Resveratrol inhibits glycine receptor-mediated ion currents.

Resveratrol is found in grapes, red wine, and berries. Resveratrol has been known to have many beneficial health effects, such as anti-cancer, neuroprotective, anti-nociceptive, and life-prolonging effects. However, the single cellular mechanisms by which resveratrol acts are relatively unknown, especially in terms of possible regulation of receptors involved in synaptic transmission. The glycine receptor is an inhibitory ligand-gated ion channel involved in fast synaptic transmission in spinal cord. In the present study, we investigated the effect of resveratrol on human glycine receptor channel activity. Glycine α1 receptors were expressed in Xenopus oocytes and glycine receptor channel activity was measured using a two-electrode voltage clamp technique. Treatment with resveratrol alone had no effect on oocytes injected with H2O or on oocytes injected with glycine α1 receptor cRNA. In the oocytes injected with glycine α1 receptor cRNA, co- or pre-treatment of resveratrol with glycine inhibited the glycine-induced inward peak current (IGly) in a reversible manner. The inhibitory effect of resveratrol on IGly was also concentration dependent, voltage independent, and non-competitive. These results indicate that resveratrol regulates glycine receptor channel activity and that resveratrol-mediated regulation of glycine receptor channel activity is one of several cellular action mechanisms of resveratrol for pain regulation.

A Preliminary Study on the Potential Protective Role of the Antioxidative Stress Markers of Cognitive Impairment: Glutathione and Glutathione Reductase.

Objective: : To investigate the relationship between reduced glutathione (GSH), a key molecule of the antioxidant defense system in the blood, and glutathione reductase (GR), which reduces oxidized glutathione (glutathione disulfide [GSSG]) to GSH and maintains the redox balance, with the prevalence of Alzheimer's dementia and cognitive decline. Methods: : In all, 20 participants with Alzheimer's dementia who completed the third follow-up clinical evaluation over 6 years were selected, and 20 participants with normal cognition were selected after age and sex matching. The GSH and GR concentrations were the independent variables. Clinical diagnosis and neurocognitive test scores were the dependent variables indicating cognitive status. Results: : The higher the level of GR, the greater the possibility of having normal cognition than of developing Alzheimer's dementia. Additionally, the higher the level of GR, the higher the neurocognitive test scores. However, this association was not significant for GSH. After 6 years, the conversion rate from normal cognition to cognitive impairment was significantly higher in the lower 50th percentile of the GR group than in the upper 50th percentile. Conclusion: : The higher the GR, the lower the prevalence of Alzheimer's dementia and incidence of cognitive impairment and the higher the cognitive test scores. Therefore, GR is a potential protective biomarker against Alzheimer's dementia and cognitive decline.

Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress.

Several studies have shown that protectins, which are ω-3 fatty acid-derived proresolution mediators, may improve insulin resistance. Recently, protectin DX (PDX) was documented to attenuate insulin resistance by stimulating IL-6 expression in skeletal muscle, thereby regulating hepatic gluconeogenesis. These findings made us investigate the direct effects of PDX on hepatic glucose metabolism in the context of diabetes. In the current study, we show that PDX regulates hepatic gluconeogenesis in a manner distinct from its indirect glucoregulatory activity via IL-6. We found that PDX stimulated AMP-activated protein kinase (AMPK) phosphorylation, thereby inducing heme oxygenase 1 (HO-1) expression. This induction blocked hepatic gluconeogenesis by suppressing endoplasmic reticulum (ER) stress in hepatocytes under hyperlipidemic conditions. These effects were significantly dampened by silencing AMPK or HO-1 expression with small interfering RNA (siRNA). We also demonstrated that administration of PDX to high fat diet (HFD)-fed mice resulted in increased hepatic AMPK phosphorylation and HO-1 expression, whereas hepatic ER stress was substantially attenuated. Furthermore, PDX treatment suppressed the expression of gluconeogenic genes, thereby decreasing blood glucose levels in HFD-fed mice. In conclusion, our findings suggest that PDX inhibits hepatic gluconeogenesis via AMPK-HO-1-dependent suppression of ER stress. Thus, PDX may be an effective therapeutic target for the treatment of insulin resistance and type 2 diabetes through the regulation of hepatic gluconeogenesis.

Protective effects of ginseng saponins on 3-nitropropionic acid-induced striatal degeneration in rats.

