Neuroprotective Effect of 1,3-dipalmitoyl-2-oleoylglycerol Derived from Rice Bran Oil against Cerebral Ischemia-Reperfusion Injury in Rats.

1,3-Dipalmitoyl-2-oleoylglycerol (POP) is a triacylglyceride found in oils from various natural sources, including palm kernels, sunflower seeds, and rice bran. In the current study, the neuroprotective effects and the specific mechanism of POP derived from rice bran oil were investigated for the first time using the middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats. Orally administered POP at 1, 3, or 5 mg/kg (three times: 0.5 h before MCAO, after 1 h of MCAO, and after 1 h of reperfusion) markedly reduced the MCAO/R-induced infarct/edema volume and neurobehavioral deficits. Glutathione depletion and the oxidative degradation of lipids in the rat brain induced by MCAO/R were prevented by POP administration. The upregulation of phosphorylated p38 MAPKs, inflammatory factors (inducible nitric oxide synthase (i-NOS) and cyclooxygenase-2 (COX-2)), and pro-apoptotic proteins (B-cell lymphoma-2 (Bcl-2) associated X protein (Bax) and cleaved caspase-3) and the downregulation of the anti-apoptotic protein (Bcl-2) in the ischemic brain were significantly inhibited by POP administration. In addition, downregulation of phosphatidylinositol 3'-kinase (PI3K), phosphorylated protein kinase B (Akt), and phosphorylated cyclic (adenosine monophosphate) AMP responsive element-binding protein (CREB) expression in the ischemic brain was inhibited by POP administration. These results suggest that POP might exert neuroprotective effects by inhibition of p38 MAPK and activation of PI3K/Akt/CREB pathway, which is associated with anti-oxidant, anti-apoptotic, and anti-inflammatory action. From the above results, the present study provides evidence that POP might be effectively applied for the management of cerebral ischemia-related diseases.

Targeting transforming growth factor-ß2 by antisense oligodeoxynucleotide accelerates T cell-mediated tumor rejection in a humanized mouse model of triple-negative breast cancer.

Transforming growth factor-beta (TGF-ß) pathway mediates suppression of antitumor immunity and is associated with poor prognosis in triple-negative breast cancer (TNBC). In this study, we generated a humanized animal model by transplanting human peripheral blood mononuclear cells into immunodeficient mice followed by inoculation of MDA-MB-231 cells and subsequently analyzed the role of TGF-ß2 in the interaction between human T cells and human tumor cells. Following reconstitution of the human immune system, inhibition of TGF-ß signaling by TGF-ß2 antisense oligodeoxynucleotide (TASO) resulted in accelerated tumor growth inhibition. TGF-ß2 inhibition also resulted in downregulation of peripheral Foxp3 + regulatory T cells (Treg), whereas no effect was seen in the expression of CD8 + cytotoxic T cells. Analysis of the TASO-treated mice serum revealed elevated levels of human IFN-γ and reduced levels of human IL-10 and TGF-ß2. Moreover, TGF-ß2 inhibition resulted in increased CD8 + T cell infiltration, whereas the reduced infiltration of Tregs into the tumor partly resulted from decreased expression of CCL22. Decreased intratumoral Tregs facilitated the activation of cytotoxic T cells, associated with increased granzyme B expression. These results indicate that TASO potentiated T cell-mediated antitumor immunity, and it is proposed that TGF-ß2 may be a promising target in the immunotherapeutic strategy of TNBC.

Blockade of transforming growth factor ß2 by anti-sense oligonucleotide improves immunotherapeutic potential of IL-2 against melanoma in a humanized mouse model.

