulated kinase 1/2 (ERK1/2) is required for new memory formation, suggesting that control of ERK signalling might be a target for the treatment of cognitive dysfunction. Previously, we reported that tanshinone congeners have ameliorating effects on drug-induced memory impairment in mice. Here, we have investigated possible modes of action of tanshinone I on learning and memory, associated with ERK phosphorylation. Experimental approach: Using immunohistochemical, Western blot techniques, and behavioural testing, we studied the effect of tanshinone I on memory impairment induced by diazepam or dizocilpine (MK-801) in mice. Key results: Tanshinone I (2 or 4 mg·kg−1, p.o.) increased latency times versus vehicle-treated control group in the passive avoidance task. Western blot analysis and immunohistochemical data showed that tanshinone I (4 mg·kg−1) increased levels of phosphorylated cAMP response element binding protein (pCREB) and phosphorylated ERK (pERK) in the hippocampus. These increases in pCREB and pERK were blocked by U0126 (inhibitor of ERK1/2), which also prevented the increase in passive avoidance task latency time after tanshinone I. In models of learning and memory impairment induced by diazepam and MK-801, tanshinone I (4 mg·kg−1) reversed learning and memory impairments detected by the passive avoidance test. Western blot analysis showed that tanshinone I reversed the diazepam- and MK-801-induced inhibitions of ERK and CREB activation in hippocampal tissues. These effects were also blocked by U0126. Conclusions and implications: Tanshinone I ameliorates the learning and memory impairments induced by diazepam and MK-801 through activation of ERK signalling.

Oroxylin A (1), a flavonoid from the roots of Scutellaria baicalensis, increased the cellular accumulation of calcein AM in a concentration-dependent manner in NCI/ADR-RES cells overexpressing P-glycoprotein over the concentration range 0-40 microM. In addition, 1 significantly (p0.05) increased the cellular accumulation of paclitaxel in NCI/ADR-RES cells while it did not alter the cellular accumulation of paclitaxel in cells lacking P-glycoprotein expression. Accordingly, the concentrations that yielded 50% cytotoxicity of vinblastine and paclitaxel were reduced by approximately 5-fold in the presence of 1. This indicated that cancer cells became more susceptible to the cytotoxicity of vinblastine and paclitaxel in the presence of 1. The concomitant use of 1 (30 mg.kg(-1)) significantly (p0.05) enhanced the oral exposure of paclitaxel (15 mg.kg(-1)) in rats. The C(max) and AUC values of paclitaxel increased by 2.1-2.6-fold in the presence of 1 with no significant change in T(max). In conclusion, 1 was effective in inhibiting P-glycoprotein-mediated drug efflux both in vitro and in vivo, suggesting that it may be useful to improve the cellular availability of P-glycoprotein substrates such as anticancer drugs.

Protease-activated receptors (PARs) play important roles in the regulation of brain function such as neuroinflammation by transmitting the signal from proteolytic enzymes such as thrombin and trypsin. We and others have reported that a member of the family, PAR-2 is activated by trypsin, whose involvement in the neurophysiological process is increasingly evident, and is involved in the neuroinflammatory processes including morphological changes of astrocytes. In this study, we investigated the role of PAR-2 in the production of nitric oxide (NO) in rat primary astrocytes. Treatment of PAR-2 agonist trypsin increased NO production in a dose-dependent manner, which was mediated by the induction of inducible nitric-oxide synthase. The trypsin-mediated production of NO was mimicked by PAR-2 agonist peptide and reduced by either pharmacological PAR-2 antagonist peptide or by siRNA-mediated inhibition of PAR-2 expression, which suggests the critical role of PAR-2 in this process. NO production by PAR-2 was mimicked by PMA, a PKC activator, and was attenuated by Go6976, a protein kinase C (PKC) inhibitor. PAR-2 stimulation activated three subtypes of mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. NO production by PAR-2 was blocked by inhibition of ERK, p38, and JNK pathways. PAR-2 stimulation also activated nuclear factor-kappaB (NF-kappaB) DNA binding and transcriptional activity as well as IkappaBalpha phosphorylation. Inhibitors of NF-kappaB pathway inhibited PAR-2-mediated NO production. In addition, inhibitors of MAPK pathways prevented transcriptional activation of NF-kappaB reporter constructs. These results suggest that PAR-2 activation-mediated NO production in astrocytes is transduced by the activation of MAPKs followed by NF-kappaB pathways.

Forsythiaside is a polyphenolic constituent of the fruits of Forsythia suspense Vahl which are widely used as anti-inflammatory herbal raw materials in traditional Chinese medicine. In the present study, the authors assessed the effects of forsythiaside on learning and memory impairments induced by scopolamine using a passive avoidance and the Morris water maze tests in mice. Drug-induced amnesia was induced by scopolamine treatment (1 mg/kg, i.p.). Forsythiaside (10 mg/kg, p.o) administration significantly prevented scopolamine-induced step-through latency reduction in the passive avoidance test and scopolamine-induced increased escape latency in the Morris water maze test (p

SUMMARY The purpose of this study was to characterize the putative anxiolytic-like effects of the 70%ethanol extract of Portulaca oleracea (EPO) using an elevated plus maze (EPM) in mice. The EPOwas orally administered at 50, 100, 200 or 400 mg/kg to ICR mice, 1 h before the behavioralevaluation in the EPM, respectively. Control mice were treated with an equal volume of 10%tween 80, and positive control mice with diazepam (1 mg/kg). Single treatments of the EPOsignificantly increased the percentage of time spent and arm entries into the open arms of theEPM versus controls (P < 0.05). Moreover, there were no changes in the locomotor activity andmyorelaxant effects in any group compared with the saline controls. In addition, the anxiolytic-like effects of the EPO were blocked by flumazenil (10 mg/kg, i.p), a GABA A antagonist not byWAY 100635 (0.3 mg/kg, i.p), a 5-HT 1A receptor antagonist. These results indicate that P. oleraceais an effective anxiolytic agent, and suggest that the anxiolytic-like effects of P. oleracea ismediated via the GABAergic nervous system.Key words: Anxiety; Portulaca oleracea; Elevated plus-maze; WAY 100635; Flumazenil