The precise cause of neuronal cell death in Huntington's disease (HD) is not known. Systemic administration of 3-nitropropionic acid (3-NP), an irreversible succinate dehydrogenase inhibitor, not only induces a cellular ATP depletions but also causes a selective striatal degeneration similar to that seen in HD. Recent accumulating reports have shown that ginseng saponins (GTS), the major active ingredients of Panax ginseng, have protective effects against neurotoxin insults. In the present study, we examined in vitro and in vivo effects of GTS on striatal neurotoxicity induced by repeated treatment of 3-NP in rats. Here, we report that systemic administration of GTS produced significant protections against systemic 3-NP- and intrastriatal malonate-induced lesions in rat striatum with dose-dependent manner. GTS also improved significantly 3-NP-caused behavioral impairment and extended survival. However, GTS itself had no effect on 3-NP-induced inhibition of succinate dehydrogenase activity. To explain the mechanisms underlying in vivo protective effects of GTS against 3-NP-induced striatal degeneration, we examined in vitro effect of GTS against 3-NP-caused cytotoxicity using cultured rat striatal neurons. We found that GTS inhibited 3-NP-induced intracellular Ca(2+) elevations. GTS restored 3-NP-caused mitochondrial transmembrane potential reduction in cultured rat striatal neurons. GTS also prevented 3-NP-induced striatal neuronal cell deaths with dose-dependent manner. The EC(50) was 12.6 +/- 0. 7microg/ml. These results suggest that in vivo protective effects of GTS against 3-NP-induced rat striatal degeneration might be achieved via in vitro inhibition of 3-NP-induced intracellular Ca(2+) elevations and cytotoxicity of striatal neurons.

Quercetin inhibits the 5-hydroxytryptamine type 3 receptor-mediated ion current by interacting with pre-transmembrane domain I.

The flavonoid, quercetin, is a low molecular weight substance found in apple, tomato and other fruit. Besides its antioxidative effect, quercetin, like other flavonoids, has a wide range of neuropharmacological actions including analgesia, and motility, sleep, anticonvulsant, sedative and anxiolytic effects. In the present study, we investigated its effect on mouse 5-hydroxytryptamine type 3 (5-HT3A) receptor channel activity, which is involved in pain transmission, analgesia, vomiting, and mood disorders. The 5-HT3A receptor was expressed in Xenopus oocytes, and the current was measured with the two-electrode voltage clamp technique. In oocytes injected with 5-HT3A receptor cRNA, quercetin inhibited the 5-HT-induced inward peak current (I(5-HT)) with an IC50 of 64.7 +/- 2.2 microM. Inhibition was competitive and voltage-independent. Point mutations of pre-transmembrane domain 1 (pre-TM1) such as R222T and R222A, but not R222D, R222E and R222K, abolished inhibition, indicating that quercetin interacts with the pre-TM1 of the 5-HT3A receptor.

Gintonin stimulates gliotransmitter release in cortical primary astrocytes.

Lysophosphatidic acid (LPA) is a simple and minor phospholipid, but serves as a lipid-derived neurotransmitter via activation of G protein-coupled LPA receptors. Astrocytes abundantly express LPA receptors and contain gliotransmitters that modulate astrocyte-neuron interactions. Gintonin is a novel ginseng-derived G protein-coupled LPA receptor ligand. Gintonin induces [Ca(2+)]i transients in neuronal and non-neuronal cells via activation of LPA receptors, which regulate calcium-dependent ion channels and receptors. A line of evidence shows that neurotransmitter-mediated [Ca(2+)]i elevations in astrocytes are coupled with gliotransmitter release. However, little is known about whether gintonin-mediated [Ca(2+)]i transients are coupled to gliotransmitter release in astrocytes. In the present study, we examined the effects of gintonin on adenosine triphosphate (ATP) and glutamate release in mouse cortical primary astrocytes. Application of gintonin to astrocytes induced [Ca(2+)]i transients in a concentration-dependent and reversible manner. However, ginsenosides, other active ingredients in ginseng, had no effect on [Ca(2+)]i transients. The induction of gintonin-mediated [Ca(2+)]i transients was attenuated/blocked by the LPA1/3 receptor antagonist Ki16425, a phospholipase C inhibitor, an inositol 1,4,5-triphosphate receptor antagonist, and an intracellular Ca(2+) chelator. Gintonin treatment on astrocytes increased ATP and glutamate release in a concentration- and time-dependent manner. BAPTA and Ki16425 attenuated gintonin-mediated ATP and glutamate release in astrocytes. The present study shows that gintonin-mediated [Ca(2+)]i transients are coupled to gliotransmitter release via LPA receptor activation. Finally, gintonin-mediated [Ca(2+)]i transients and gliotransmitter release from astrocytes via LPA receptor activation might explain one mechanism of gintonin-mediated neuromodulation in the central nervous system.

Peroxiredoxin II preserves cognitive function against age-linked hippocampal oxidative damage.