BACKGROUND AIMS: IL-2 is a potent cytokine that activates natural killer cells and CD8+ cytotoxic T lymphocytes (CTLs) and has been approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma. However, the medical use of IL-2 is restricted because of its narrow therapeutic window and potential side effects, including the expansion of regulatory T cells (Tregs). METHODS: In this study, the authors investigated the complementary effects of transforming growth factor-ß2 (TGF-ß2) anti-sense oligodeoxynucleotide (TASO) on the immunotherapeutic potential of IL-2 in a melanoma-bearing humanized mouse model. RESULTS: The authors observed that the combination of TASO and IL-2 facilitated infiltration of CTLs into the tumor, thereby potentiating the tumor killing function of CTLs associated with increased granzyme B expression. In addition, TASO attenuated the increase in Tregs by IL-2 in the peripheral blood and spleen and also inhibited infiltration of Tregs into the tumor, which was partly due to decreased CCL22. Alteration of T-cell constituents at the periphery by TGF-ß2 inhibition combined with IL-2 might be associated with the synergistic augmentation of serum pro-inflammatory cytokines (such as interferon Î³ and tumor necrosis factor α) and decreased ratio of Tregs to CTLs in tumor tissues, which consequently results in significant inhibition of tumor growth CONCLUSIONS: These results indicate that the application of TASO improves IL-2-mediated anti-tumor immunity, thus implying that blockade of TGF-ß2 in combination with IL-2 may be a promising immunotherapeutic strategy for melanoma.

The risk of vancomycin toxicity in patients with liver impairment.

BACKGROUND: The influence of liver disease on the pharmacokinetic profile, the risk of acute kidney injury, and excessive drug exposure in patients treated with vancomycin was examined. METHODS: A retrospective cohort study was performed with patients discharged from a medical center between January 2011 and June 2018 who received vancomycin therapy. Patients were stratified according to liver dysfunction (no to mild liver dysfunction (NMLD) and moderate to severe liver dysfunction (MSLD) based on the Child-Pugh score. The risk of acute kidney injury was compared between patients who were stratified by the attainment of a target serum trough concentration (10 mg/dL to 20 mg/dL) and the vancomycin ratio formed between the area under the curve and minimum inhibitory concentration. The impact of liver dysfunction and a daily dose of vancomycin on the risk of acute kidney injury and vancomycin AUC:MIC > 600 were tested using logistic regression with and without adjusting for the study variables. RESULTS: A total of 408 patients empirically treated with vancomycin were included in this study (237 with NMLD and 171 with MSLD). Mean vancomycin trough concentrations (17.5 ± 8.4 mg/dL versus 15.3 ± 5.2 mg/dL, p = 0.0049) and AUC:MIC ratios (549.4 ± 217.2 versus 497.5 ± 117.3, 0.0065) were significantly higher in the MSLD group when compared to the NMLD group, respectively. Vancomycin clearance was also lower in the MSLD group and corresponded to a longer half-life. The proportion of patients who developed acute kidney injury was greater in patients with MSLD when compared to NMLD (7.6% versus 3.8%, respectively; p = 0.0932); however, the difference was statistically insignificant. Furthermore, supratherapeutic serum trough concentrations and AUC:MIC ratios were more common in the MSLD group versus the NMLD group (27.5% versus 13.9%, p = 0.0007 and 28.7% versus 17.3%, respectively; p = 0.0063). CONCLUSIONS: MSLD correlates with an increased risk of supratherapeutic vancomycin exposure. Although patients with MSLD had a higher risk of acute kidney injury, the difference was not significant.

Phytoceramide ameliorates ß-amyloid protein-induced memory impairment and neuronal death in mice.

The present study was performed to investigate the protective effect of phytoceramide against ß-amyloid protein (Aß) (25-35)-induced memory impairment and its underlying mechanisms in mice. Memory impairment in mice was induced by intracerebroventricular injection of 15 nmol Aß (25-35) and measured by the passive avoidance test and Morris water maze test. Chronic administration of phytoceramide (10, 25 and 50 mg/kg, p.o.) resulted in significantly less Aß (25-35)-induced memory loss and hippocampal neuronal death in treated mice compared to controls. The decrease of glutathione level and increase of lipid peroxidation in brain tissue following injection of Aß (25-35) was reduced by phytoceramide. Alteration of apoptosis-related proteins, increase of inflammatory factors, and phosphorylation of mitogen activated proteins kinases (MAPKs) in Aß (25-35)-administered mice hippocampus were inhibited by phytoceramide. Phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and phosphorylation of cyclic AMP response element-binding protein (CREB) were suppressed, while phosphorylation of tau (p-tau) was increased in Aß (25-35)-treated mice brain; these effects were significantly inhibited by administration of phytoceramide. These results suggest that phytoceramide has a possible therapeutic role in managing cognitive impairment associated with Alzheimer's disease. The underlying mechanism might involve inhibition of p-tau formation via anti-apoptosis and anti-inflammation activity and promotion of PI3K/Akt/CREB signaling process.