Coptis japonica (C. japonica) is a perennial medicinal plant that has anti-inflammatory activity. C. japonica contains numerous biologically active alkaloids including berberine, palmatine, epi-berberine, and coptisine. The most well-known anti-inflammatory principal in C. japonica is berberine. For example, berberine has been implicated in the inhibition of iNOS induction by cytokines in microglial cells. However, the efficacies of other alkaloids components on microglial activation were not investigated yet. In this study, we investigated the effects of three alkaloids (palmatine, epi-berberine and coptisine) from C. japonica on lipopolysaccharide (LPS)-induced microglial activation. BV2 microglial cells were immunostimulated with LPS and then the production of several inflammatory mediators such as nitric oxide (NO), reactive oxygen species (ROS) and matrix metalloproteinase-9 (MMP-9) were examined as well as the phosphorylation status of Erk1/2 mitogen activated protein kinase (MAPK). Palmatine and to a lesser extent epi-berberine and coptisine, significantly reduced the release of NO, which was mediated by the inhibition of LPS-stimulated mRNA and protein induction of inducible nitric oxide synthase (iNOS) from BV2 microglia. In addition to NO, palmatine inhibited MMP-9 enzymatic activity and mRNA induction by LPS. Palmatine also inhibited the increase in the LPS-induced MMP-9 promoter activity determined by MMP-9 promoter luciferase reporter assay. LPS stimulation increased Erk1/2 phosphorylation in BV2 cells and these alkaloids inhibited the LPS-induced phosphorylation of Erk1/2. The anti-inflammatory effect of palmatine in LPS-stimulated microglia may suggest the potential use of the alkaloids in the modulation of neuroinflammatory responses, which might be important in the pathophysiological events of several neurological diseases including Alzheimer`s disease (AD), multiple sclerosis (MS), Parkinson`s disease (PD) and stroke.

Schizandra chinensis (S. chinensis) exhibits a harmless, 'adaptogen-type' effect leading to improvements in mental performance and learning efficacy in brain. Activated microglia contributes to neuronal injury by releasing neurotoxic products, which make it important to regulate microglial activation to prevent further cytological as well as functional brain damage. However, the effect of S. chinensis on microglial activation has not been examined yet. We have investigated the effects of four compounds (Gomisin A, Gomisin N, Schizandrin and Schizandrol A) from S. chinensis on lipopolysaccharide (LPS)- induced microglial activation. In this study, BV2 microglial cells were activated with LPS and the microglial activation was assessed by up-regulation of activation markers such as nitric oxide (NO), reactive oxygen species (ROS), and matrix metalloproteinase-9 (MMP-9). The results showed that all four compounds significantly reduced the intracellular level of ROS, the release of NO and MMP-9 as well as LPS-induced phosphorylation of ERK1/2. These results strongly suggested that S. chinensis may be useful to modulate inflammation-mediated brain damage by regulating microglial activation.

To understand memory-enhancing effect of red ginseng biotransformed by Bifidobacterium longum H-1 (RGB), which more potently improved scopolamine-induced learning deficit than red ginseng in the preliminary experiment, its main constituents, ginsenosides Rb1, Rg3 and Rh2, were isolated and their memory-enhancing effects investigated in scopolamine-treated mice by using passive avoidance and Y-maze tests. Among them, ginsenoside Rh2 most potently reversed memory impairment caused by scopolamine. Ginsenoside Rh2 also significantly shortened the escape latencies prolonged by scopolamine in the Morris water maze test (p

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by hyperactivity, inattention, and impulsiveness. Current estimates suggest that 4-12% of school age children are affected by ADHD, which hampers proper social relationship and achievements in school. Even though the exact etiology of the disorder is still in the middle of active investigation, the availability of pharmacological treatments for the disorder suggest that at least the symptoms of ADHD are manageable. To develop drugs with higher efficacy and fewer side effects, it is essential to have appropriate animal models for in vivo drug screening processes. Good animal models can also provide the chances to improve our understanding of the disease processes as well as the underlying etiology of the disorder. In this review, we summarized current animal models used for ADHD research and discussed the point of concerns about using specific animal models.

− Several lines of evidence indicate that adenosine A 2A agonist disrupts spatial working memory. How-ever, it is unclear which stages of learning and memory are affected by the stimulation of adenosine A 2A recep-tor. To clarify these points, we employed CV-1808 as adenosine A 2A agonist and investigated its effects onacquisition, consolidation, and retrieval phases of learning and memory using passive avoidance and the Mor-ris water maze tasks. During the acquisition phase, CV-1808 (2-phenylaminoadenosine, 1 and 2 mg/kg, i.p.)decreased the latency time in passive avoidance task and the mean savings in the Morris water maze task,respectively. During the consolidation and retrieval phase tests, CV-1808 did not exhibited any effects onlatency time in passive avoidance task and the mean savings in the Morris water maze task. These results sug-gest that CV-1808 as an adenosine A 2A agonist impairs memory acquisition but not consolidation or retrieval. Keywords: CV-1808, Adenosine A