Reactive oxygen species (ROS), routinely produced in biological reactions, contribute to both normal aging and age-related decline in cognitive function. However, little is known regarding the involvement of specific antioxidants in the underlying mechanism(s). Here, we examined if peroxiredoxin II (Prx II) scavenges intracellular ROS that cause age-dependent mitochondrial decay in hippocampal CA1 pyramidal neurons and subsequent impairment of learning and memory. Age-dependent mitochondrial ROS generation and long-term potentiation (LTP) decline were more prominent in hippocampal neurons in Prx II(-/-) than in wild-type mice. Additionally, Prx II(-/-) mice failed to activate synaptic plasticity-related cellular signaling pathways involving CREB, CaMKII, and ERK, or to maintain functional integrity of their mitochondria. Dietary vitamin E alleviated Prx II deficiency-related deficits, including mitochondrial decay and CREB signaling, resulting in restoration of the abrupt cognitive decline in aged Prx II(-/-) mice. These results suggest that Prx II help maintain hippocampal synaptic plasticity against age-related oxidative damage.

Endovascular treatment of type B aortic dissection: the challenge of late success.

BACKGROUND: Thoracic endovascular aortic repair of type B aortic dissection is a therapeutic option for selected patients. However, late outcomes of this intervention are virtually unknown, and the series already published are heterogenous regarding demographics, indications, and type of devices. METHODS: From 1997 to 2004, 106 patients exclusively with classic complicated or symptomatic type B aortic dissection were treated with thoracic endovascular aortic repair, using the same device. We present in-hospital outcomes and late follow-up for 73 patients. RESULTS: Technical success was achieved for 99% of patients, and the clinical success rate was 83% (exclusion of the false lumen, no early death or surgical conversion). In-hospital death occurred in 5 patients, 2 of them after surgical conversion. Three patients required urgent surgical conversion. Neurologic complications occurred in 5 patients (1 case of paraplegia). The average time of follow-up was 35.9 +/- 28.5 months. During follow-up, 37% of patients initially successfully treated reached a failure criterion (new endovascular or surgical intervention in the same aortic segment or death due to aortic or unknown cause). Kaplan-Meier curve showed late survival rates higher than 80% in 2 years. CONCLUSIONS: Patients with both acute and chronic type B aortic dissection had excellent initial results with thoracic endovascular aortic repair. Although event-free survival rates decreased gradually with time owing to the frequent need for new interventions, survival curves were comparable to those for less complex patients undergoing clinical or surgical treatment. Randomized studies are required to establish the actual benefit of this new approach.

Patent ductus arteriosus: endovascular treatment in adult patient.

The patent ductus arteriosus (PDA) is a common type of congenital heart defect and its correction is simple when performed early in life. Surgery is performed using stitches or clips. In adults, the anomaly can lead to pulmonary hypertension and ventricular dysfunction. Surgery in adults is controversial and high-risk. This report describes an alternative endovascular approach in an adult patient.

Sanjoinine A isolated from Zizyphi Spinosi Semen augments pentobarbital-induced sleeping behaviors through the modification of GABA-ergic systems.

Zizyphi Spinosi Semen (ZSS) has been widely used for the treatment of insomnia in oriental countries. This experiment was performed to investigate whether sanjoinine A, one of major alkaloid compounds of ZSS, has hypnotic effects and/or enhances pentobarbital-induced sleeping behaviors through the gamma-aminobutyric acid (GABA)-ergic systems. Sanjoinine A itself did not induce sleeping at the higher dose used in this experiment. However, sanjoinine A prolonged sleeping time and reduced the sleeping latency induced by pentobarbital in a dose-dependent manner similar to muscimol, a GABA(A) receptor agonist. Sanjoinine A also increased sleeping rate and sleeping time when administered combined with pentobarbital at a sub-hypnotic dosage and showed synergistic effects with muscimol in potentiating sleeping onset and enhancing sleeping time induced by pentobarbital. In addition, both sanjoinine A and pentobarbital increased chloride influx in primary cultured cerebellar granule cells. Sanjoinine A also showed similar effects with muscimol in potentiating chloride influx inducing effects of low dose pentobarbital. Sanjoinine A decreased GABA(A) receptor alpha-subunit expression and increased gamma-subunit expression, and had no effects on the abundance of beta-subunits in primary cultured cerebellar granule cells, showing different subunit expression from pentobarbital. In addition, we found that sanjoinine A also enhanced expression of glutamic acid decarboxylase (GAD), but pentobarbital did not. In conclusion, sanjoinine A itself does not induce sleeping, but it augments pentobarbital-induced sleeping behaviors through the modification of GABA-ergic systems.