Effects of estrogen on esophageal function through regulation of Ca2+-related proteins.

BACKGROUND: The calcium ion is important for physiological functions in all tissues and organs and essential to many vital functions, including hormone secretion and muscle contraction. The intracellular concentration of calcium is regulated by calcium related proteins such as CaBP-9k, PMCA1, and NCX1. In this study, we investigated the relationship between calcium regulation and esophageal functions such as mucin secretion and smooth muscle contraction. METHODS: To evaluate the influence of sex steroid hormones, immature rats were treated for 3 days with estradiol (E2), progesterone (P4), and their antagonists (ICI 182,780, and RU486). Esophageal function, transcription level, and localization of CaBP-9k, PMCA1, NCX1, ERα, and MUC2 were examined in the esophagus. RESULTS: Transcriptional level of Cabp-9k and Muc2 was increased by E2, but not by P4. CaBP-9k, PMCA1, and MUC2 were mainly localized in the mucosal layer. Acidic mucosubstances in the esophagus were increased by E2 and recovered by ICI treatment. Unlike the expression of Cabp-9k, mRNA levels of Pmca1, Ncx1, and Erα were only decreased in response to E2, and recovered by ICI co-treatment group. The contraction of the esophagus and mRNA level of Mylk were reduced by E2. Overall, E2 upregulated mucus secretion, but downregulated muscle contraction in the esophagus through regulation of the expression of calcium related genes and the resultant intracellular calcium level. CONCLUSIONS: The regulation of E2 in the function of esophagus may be applied to treat esophageal diseases such as reflux esophagitis, achalasia, and esophageal cancer.

Neurotoxicity of Synthetic Cannabinoids JWH-081 and JWH-210.

Synthetic cannabinoids JWH-018 and JWH-250 in 'herbal incense' also called 'spice' were first introduced in many countries. Numerous synthetic cannabinoids with similar chemical structures emerged simultaneously and suddenly. Currently there are not sufficient data on their adverse effects including neurotoxicity. There are only anecdotal reports that suggest their toxicity. In the present study, we evaluated the neurotoxicity of two synthetic cannabinoids (JWH-081 and JWH-210) through observation of various behavioral changes and analysis of histopathological changes using experimental mice with various doses (0.1, 1, 5 mg/kg). In functional observation battery (FOB) test, animals treated with 5 mg/kg of JWH-081 or JWH-210 showed traction and tremor. Their locomotor activities and rotarod retention time were significantly (p<0.05) decreased. However, no significant change was observed in learning or memory function. In histopathological analysis, neural cells of the animals treated with the high dose (5 mg/kg) of JWH-081 or JWH-210 showed distorted nuclei and nucleus membranes in the core shell of nucleus accumbens, suggesting neurotoxicity. Our results suggest that JWH-081 and JWH-210 may be neurotoxic substances through changing neuronal cell damages, especially in the core shell part of nucleus accumbens. To confirm our findings, further studies are needed in the future.

Neuroprotective effect of phytoceramide against transient focal ischemia-induced brain damage in rats.