Oroxylin A is a flavonoid isolated from Scutellaria baicalensis, which is one of the most important medicinal herbs in traditional Korean medicine. In this study, we investigated the psychopharmacological activi- ties of oroxylin A using the open field, rota-rod, balanced wire and plus-maze tests in Spontaneously Hyperten- sive Rats (SHR) and Wistar Kyoto Rats (WKY). Oroxylin A reduced hyperactivity in SHR (ADHD animal model) although it tended to increase locomotor activity in WKY. Methylphenidate did not reduce hyperactivity. Oroxylin A alleviated impulsive behaviors such as rearing, the percentage of moving time to the central area and the ten- dency to move into an unstable condition (open area in elevated plus-maze). Methylphenidate also reduced the percentage of staying time in the central area and the tendency to move into an unstable condition. Both orox- ylin A and methylphenidate enhanced motor attention in SHR and WKY. Oroxylin A antagonized the muscimol (GABA A receptor agonist)-induced Cl - current and its action was similar to that of bicuculline (GABA A receptor antagonist). The effects of oroxylin A may be caused by the antagonism at the GABA A receptor. Thus, oroxylin A may be a candidate of drug for treatment of ADHD.

To search for new neuroprotective compounds, novel benzylideneacetophenone compounds (JCI, (3E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one; JC2, (1E)-1-(4-hydroxy-3-methoxyphenyl)hept-1-en-3-one; JC3, (2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one; JC4, (1E)-1-(4-hydroxy-3-methoxyphenyl)-5-phenylpent-1-en-3-one; JC5, (1E)-3-(4-hydroxy-3-methoxyphenyl)-6-phenylhex-1-en-3-one; JC6, (1E)-1-(4-hydroxy-3-methoxyphenyl]-7-phenylhept-1-en-3-one) were synthesized, and their potential to prevent neurotoxicities were evaluated. All compounds (JC1-JC6) showed considerable effect on free radical scavenging, the inhibition of glutamate-induced neurotoxicity in cortical cells, and the suppression of lipopolysaccharide (LPS)-induced nitric oxide (NO) generation in microglia. (2E)-3-(4-Hydroxy-3-methoxyphenyl)-phenylpro-2-en-1-one (JC3) exhibited the most potent neuroprotective effect in ischemia model using organotypic hippocampal culture and middle cerebral artery occlusion (MCAO). Based on the above-mentioned results, the mechanisms underlying the biological activity of JC3, which exhibited potent antiexcitotoxic and anti-inflammatory effects, were determined using cortical neuronal cells and microglia. Compound JC3 exerted a neuroprotective effect on oxygen-glucose deprivation- and hydrogen peroxide-induced cytotoxicity in cultured cortical cells. In addition, it suppressed the generation of NO, proinflammatory cytokines, and reactive oxygen species in LPS-treated microglial cells. It also suppressed the activation of phosphorylated Janus tyrosine kinase 2/phosphorylated signal transducer and activator of transcription 3 and mitogen-activated protein kinase (MAPK) in activated microglia and in cortex and striatum after 3 days of the MCAO in mice. These results demonstrated that JC3 might affect a set of intracellular signaling cascades, including the Janus tyrosine kinase/signal transducers and activators of transcription and MAPK pathways. This study suggests that benzylideneacetophenone derivative could be useful antineurotoxic agents.

−Several lines of evidence indicate that scopolamine as a nonselective muscarinic antagonist dis-rupts object recognition performance and spatial working memory when administered systemically. In thepresent study, we investigated the different effects of scopolamine on acquisition, consolidation, and retrievalphases of object recognition performance and spatial working memory using the object recognition and theMorris water maze tasks in mice. In the acquisition phase test, scopolamine decreased recognition index onobject recognition task and the trial 1 to trial 2 differences on Morris water maze task. In the consolidation andretrieval phase tests, scopolamine also decreased recognition index on object recognition task, where as sco-polamine did not exhibited any effects on the Morris water maze task. Keywords : Scopolamine, Object recognition test, Morris water maze, Acquisition, Consolidation, Retrieval INTRODUCTION There are three stages for learning and memory pro-cessing including acquisition, consolidation, and retrievalprocesses (Abel and Lattal, 2001). After detection by thesensory system, information is rapidly encoded and maypass into labile memory. During consolidation, this mem-ory may then be consolidated into long-term storage. Theretrieval process is the final stage which uses the consoli-dated and more fixed memory. It is important to know theeffects of a compound on each stage of memory pro-cessing as the compound which improves multiple cogni-tive processes will be most useful as a treatment formemory deficits (Prickaerts

Voluntary exercise, such as running, can induce dramatic increases in adult hippocampal neurogenesis and improve learning and memory function. A recent report showed that exercise also improved memory problems in postmenopausal women. In this study, we examined whether voluntary running exercise could increase new cell formation in the hippocampus under menopausal conditions, modeled with ovariectomized (OVX) mice. Voluntary running exercise for 1 week significantly increased the number of bromodeoxyuridine (BrdU)- and Ki-67-immunoreactive cells in the hippocampus of mice 2 weeks after ovariectomy. In addition, 1 week of voluntary running exercise after 2 weeks in OVX mice increased the numbers of doublecortin- and calretinin-immunoreactive cells in the hippocampus. These data demonstrate that exercise may increase the birth of new cells in the hippocampus under estrogen-deprived conditions, suggesting that exercise may be helpful in improving brain function in climacteric women.