Tratamento endovascular nos aneurismas verdadeiros e na dissecção aórtica do tipo B: fase intra-hospitalar, seguimento de médio prazo e uma reflexão sobre seleção de pacientes / Endovascular treatment of aortic aneurysms and type B dissections: in-hospital results, mid-term follow-up and a consideration of patient selection

Introdução: O tratamento endovascular das doenças da aorta é procedimento estabelecido, mas com resultados tardios e diferenças nos resultados entre diferentes grupos demográficos ainda desconhecidos. Método: No período de dezembro de 1996 a dezembro de 2004, 92 pacientes com aneurismas verdadeiros ou úlcera penetrante de aorta em posição torácica (G1) e 130 pacientes com dissecção aórtica do tipo B ou hematoma intramural (G2) foram submetidos a tratamento endovascular primário ou secundário. Na fase hospitalar, sucesso clínico foi considerado como exclusão da lesão, sem morte ou conversão cirúrgica. Falência tardia foi definida pela ocorrência de morte por qualquer causa, conversão cirúrgica ou reintervenção. Resultados: A média de idade do G1 foi de 65 ± 11 anos e de 56 ± 11 anos no G2 (P < 0,0001). Quanto aos dados demográficos, destacou-se a alta frequência de acidente vascular cerebral prévio no G1 (8,7% vs. 0; P = 0,0007). Sucesso clínico do procedimento foi obtido em 71% do G1 e em 84% dos pacientes do G2 (P = 0,02), com maior mortalidade intra-hospitalar no G1 (14% vs. 4,6%; P = 0,01). Complicações neurológicas foram semelhantes (6,5% vs. 3%; P = 0,32), com discreto predomínio de paraplegia no G1 (3,2% vs. 0,8%; P = 0,3). Em seguimento de 33 ± 27 meses, falência tardia foi atingida em 60% (28/47) dos pacientes do G1 e em 43% (31/74) do G2 (P = 0,09). Conclusão: Resultados em pacientes com aneurismas verdadeiros submetidos a tratamento endovascular são discretamente inferiores aos de pacientes com dissecção aórtica do tipo B. Isso pode ser explicado pelas diferenças demográficas entre os grupos e pelas dificuldades técnicas inerentes à anatomia. O conhecimento dessas peculiaridades permite a melhor seleção de pacientes nos quais o procedimento será eficaz em reduzir a mortalidade.

Background: Endovascular treatment of thoracic aortic diseases is a well established procedure although late results and differences among demographic groups are unknown. Method: From December/1996 to December/ 2004, 92 patients with true aneurysms or penetrating ulcers (G1) and 130 patients with type B dissection or intramural hematoma (G2) were submitted to primary or complementary endovascular treatment. Clinical success was defined as sustained technical success without death or surgical conversion. Late failure was defined as death of any cause, surgical conversion or re-intervention. Results: G1 mean age was 65 ± 11 years and 56 ± 11 years in G2 (P < 0.0001). A high frequency of previous stroke was observed in G1 (8.7% vs. 0; P = 0.0007). Clinical success was observed in 71% in G1 and 84% in G2 (P = 0.02) with higher in-hospital death rates in G1 (14% vs. 4.6%; P = 0.01). Neurologic complications were similar (6.5% vs. 3%, respectively; P = 0.32), with a mild prevalence of paraplegia in G1 (3.2% vs. 0.8%; P = 0.3). Late failure rates of 60% were observed in G1 and 43% in G2 (P = 0.09) at 33 ± 27 months of follow-up. Conclusions: Endovascular treatment in patients with true aneurysms may be slightly inferior to those achieved in patients with type B dissection. This might be due to demographic differences between groups and technical difficulties related to aortic anatomy. The knowledge and understanding of these peculiarities enables better patient selection for theprocedure resulting in decreased mortality rates.

Tratamento endovascular da persistência do canal arterial em adulto / Patent ductus arteriosus: endovascular treatment in adult patient

A persistência do canal arterial (PCA) é uma anomalia relativamente freqüente e de simples correção. A correção envolve a ligadura do ducto com ou sem a sua secção. A anomalia em adultos pode provocar hipertensão pulmonar persistente e disfunção ventricular. A correção em adultos é controversa e de maior risco. Um caso de correção endovascular com acesso intra-abdominal da PCA em adulto é descrito.

The patent ductus arteriosus (PDA) is a common type of congenital heart defect and its correction is simple when performed early in life. Surgery is performed using stitches or clips. In adults, the anomaly can lead to pulmonary hypertension and ventricular dysfunction. Surgery in adults is controversial and high-risk. This report describes an alternative endovascular approach in an adult patient.