The present study was conducted to investigate the protective effect of phytoceramide against focal transient ischemic brain damage and the underlying mechanisms. Focal transient ischemic brain damage was produced in rats by occlusion of the middle cerebral artery for 2 h followed by 24 h of reperfusion (MCAO/reperfusion). Orally administered phytoceramide (10, 25, and 50 mg/kg) significantly reduced MCAO/reperfusion-induced brain infarction and edema as well as the development of behavioral disabilities in the animals. Depletion of glutathione levels and lipid peroxidation in brain tissue following MCAO/reperfusion was reduced by administration of phytoceramide. The expressions of phosphorylated extracellular signaling-regulating kinases/mitogen-activated protein kinase (p-ERK1/2 MAPK), inflammatory factors such as cyclooxygenase-2 and inducible nitric oxide synthase, and pro-apoptotic proteins Bax and caspase-3 were increased while the anti-apoptotic protein Bcl-2 was decreased in ischemic brain; these effects were significantly inhibited by treatment with phytoceramide. Furthermore, phytoceramide activated the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway to prevent ischemic brain damage. These results suggest that phytoceramide may help prevent neurodegeneration caused by ischemic stroke due to its anti-oxidant, anti-apoptotic, and anti-inflammatory properties.

Ilex latifolia Prevents Amyloid ß Protein (25-35)-Induced Memory Impairment by Inhibiting Apoptosis and Tau Phosphorylation in Mice.

Ilex latifolia Thunb. (Aquifoliaceae), a Chinese bitter tea called "kudingcha," has been widely consumed as a health beverage and found to possess antioxidant, antidiabetic, antihypertensive, anti-inflammatory, and anti-ischemic activities. The aim of the present study was to investigate the neuroprotective effects of an ethanol extract of I. latifolia against amyloid ß protein (Aß)-induced memory impairment in mice and neurotoxicity in cultured rat cortical neurons. Memory impairment in mice was induced by intracerebroventricular injection of 15 nmol Aß (25-35) and measured by the passive avoidance test and Morris water maze test. Chronic administration of I. latifolia (25-100 mg/kg, p.o.) significantly prevented Aß (25-35)-induced memory loss. I. latifolia also prevented the decrease of glutathione concentrations, increased lipid peroxidation, expression of phosphorylated tau (p-tau), and changes in apoptosis-associated proteins in the memory-impaired mouse brain. Exposure of cultured cortical neurons to 10 µM Aß (25-35) for 36 h induced neuronal apoptotic death. The neuronal cell death, elevation of intracellular Ca(2+) concentration, generation of reactive oxygen species, and expression of proapoptotic proteins caused by Aß (25-35) in the cultured neurons were inhibited by treatment with I. latifolia (1-50 µg/mL). These results suggest that I. latifolia may have a possible therapeutic role in managing cognitive impairment associated with Alzheimer's disease. The underlying mechanism might involve the antiapoptotic effects mediated by antioxidant activity and inhibition of p-tau formation.

Effect of trans-ε-viniferin on in vitro porcine oocyte maturation and subsequent developmental competence in preimplantation embryos.

Trans-ε-viniferin is a naturally occurring polyphenol belonging to the stilbenoid family that has been isolated from Vitis amurensis, one of the most common wild grapes in Asia. We investigated the effects of trans-ε-viniferin on in vitro maturation (IVM) and developmental competence after in vitro fertilization (IVF) or parthenogenesis (PA). We observed that trans-ε-viniferin treatment during IVM did not improve nuclear maturation rates of oocytes in any group, but significantly increased (P<0.05) intracellular glutathione (GSH) levels and reduced reactive oxygen species (ROS) levels in the 0.5 µM treatment group. Trans-ε-viniferin treatment during IVM of recipient oocytes promoted higher (P<0.05) expression of DNA methyltransferase-1 (DNMT1) mRNA in the 0.5 µM treatment group as compared with the control group. However, the expression of essential transcriptional and apoptosis-related genes did not significantly differ from that of the control. In cumulus cells, pro-apoptosis gene expressions were changed as apoptosis decreased. Oocytes treated with trans-ε-viniferin during IVM did not have significantly different cleavage rates or blastocyst formation rates after PA, but total cell numbers were significantly higher (P<0.05) in the 0.5 and 5.0 µM treatment groups compared with those in the control group. IVF embryos showed similar results. In conclusion, these results indicate that trans-ε-viniferin treatment during porcine IVM increased the total cell number of blastocysts, possibly by increasing intracellular GSH synthesis, reducing ROS levels, increasing DNMT1 gene expression of oocytes and decreasing pro-apoptosis gene expressions of cumulus cells.