Gardenia jasminoides (G. jasminoides) is traditionally used to treat insomnia, jaundice, emo- tional disorders, hepatic disease, and inflammatory disease. Previously, we found that geniposide and the water extract of G. jasminoides increased Cl - influx in neuroblastoma. Here we examined the psychophar- macological activities of G. jasminoides and its constituents. G. jasminoides extract was orally administered at 100 and 200 mg/kg, and genipin and geniposide were intraperitoneally injected at 2, 10, and 20 mg/kg. G. jasminoides extract (200 mg/kg) significantly decreased total open field activity but increased rearing activity in the center of the open field, suggesting an increase in exploratory activity. Genipin and genipo- side did not change open field activity, but geniposide (20 mg/kg) increased rearing activity in the central area. The extract (200 mg/kg) significantly decreased rotarod and wire-balancing activity, but genipin and geniposide did not. No compounds influenced thiopental-induced sleeping or electroshock-induced sei- zures. The extract (200 mg/kg) significantly increased staying time in the open arms of the elevated plus maze and the entry ratio into the open arms, and geniposide (20 mg/kg) also increased open arm entry. Electroshock stress decreased open arm activity, but the extract and geniposide (20 mg/kg) significantly reversed that effect. This results indicate that G. jasminoides extract and geniposide alleviated anxiety with greater efficacy in stressed animals than normal animals.

We previously reported that uridine blocked glucose deprivation-induced death of immunostimulated astrocytes by preserving ATP levels. Uridine phosphorylase (UPase), an enzyme catalyzing the reversible phosphorylation of uridine, was involved in this effect. Here, we tried to expand our previous findings by investigating the uridine effect on the brain and neurons using in vivo and in vitro ischemic injury models. Orally administrated uridine (50-200 mg/kg) reduced middle cerebral artery occlusion (1.5 h)/reperfusion (22 h)-induced infarct in mouse brain. Additionally, in the rat brain subjected to the same ischemic condition, UPase mRNA and protein levels were up-regulated. Next, we employed glucose deprivation-induced hypoglycemia in mixed cortical cultures of neurons and astrocytes as an in vitro model. Cells were deprived of glucose and, two hours later, supplemented with 20 mM glucose. Under this condition, a significant ATP loss followed by death was observed in neurons but not in astrocytes, which were blocked by treatment with uridine in a concentration-dependent manner. Inhibition of cellular uptake of uridine by S-(4-nitrobenzyl)-6-thioinosine blocked the uridine effect. Similar to our in vivo data, UPase expression was up-regulated by glucose deprivation in mRNA as well as protein levels. Additionally, 5-(phenylthio)acyclouridine, a specific inhibitor of UPase, prevented the uridine effect. Finally, the uridine effect was shown only in the presence of astrocytes. Taken together, the present study provides the first evidence that uridine protects neurons against ischemic insult-induced neuronal death, possibly through the action of UPase.

The purpose of this study was to investigate the feasibility of a supercritical fluid process, called aerosol solvent extraction system (ASES), for producing solid-state inclusion complexes of itraconazole (ITR) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). ITR was complexed with HP-β-CD at temperatures of 35–55 °C, pressures of 83–140 bar, CO2 densities of 0.498–0.801 g/cm3, and solution concentrations of 1–5% (w/v). The ASES-processed inclusion complex powders were observed to consist of agglomerates of very fine (100–500 nm) particles. From the experimental results of X-ray diffraction and differential scanning calorimetry, it was found that ITR intermolecularly interacted with the HP-β-CD cavity, resulting in the formation of inclusion complex. Furthermore, the ASES-processed ITR/HP-β-CD powders showed a significant enhancement in the ITR solubility (up to 753.6 μg/mL) in an aqueous medium of pH 1.2. The aqueous solubility of ITR increased with pressure at a constant temperature, and we could obtain a relatively high solubility of 341 μg/mL at 140 bar and 35 °C. In a solution concentration range of 1–5% (w/v), the solubility increased with decreasing concentration, yielding 289–407 μg/mL. When the molar ratio of ITR to HP-β-CD was varied from 1:1 to 1:3, the ITR solubility increased with HP-β-CD content, giving a value of 753.6 μg/mL for the 1:3 ratio. For the ASES-processed ITR/HP-β-CD powders, the percent dissolution of ITR also increased considerably and about 90% of ITR was dissolved within 5–10 min.

The precise causative factors in neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease remain elusive, but mechanisms implicated comprise excitotoxicity, mitochondrial dysfunction, and in the case of AD, the amyloid beta peptide (Aβ). Current therapeutic strategies for such disorders are very limited; thus, traditional herbal medicines currently receive increased attention. The seeds of Cassia obtisufolia have long been used in traditional eastern medicine and more recently the ethanolic fraction of the seeds (COE) has been shown to attenuate memory impairments in mice. In this study, we set out to determine the effect of COE (range: 0.1 – 10 μg/ml) on calcium dysregulation and cell death models in mouse primary hippocampal cultures implicated in general neurodegenerative processes and in the pathogenesis of AD: excitotoxicity, mitochondrial dysfunction, and Aβ toxicity. It was found that treatment with COE attenuated secondary Ca2+ dysregulation induced by NMDA (700 μM), while a pre-application of COE also reduced NMDA-induced cell death. Furthermore, COE was neuroprotective against the mitochondrial toxin 3-NP (1 mM), while having no significant effect on cell death induced by incubation with naturally-secreted oligomers of Aβ (8.2 pg/ml). Collectively, these results are important for the therapeutic use of COE in the treatment of neurodegenerative disorders. Keywords:: Alzheimer’s disease, amyloid, excitotoxicity, mitochondria, hippocampus