Neuroprotection of Ilex latifolia and caffeoylquinic acid derivatives against excitotoxic and hypoxic damage of cultured rat cortical neurons.

Ilex latifolia (Aquifoliaceae), one of the primary components of "Ku-ding-cha", has been used in Chinese folk medicine to treat headaches and various inflammatory diseases. A previous study demonstrated that the ethanol extract of I. latifolia could protect against ischemic apoptotic brain damage in rats. The present study investigated the protective activity of I. latifolia against glutamate-induced neurotoxicity using cultured rat cortical neurons in order to explain a possible mechanism related to its inhibitory effect on ischemic brain damage and identified potentially active compounds from it. Exposure of cultured cortical neurons to 500 µM glutamate for 12 h triggered neuronal cell death. I. latifolia (10-100 µg/mL) inhibited glutamate-induced neuronal death, elevation of intracellular calcium ([Ca(2+)](i)), generation of reactive oxygen species (ROS), the increase of a pro-apoptotic protein, BAX, and the decrease of an anti-apoptotic protein, BcL-2. Hypoxia-induced neuronal cell death was also inhibited by I. latifolia. 3,4-Dicaffeoylquinic acid (diCQA), 3,5-diCQA, and 3,5-diCQA methyl ester isolated from I. latifolia also inhibited the glutamate-induced increase in [Ca(2+)](i), generation of ROS, the change of apoptosis-related proteins, and neuronal cell death; and hypoxia-induced neuronal cell death. These results suggest that I. latifolia and its active compounds prevented glutamate-induced neuronal cell damage by inhibiting increase of [Ca(2+)](i), generation of ROS, and resultantly apoptotic pathway. In addition, the neuroprotective effects of I. latifolia on ischemia-induced brain damage might be associated with the anti-excitatory and anti-oxidative actions and could be attributable to these active compounds, CQAs.

Inhibitory effects of Glycyrrhizae radix and its active component, isoliquiritigenin, on Aß(25-35)-induced neurotoxicity in cultured rat cortical neurons.

This study investigated an ethanol extract from Glycyrrhizae radix (GR), the root of Glycyrrhiza uralensis (Leguminosae), for possible neuroprotective effects on neurotoxicity induced by amyloid ß protein (Aß) (25-35) in cultured rat cortical neurons. Exposure of cultured cortical neurons to 10 µM Aß (25-35) for 36 h induced neuronal apoptotic death. GR (10-50 µg/mL) prevented the Aß (25-35)-induced neuronal apoptotic death, as assessed by a MTT assay and Hoechst 33342 staining. Furthermore, GR decreased the expression of Bax and active caspase-3, proapoptotic proteins, and increased Bcl-2, an antiapoptotic protein. GR also significantly inhibited Aß (25-35)-induced elevation of the intracellular Ca(2+) concentration ([Ca(2+)](i)) and generation of reactive oxygen species (ROS) measured by fluorescent dyes. Isoliquiritigenin (1-20 µM), isolated from GR as an active component, inhibited Aß (25-35)-induced neuronal apoptotic death, elevation of [Ca(2+)](i), ROS generation, and the change of apoptosis-associated proteins in cultured cortical neurons, suggesting that the neuroprotective effect of GR may be, at least partly, attributable to this compound. These results suggest that GR and isoliquiritigenin prevent Aß (25-35)-induced neuronal apoptotic death by interfering with the increases of [Ca(2+)](i) and ROS, and GR may have a possible therapeutic role for preventing the progression of neurodegenerative disease such as Alzheimer's disease.

Neuroprotection of the leaf and stem of Vitis amurensis and their active compounds against ischemic brain damage in rats and excitotoxicity in cultured neurons.

Vitis amurensis (Vitaceae) has been reported to have anti-oxidant and anti-inflammatory activities. The present study investigated a methanol extract from the leaf and stem of V. amurensis for neuroprotective effects on cerebral ischemic damage in rats and on excitotoxicity induced by glutamate in cultured rat cortical neurons. Transient focal cerebral ischemia was induced by 2h middle cerebral artery occlusion followed by 24h reperfusion (MCAO/reperfusion) in rats. Orally administered V. amurensis (25-100 mg/kg) reduced MCAO/reperfusion-induced infarct and edema formation, neurological deficits, and neuronal death. Depletion of glutathione (GSH) level and lipid peroxidation induced by MCAO/reperfusion was inhibited by administration of V. amurensis. The increase of phosphorylated mitogen-activated protein kinases (MAPKs), cyclooxygenase-2 (COX-2), and pro-apoptotic proteins and the decrease of anti-apoptotic protein in MCAO/reperfusion rats were significantly inhibited by treatment with V. amurensis. Exposure of cultured cortical neurons to 500 µM glutamate for 12h induced neuronal cell death. V. amurensis (1-50 µg/ml) and (+)-ampelopsin A, γ-2-viniferin, and trans-ε-viniferin isolated from the leaf and stem of V. amurensis inhibited glutamate-induced neuronal death, the elevation of intracellular calcium ([Ca(2+)](i)), the generation of reactive oxygen species (ROS), and changes of apoptosis-related proteins in cultured cortical neurons, suggesting that the neuroprotective effect of V. amurensis may be partially attributed to these compounds. These results suggest that the neuroprotective effect of V. amurensis against focal cerebral ischemic injury might be due to its anti-apoptotic effect, resulting from anti-excitotoxic, anti-oxidative, and anti-inflammatory effects and that the leaf and stem of V. amurensis have possible therapeutic roles for preventing neurodegeneration in stroke.

A Comparison between Extract Products of Magnolia officinalis on Memory Impairment and Amyloidogenesis in a Transgenic Mouse Model of Alzheimer's Disease.

The components of Magnolia officinalis have well known to act anti-inflammatory, anti-oxidative and neuroprotective activities. These efficacies have been sold many products as nutritional supplement extracted from bark of Magnolia officinalis. Thus, to assess and compare neuroprotective effect in the nutritional supplement (Magnolia Extract(TM), Health Freedom Nutrition LLC, USA) and our ethanol extract of Magnolia officinalis (BioLand LTD, Korea), we investigated memorial improving and anti-Alzheimer's disease effects of extract products of Magnolia officinalis in a transgenic AD mice model. Oral pretreatment of two extract products of Magnolia officinalis (10 mg/kg/day in 0.05% ethanol) into drinking water for 3 months ameliorated memorial dysfunction and prevented Aß accumulation in the brain of Tg2576 mice. In addition, extract products of Magnolia officinalis also decreased expression of ß-site APP cleaving enzyme 1 (BACE1), amyloid precursor protein (APP) and its product, C99. Although both two extract products of Magnolia officinalis could show preventive effect of memorial dysfunction and Aß accumulation, our ethanol extract of Magnolia officinalis (BioLand LTD, Korea) could be more effective than Magnolia Extract(TM) (Health Freedom Nutrition LLC, USA). Therefore, our results showed that extract products of Magnolia officinalis were effective for prevention and treatment of AD through memorial improving and anti-amyloidogenic effects via down-regulating ß-secretase activity, and neuroprotective efficacy of Magnolia extracts could be differed by cultivating area and manufacturing methods.

Protective effect of Ilex latifolia, a major component of "kudingcha", against transient focal ischemia-induced neuronal damage in rats.