Tanshinones are a group of diterpenoids found in the roots of Salvia miltiorrhiza Bunge which has been used to treat cardiac disease. In the present study, we investigated the effect of the tanshinone congeners, tanshinone I, tanshinone IIA, cryptotanshinone, and 15, 16-dihydrotanshinone I, on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.), a muscarinic antagonist, using passive avoidance tasks in mice. Tacrine was used as a positive control. Tanshinone I (2 or 4 mg/kg, p.o.), tanshinone IIA (10 or 20 mg/kg, p.o.), cryptotanshinone (10 mg/kg, p.o.), and 15, 16-dihydrotanshinone I (2 or 4 mg/kg, p.o.) significantly reversed scopolamine-induced cognitive impairments (P0.05). Tanshinone I (2 mg/kg, p.o.) and tanshinone IIA (10 or 20 mg/kg, p.o.) were also reversed diazepam-induced cognitive dysfunctions (P0.05). In addition, cryptotanshinone and 15, 16-dihydrotanshinone I were found to have an inhibitory effect on acetylcholinesterase in vitro with IC(50) values 82 and 25 microM, respectively. Furthermore, cryptotanshinone inhibited acetylcholinesterase activity for 3 h and 15, 16-dihydrotanshinone I for 6 h in an ex-vivo study. These results suggest that tanshinone congeners may be useful for the treatment of cognitive impairment and that their beneficial effects are mediated, in part, by cholinergic signaling enhancement.

【In the present study, we investigated the neuroprotective effects of standardized Ginkgo biloba extract (GBB) (total terpene trilactones, 13 ${\pm}$ 3%; biflavone, 4.5 ${\pm}$ 1.5%; flavonol glycoside,】

The roots of Liriope platyphylla (Liliaceae) are widely used in traditional Chinese medicine. In the present study, we investigated the effects of ethanol (70%) extract of the roots of Liriope platyphylla (ELP70) on learning and memory using behavioral and immunohistochemical methods in mice. Control animals were treated with vehicle (10% Tween 80). With sub-chronic treatments of ELP70 (p.o.) for 14 days, the latency time was significantly increased compared with that of the vehicle-treated control group (50, 100 and 200 mg/kg; P

Oroxylin A is a flavonoid and was originally isolated from the root of Scutellaria baicalensis Georgi., one of the most important medicinal herbs in traditional Chinese medicine. The aim of this study was to investigate the ameliorating effects of oroxylin A on memory impairment using the passive avoidance test, the Y-maze test, and the Morris water maze test in mice. Drug-induced amnesia was induced by administering scopolamine (1 mg/kg, i.p.) or diazepam (1 mg/kg, i.p.). Oroxylin A (5 mg/kg) significantly reversed cognitive impairments in mice by passive avoidance and the Y-maze testing (P

Nodakenin is a coumarin compound initially isolated from the roots of Angelica gigas. In the present study, we investigated the effects of nodakenin on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.) using the passive avoidance test, the Y-maze test, and the Morris water maze test in mice. Nodakenin (10 mg/kg, p.o.) administration significantly reversed scopolamine-induced cognitive impairments in the passive avoidance test and the Y-maze test (P

The preventive effect of Anemarrhena asphodeloides BUNGE (Liliaceae), a traditional Chinese medicine, on ischemia-reperfusion-induced brain injury was evaluated in the rat brain. Ischemia was induced by intraluminal occlusion of the right middle cerebral artery for 2 h and reperfusion was continued for 22 h. Water extract of Anemarrhena asphodeloides (WEAA) was orally administered promptly prior to and 2 h after reperfusion. Total infarct volume and edema in the ipsilateral hemispheres of ischemia-reperfusion rats were significantly reduced by treatment with WEAA in a dose-dependent manner (p

Dysregulation of the immune system contributes to the pathogenesis of neuropsychiatric disorders including schizophrenia. Here, we demonstrated that toll-like receptor (TLR)-2, a family of pattern-recognition receptors, is involved in the pathogenesis of schizophrenia-like symptoms. Psychotic symptoms such as hyperlocomotion, anxiolytic-like behaviors, prepulse inhibition deficits, social withdrawal, and cognitive impairments were observed in TLR-2 knock-out (KO) mice. Ventricle enlargement, a hallmark of schizophrenia, was also observed in TLR-2 KO mouse brains. Levels of p-Akt and p-GSK-3α/β were markedly higher in the brain of TLR-2 KO than wild-type (WT) mice. Antipsychotic drugs such as haloperidol or clozapine reversed behavioral and biochemical alterations in TLR-2 KO mice. Furthermore, p-Akt and p-GSK-3α/β were decreased by treatment with a TLR-2 ligand, lipoteichoic acid, in WT mice. Thus, our data suggest that the dysregulation of the innate immune system by a TLR-2 deficiency may contribute to the development and/or pathophysiology of schizophrenia-like behaviors via Akt-GSK-3α/β signaling.

Ethnopharmacological relevance Tea infused with the seed of Cassia obtusifolia has been traditionally used as an herbal remedy for liver, eye, and acute inflammatory diseases. Recent pharmacological reports have indicated that Cassiae semen has neuroprotective effects, attributable to its anti-inflammatory actions, in ischemic stroke and Parkinson's disease models. Aim of the study Previously, the ethanol extract of C. obtusifolia seeds (COE) was reported to have memory enhancing properties. However, the effects of COE in an Alzheimer's disease (AD) model are currently unknown. In this study, we investigated the effect(s) of COE on aberrant synaptic plasticity and memory impairment induced by amyloid β (Aβ), a key toxic component found in the AD brain. Materials and methods To determine the effect of COE on Aβ-induced aberrant synaptic plasticity, we used acute mouse hippocampal slices and delivered theta burst stimulation to induce long-term potentiation (LTP). Western blots were used to detect Aβ- and/or COE-induced changes in signaling proteins. The novel object location recognition test was conducted to determine the effect of COE on Aβ-induced recognition memory impairment. Results COE was found to ameliorate Aβ-induced LTP impairment in the acute hippocampal slices. Glycogen synthase kinase-3β (GSK-3β), a key molecule in LTP impairment, was activated by Aβ. However, this process was inhibited by COE via Akt signaling. Moreover, COE was found to attenuate Aβ-induced microglia, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX) activation. In the in vivo studies performed, COE ameliorated the Aβ-induced object recognition memory impairment. Conclusion These results suggest that COE exhibits neuroprotective activities against Aβ-induced brain disorders.

The hippocampus is a key region responsible for processing spatial information. However, the role of the hippocampus in non-spatial recognition memory is still controversial. In the present study, we performed hippocampal lesioning to address this controversy. The hippocampi of mice were disrupted with bilateral cytotoxic lesions, and standard object recognition (non-spatial) and object location recognition (spatial) were tested. In the habituation period, mice with hippocampal lesions needed a significantly longer time to fully habituate to the test box. Interestingly, after 4 days of habituation (insufficient habituation), the recognition index was similar in the sham and hippocampal lesion groups. However, exploration time was significantly shorter in mice with hippocampal lesions compared with that in control mice. Interestingly, if mice were subjected to a 10-days-long period of habituation (full habituation), the recognition index was significantly lower in mice with hippocampal lesions compared with that in control mice; however, total exploration time was similar in both groups. Furthermore, the object recognition test after full habituation occluded hippocampal long-term potentiation, a cellular model of memory. These results indicate that sufficient habituation is required to observe the effects of hippocampal lesions on object recognition memory.

Tau is required for the induction of long-term depression (LTD) of synaptic transmission in the hippocampus. Here we probe the role of tau in LTD, finding that an AMPA receptor internalization mechanism is impaired in tau KO mice, and that LTD causes specific phosphorylation at the serine 396 and 404 residues of tau. Surprisingly, we find that phosphorylation at serine 396, specifically, is critical for LTD but has no role in LTP. Finally, we show that tau KO mice exhibit deficits in spatial reversal learning. These findings underscore the physiological role for tau at the synapse and identify a behavioral correlate of its role in LTD.

Proteinase 3 (PR3) is released from neutrophil granules and is involved in the inflammatory process. PR3 is implicated in antimicrobial defense and cell death, but the exact role of PR3 in the brain is less defined. Microglia is the major immune effector cells in the CNS and is activated by brain injury. In the present study, the effect of PR3 on glial activation was investigated. Microglial activation was assessed by the intracellular level of reactive oxygen species and expression of inflammatory cytokines. The conditioned media from activated microglia by PR3 was used for measuring the neurotoxic effects of PR3-stimulated microglia. The effects of PR3 in vivo were measured by microinjecting PR3 into the rat brain. Herein we show that PR3 increased the inflammatory responses including the intracellular ROS and pro-inflammatory cytokine production in rat primary microglia. Conditioned media from PR3-treated microglia induced neuronal cell death in a concentration dependent manner. Furthermore, microinjected PR3 into the striatum of the rat brain induced microglial activation and neuronal cell death. Interestingly treatment with anti-PR3 monoclonal antibody and protease inhibitors ameliorated microglial activation induced by PR3 in primary microglia and striatum, which also prevented neuronal cell death in both conditions. The data presented here suggest that PR3 is a direct modulator of microglial activation and causes neuronal death through the augmentation of inflammatory responses. We suggest that PR3 could be a new modulator of neuroinflammation, and blocking PR3 would be a promising novel therapeutic target for neuroinflammatory disease such as stroke and Alzheimer's disease.

Sleep loss, insomnia, is considered a sign of imbalance of physiological rhythm, which can be used as pre-clinic diagnosis of various neuropsychiatric disorders. The aim of the present study is to understand the pharmacological actions of α- or β-amyrin, natural triterpene compound, on the sleep in mice. To analyze the sleeping behavior, we used the well-known pentobarbital-induced sleeping model after single administration of either α- or β-amyrin. The sleeping onset time was remarkably decreased and duration was prolonged by β-amyrin (1, 3, or 10mg/kg) but not by α-amyrin (1, 3, or 10mg/kg). These effects were significantly blocked by GABAA receptor antagonist, bicuculline. Moreover, β-amyrin increased brain GABA level compared to the vehicle administration. Overall, the present study suggests that β-amyrin would enhance the total sleeping behavior in pentobarbital-induced sleeping model via the activation of GABAergic neurotransmitter system through GABA content in the brain.

EGb 761(®) , a standardized extract of Ginkgo biloba leaves, has antioxidant and antiinflammatory properties in experimental models of neurodegenerative disorders such as stroke and Alzheimer's disease. Tissue plasminogen activator (tPA) acts a neuromodulator and plays a crucial role in the manifestation of neurotoxicity leading to exaggerated neuronal cell death in neurological insult conditions. In this study, we investigated the effects of EGb 761 on the basal and glutamate-induced activity and expression of tPA in rat primary cortical neurons. Under basal condition, EGb 761 inhibited both secreted and cellular tPA activities, without altering tPA mRNA level, as modulated by the activation of p38. Compared with basal condition, EGb 761 inhibited the glutamate-induced up-regulation of tPA mRNA resulting in the normalization of overt tPA activity and expression. c-Fos is a component of AP-1, which plays a critical role in the modulation of tPA expression. Interestingly, EGb 761 inhibited c-Fos nuclear translocation without affecting c-Fos expression in glutamate-induced rat primary cortical neurons. These results demonstrated that EGb 761 can modulate tPA activity under basal and glutamate-stimulated conditions by both translational and transcriptional mechanisms. Thus, EGb 761 could be a potential and effective therapeutic strategy in tPA-excessive neurotoxic conditions.