AIMS OF THE STUDY: Ilex latifolia (Aquifoliaceae), a primary component of "kudingcha", has been used in Chinese folk medicine to treat various kinds of diseases including headaches, inflammatory diseases, and cardiac ischemic injury. The present study investigated the protective effect of the ethanol extract of Ilex latifolia against transient, focal, ischemia-induced neuronal damage. MATERIALS AND METHODS: Transient focal ischemia was induced by 2 h middle cerebral artery occlusion followed by 24 h reperfusion (MCAO/reperfusion) in rats. After MCAO/reperfusion, brain infarction and neuronal death were measured by triphenyltetrazolium chloride and hematoxylin and eosin staining, respectively. Glutathione concentration and lipid peroxidation rate were measured. The expression levels of phosphorylated mitogen activated proteins kinases (MAPKs), cyclooxygenase 2 (COX-2), and anti-apoptotic and pro-apoptotic proteins were detected by Western blot. RESULTS: Ilex latifolia (50-200 mg/kg) significantly reduced MCAO/reperfusion-induced infarction and edema formation, neurological deficits, and brain cell death. Depletion of glutathione level and lipid peroxidation induced by MCAO/reperfusion were inhibited by administration of Ilex latifolia. The increase of phosphorylated MAPKs, COX-2, and proapoptotic proteins and the decrease of antiapoptotic protein in MCAO/reperfusion rats were significantly inhibited by treatment with Ilex latifolia. CONCLUSION: Ilex latifolia ameliorated ischemic injury induced by MCAO/reperfusion in rats, and this neuroprotective effect might be associated with its anti-apoptotic effect, resulting from anti-oxidative and anti-inflammatory actions.

Leaf and stem of Vitis amurensis and its active components protect against amyloid ß protein (25-35)-induced neurotoxicity.

This study investigated a methanol extract from the leaf and stem of Vitis amurensis (Vitaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid ß protein (Aß) (25-35) in cultured rat cortical neurons and also for antidementia activity in mice. Exposure of cultured cortical neurons to 10 µM Aß (25-35) for 36 h induced neuronal apoptotic death. At concentrations of 1-10 µg/mL, V. amurensis inhibited neuronal death, the elevation of intracellular calcium ([Ca(2+)](i)) and the generation of reactive oxygen species (ROS), all of which were induced by Aß (25-35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 16 nmol Aß (25-35) was inhibited by chronic treatment with V. amurensis extract (50 and 100 mg/kg, p.o. for 7 days), as measured by a passive avoidance test. Amurensin G, r-2-viniferin and trans-ɛ-viniferin isolated from V. amurensis also inhibited neuronal death, the elevation of [Ca(2+)](i) and the generation of ROS induced by Aß (25-35) in cultured rat cortical neurons. These results suggest that the neuroprotective effect of V. amurensis may be partially attributable to these compounds. These results suggest that the antidementia effect of V. amurensis is due to its neuroprotective effect against Aß (25-35)-induced neurotoxicity and that the leaf and stem of V. amurensis have possible therapeutic roles for preventing the progression of Alzheimer's disease.

Syringin from stem bark of Fraxinus rhynchophylla protects Abeta(25-35)-induced toxicity in neuronal cells.

The medicinal herb Jinpi, derived from the dried stem barks of Fraxinus rhynchophylla belonging to Oleaceae is widely used as a variety of Korean folk remedies for anti-inflammatory, febricide, antidiarrhea, and antileukorrhea diseases. In the course of screening antidementia agents from natural products, F. rhynchophylla showed significant inhibitory activity toward Abeta(25-35)-induced neuronal cell death. An active principle was isolated and identified as syringin. When the neuroblastoma cells were exposed to 50 microM Abeta(25-35), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction rate (survival rate) decreased to 60.21 +/- 2.16% over control while syringin treated ones recovered cell viability up to 79.12 +/- 1.39% at 20 microM. In addition, 20 microM syringin almost completely removed Abeta(25-35)-induced reactive oxygen species. The neuroprotective effect of syringin seemed to be originated from the reduction of apoptosis since decrease in caspase-3 activity and expression, reduction in cleaved PARP, and DNA fragmentation were observed. These results suggest that F. rhynchophylla and syringin are expected to be useful for preventing Abeta(25-35)-induced neuronal cell damage.

Protective effects of the pyrolyzates derived from bamboo against neuronal damage and hematoaggregation.