Dysregulation of the immune system contributes to the pathogenesis of neuropsychiatric disorders including schizophrenia. Here, we demonstrated that toll-like receptor (TLR)-2, a family of pattern-recognition receptors, is involved in the pathogenesis of schizophrenia-like symptoms. Psychotic symptoms such as hyperlocomotion, anxiolytic-like behaviors, prepulse inhibition deficits, social withdrawal and cognitive impairments were observed in TLR-2 knock-out (KO) mice. Ventricle enlargement, a hallmark of schizophrenia, was also observed in TLR-2 KO mouse brains. Levels of p-Akt and p-GSK-3α/β were markedly higher in the brain of TLR-2 KO than wild-type (WT) mice. Antipsychotic drugs such as haloperidol or clozapine reversed behavioral and biochemical alterations in TLR-2 KO mice. Furthermore, p-Akt and p-GSK-3α/β were decreased by treatment with a TLR-2 ligand, lipoteichoic acid, in WT mice. Thus, our data suggest that the dysregulation of the innate immune system by a TLR-2 deficiency may contribute to the development and/or pathophysiology of schizophrenia-like behaviors via Akt-GSK-3α/β signaling.

In recent years, the average consumption of sugar in humans from all ages has remarkably increased, exceeding the recommended limit. Pregnancy is a critical time for the global development of offsprings who are vulnerable to the deleterious effects of environmental factors. In this study, we investigated whether high sucrose consumption during pregnancy could affect the attention-deficit hyperactivity disorder (ADHD)-like neurobehavioral outcomes in offspring mice. Pregnant mice were randomly grouped and orally administered with either water as control (Con) or 30% wt/vol sucrose diluted in water at 6 (Suc6) or 9 (Suc9) g/kg dosage per day from gestational days 6 to 15. After the weaning period, offspring mice underwent a series of behavioral testing for locomotor activity, attention, and impulsivity. Although there is no obvious difference in gross development of offspring mice such as weight gain, high sucrose-exposed offspring mice showed a significantly increased locomotor activity. Moreover, these mice exhibited a dose-dependent decrease in attention and increase in impulsivity. In the striatum, a significantly increased dopamine transporter (DAT) mRNA expression was found in the Suc9 group along with dose-dependent decreases in the Drd1, Drd2 and Drd4 dopamine receptor subtypes. Furthermore, synaptosomal DAT protein expression was increased about twofold in the Suc9 group. Prenatal fructose exposure also induced hyperactive behavior in offspring mice suggesting the essential role of fructose in the dysregulated neurobehavioral development. These findings suggest prenatal sucrose consumption as a new risk factor for ADHD, which may need further attention and investigation in humans.

Memory consolidation is an important process for the formation of long-term memory. We have previously reported that mature brain-derived neurotrophic factor enhances memory consolidation within 9 h after initial learning. Recent studies suggest that insulin-like growth factor 2 (IGF2) significantly enhances memory consolidation and prevents forgetting. Thus, we hypothesized that IGF2 exerts its activity on cognitive performance in a time-dependent manner as observed in our previous study. In the one-trial step-through inhibitory avoidance task, we demonstrate that a bilateral injection of IGF2 into the dorsal hippocampus 6 or 9 h after training significantly enhanced the step-through latencies compared with the vehicle-treated controls in the retention trial, which was conducted 24 h after the acquisition trial. However, 12 h post-training, IGF2 injection did not increase the step-through latencies. Intriguingly, in the retention trial at 21 days after the training, hippocampal IGF2 injection 6, 9 or 12 h after the acquisition trial significantly increased the step-through latencies compared with the vehicle-treated controls. IGF2 administration at 9 h and 12 h after the acquisition trial significantly increased discrimination index and exploration time on the novel-located object in the test trial at 24 h and 21 days, respectively, after the acquisition trial in the novel location recognition task. In addition, IGF2-induced an increase in the step-through latencies in the retention trial 24 h or 21 days, respectively, after the initial learning was completely abolished by co-injected anti-IGF2 receptor antibody. These results suggest that IGF2 enhances memory consolidation within 9 h after initial learning, and increased IGF2 within the 12 h after the acquisition trial, which represents a delayed consolidation phase, is also critical for memory persistence.

The physicochemical properties and antioxidant activity of a molecule could be improved by the substitution of an oxygen atom in a molecule with selenium. We synthesized selenoflavanones and flavanones to evaluate their neuroprotective effects. The selenoflavanones showed improved physicochemical properties, suggestive of the ability to pass through the blood-brain barrier (BBB). They showed in vitro antioxidant effects against hydrogen peroxide, and did not result in severe cytotoxicity. Moreover, infarction volumes in a transient ischemia mouse model were significantly reduced by the selenoflavanone treatments.

Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.

Kyung-Ok-Ko (KOK), a well-known traditional Korean medicinal formula, has long been used to invigorate the essentialqi. This use of KOK may be associated with reproductive ability as a more modern concept. The protective effect of KOK was evaluated against deterioration of testicular function induced by heat exposure in male mice. Male fertility was disrupted by scrotal heat stress at 43°C for 5 weeks. KOK (0.25, 0.50, and 2.00 g/kg/day) was administered orally at 3 h after the stress. To evaluate the protective effect of KOK, body weight, testicular weight, sperm count, sperm motility, and histopathological changes in the testes were evaluated. KOK-treated mice significantly recovered their general health, as evidenced by body weight. KOK-treated mice also showed significantly higher testes weights, sperm counts, and sperm motility than did the heat stress group. KOK-treated mice significantly recovered the morphological appearance of the seminiferous tubules and seminiferous epithelium. Furthermore, KOK-treated mice significantly increased antioxidant enzyme activities and reduced the protein expressions of apoptosis in the testes. KOK significantly protects against heat-induced damage to testicular function in male mice by inhibiting oxidative stress and apoptosis, indicating that KOK may be an effective agent for treatment of heat-induced male infertility.

The purpose of this study was to characterize the putative anxiolytic-like effects of the aqueous extract of hooks with stem of Uncaria rhynchophylla using the elevated plus maze (EPM) and the hole-board apparatus in rats and mice. Control rats were treated with an equal volume of saline, and positive control rats with buspirone (1 mg/kg). Single or repeated treatments of the aqueous extract of Uncaria rhynchophylla (200 mg/kg/day, p.o.) for 7 days significantly increased the time-spent and entries into open arms of the EPM, and reduced the time-spent and entries into the closed arms versus saline controls (P

Gomisin A is a component of the fruits of Schizandra chinesis which are widely used as a tonic in traditional Chinese medicine. In the present study, we assessed the effect of gomisin A on the learning and memory impairments induced by scopolamine. The cognition-enhancing effect of gomisin A was investigated using a passive avoidance test, the Y-maze test, and the Morris water maze test in mice. Drug-induced amnesia was induced by treating animals with scopolamine (1 mg/kg, i.p.). Gomisin A (5 mg/kg, p.o.) administration significantly reversed scopolamine-induced cognitive impairments in mice by the passive avoidance test and the Y-maze test (P

The anti-inflammatory effect of ginsenosides Rg3 and Rh2, which improves ischemic brain injury induced by middle cerebral artery occlusion, was investigated in lipopolysaccharide (LPS) and IFN-gamma-induced murine BV-2 microglial cells. Ginsenoside Rh2 inhibited the production of NO, with an IC50 value of 17 microM. The inhibitory effect of Rh2 on NO correlates with the decreased protein and mRNA expression of an inducible NO synthase (iNOS) gene. Additionally, ginsenoside Rh2 inhibited the expression of COX-2, pro-inflammatory TNF-alpha and IL-1beta in BV-2 cells induced by LPS/IFN-gamma, while it increased the expression of the anti-inflammatory cytokine IL-10. Electrophoretic mobility shift assays revealed that ginsenoside Rh2 significantly inhibited the LPS/IFN-gamma-induced AP-1 DNA binding activity, while it enhanced the protein binding to CRE sequences. However, it did not affect NF-kappaB binding activity. Thus, the anti-inflammatory effect of Rh2 appears to depend on the AP-1 and protein kinase A (PKA) pathway. The anti-inflammatory effect of ginsenoside Rg3 against LPS/IFN-gamma-activated BV-2 cells was less potent than that of ginsenoside Rh2. These findings suggest that the in vivo anti-ischemic effect of ginsenoside Rg3 may originate from ginsenoside Rh2, which is a main metabolite of ginsenoside Rg3 by intestinal microflora, and that of ginsenoside Rh2 may be due to its anti-inflammatory effect in brain microglia.

Several neurological disorders such as Alzheimer's and Parkinson's diseases have been attributed to gamma-aminobutyric acid (GABA) depletion in the brain. In order to provide a pharmacological basis for the neuroprotective actions of the enhanced accumulation of GABA in mulberry leaves (ML) against cerebral ischemia in vitro and in vivo, a process was developed to enhance the accumulation of GABA in mulberry leaves (GAML) as a result of the various anaerobic treatments. The GABA concentrations were changed by N(2) gas purging, the reaction temperature, reaction time, pH and the leaf size. GABA enhanced the potential of neuroprotection in the PC12 cells damaged by H(2)O(2)-induced oxidation. GAML reduced the cytotoxicity in the PC12 cells against oxygen glucose deprivation-induced cerebral ischemic condition. The neuroprotective effect of GAML was further demonstrated in vivo using middle cerebral artery occlusion brain injury model. GAML significantly decreased the infarct volume of the brain compared with than control group. Overall, these results suggest that the anaerobic treatment of ML makes GAML enhance the neuroprotection effect against in vivo cerebral ischemia such as in vitro.

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 naive mice in a passive avoidance task, and the results showed that nodakenin significantly increased the latency time in normal naive 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.

5-Hydroxymethyl-2-furaldehyde (5-HMF) is a compound derived from the dehydration of certain sugars. The aim of the present study was to evaluate the effect of 5-HMF on the cognitive impairment induced by scopolamine, a muscarinic receptor antagonist. To measure various cognitive functions, we conducted the step-through passive avoidance task, the Y-maze task and the Morris water maze task. A single administration of 5-HMF (5 or 10mg/kg, p.o.) significantly attenuates scopolamine-induced cognitive impairment in these behavioral tasks without changes in locomotor activity, and the effect of 5-HMF on scopolamine-induced cognitive impairment was significantly reversed by a sub-effective dose of MK-801, an NMDA receptor antagonist. In addition, a single administration of 5-HMF (10mg/kg, p.o.) enhanced the cognitive performance of normal naive mice in the passive avoidance task. Furthermore, Western blot analysis revealed that the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II-α (CaMKII) and extracellular signal-regulated kinases (ERK) were significantly enhanced by the single administration of 5-HMF in the hippocampal tissues. Taken together, the present study suggests that 5-HMF may block scopolamine-induced learning deficit and enhance cognitive function via the activation of NMDA receptor signaling, including CaMKII and ERK, and would be an effective candidate against cognitive disorders, such as Alzheimer's disease.