ETHNOPHARMACOLOGICAL RELEVANCE: Bamboo species are thought to be originally from Central China, but are now found in many temperate and semi-tropical regions around the world. Although the extracts from bamboo may have antioxidant activities and anti-inflammatory effects, their exact biological activities have not been elucidated. AIM OF THE STUDY: Two biological activities of bamboo-derived pyrolyzates were investigated; the protective effects against N-methyl-d-aspartate (NMDA)-induced cell death in primary cultured cortical neuron and the anti-plasmin effects determined by using fibrin and fibrinogen degradation products (FDPs) assay. RESULTS: Treatment of neuronal cells with pyrolyzates of Phyllostachys pubescens, Phyllostachys nigra and Phyllostachys bambusoides resulted in restored cell viability when compared to untreated cells in an NMDA-induced neuronal cell death assay. In addition, cortical neurons treated with Phyllostachys pubescens and Phyllostachys nigra showed a reduction of apoptosis following exposure to NMDA, as determined by Hoechst 33342 staining. In addition, Phyllostachys nigra pyrolyzates also exhibited anti-plasmin action in a FDP assay. It is of interest to note that pyrolyzates exhibited activities of NMDA-receptor antagonist and antifebrin (ogen), since a combination of NMDA receptor antagonists, glucocorticosteroids, GABAergic drugs and heparin are useful for treatment in delayed postischemic injury. CONCLUSION: Our results indicate that the pyrolyzates derived from bamboo may have anti-apoptotic effects, and can be useful as a supplement for ischemic injury treatment.

Aralia cordata protects against amyloid beta protein (25-35)-induced neurotoxicity in cultured neurons and has antidementia activities in mice.

The present study investigated an ethanol extract of the aerial part of Aralia cordata Thunb. (Araliaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid beta (Abeta) protein (25 - 35) in cultured rat cortical neurons and antidementia activity in mice. Exposure of cultured cortical neurons to 10 muM Abeta(25 - 35) for 36 h induced neuronal apoptotic death. At 1 - 10 mug/ml, A. cordata inhibited neuronal death, elevation of intracellular calcium ([Ca(2+)](i)), glutamate release into the medium, and generation of reactive oxygen species (ROS) induced by Abeta(25-35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 15 nmol Abeta(25-35) was inhibited by chronic treatment with A. cordata (50 and 100 mg/kg, p.o. for 7 days) as measured by a passive avoidance test, and corresponding reductions were observed in brain cholinesterase activity and neuronal death measured histologically in the hippocampal region. Oleanolic acid isolated from A. cordata also inhibited neuronal death, elevation of [Ca(2+)](i), glutamate release, and generation of ROS induced by Abeta(25-35) in cultured rat cortical neurons, suggesting that the neuroprotective effect of A. cordata may be, at least in part, attributable to this compound. From these results, we suggest that the antidementia effect of A. cordata is due to its neuroprotective effect against Abeta(25-35)-induced neurotoxicity and that A. cordata may have a therapeutic role in preventing the progression of Alzheimer's disease.

Anti-ischemic activities of aralia cordata and its active component, oleanolic acid.

Aralia has been reported to exhibit various pharmacological properties, including anti-inflammatory, antidiabetic and antioxidant activities. We performed in vitro and in vivo analyses on the neuroprotective effects of an ethanolic extract of the aerial parts of Aralia cordata Thunb. (Araliaceae). In cultured cortical neurons from rats, A. cordata (5-20 microg/mL) inhibited 100 muM hydrogen peroxide (H(2)O(2))-induced apoptotic neuronal death, elevation of intracellular calcium concentration ([Ca(2+)](i)) and generation of reactive oxygen species (ROS). Since oleanolic acid isolated from A. cordata also inhibited H(2)O(2)-induced neuronal death, increase in [Ca(2+)](i) and ROS generation in cultured cortical neurons, some of the neuroprotective effects of A. cordata might be attributable to this compound. In rats, A. cordata prevented cerebral ischemic injury induced by 3 h of middle cerebral artery occlusion, followed by 24 h of reperfusion. Ischemic infarct and edema volumes were significantly reduced in rats that received A. cordata (50 mg/kg, orally). These animals exhibited a corresponding improvement in neurological function and a reduction of neuronal death, as determined histologically from the cortex and hippocampal regions. It is possible that the anti-oxidative properties of A. cordata may be responsible for its neuroprotective effects against focal cerebral ischemic injury. In future, A. cordata might play a therapeutic role in the prevention and treatment of neurodegeneration in stroke.