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Pregabalin Attenuates Excitotoxicity in Diabetes  [PDF]
Chin-Wei Huang, Ming-Chi Lai, Juei-Tang Cheng, Jing-Jane Tsai, Chao-Ching Huang, Sheng-Nan Wu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065154
Abstract: Diabetes can exacerbate seizures and worsen seizure-related brain damage. In the present study, we aimed to determine whether the standard antiepileptic drug pregabalin (PGB) protects against pilocarpine-induced seizures and excitotoxicity in diabetes. Adult male Sprague-Dawley rats were divided into either a streptozotocin (STZ)-induced diabetes group or a normal saline (NS) group. Both groups were further divided into subgroups that were treated intravenously with either PGB (15 mg/kg) or a vehicle; all groups were treated with subcutaneous pilocarpine (60 mg/kg) to induce seizures. To evaluate spontaneous recurrent seizures (SRS), PGB-pretreated rats were fed rat chow containing oral PGB (450 mg) for 28 consecutive days; vehicle-pretreated rats were fed regular chow. SRS frequency was monitored for 2 weeks from post-status epilepticus day 15. We evaluated both acute neuronal loss and chronic mossy fiber sprouting in the CA3 area. In addition, we performed patch clamp recordings to study evoked excitatory postsynaptic currents (eEPSCs) in hippocampal CA1 neurons for both vehicle-treated rats with SRS. Finally, we used an RNA interference knockdown method for Kir6.2 in a hippocampal cell line to evaluate PGB's effects in the presence of high-dose ATP. We found that compared to vehicle-treated rats, PGB-treated rats showed less severe acute seizure activity, reduced acute neuronal loss, and chronic mossy fiber sprouting. In the vehicle-treated STZ rats, eEPSC amplitude was significantly lower after PGB administration, but glibenclamide reversed this effect. The RNA interference study confirmed that PGB could counteract the ATP-sensitive potassium channel (KATP)-closing effect of high-dose ATP. By opening KATP, PGB protects against neuronal excitotoxicity, and is therefore a potential antiepileptogenic in diabetes. These findings might help develop a clinical algorithm for treating patients with epilepsy and comorbid metabolic disorders.
BMP4 Is a Peripherally-Derived Factor for Motor Neurons and Attenuates Glutamate-Induced Excitotoxicity In Vitro  [PDF]
Hui-Ju Chou, Dar-Ming Lai, Cheng-Wen Huang, Ian S. McLennan, Horng-Dar Wang, Pei-Yu Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058441
Abstract: Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGF-β) superfamily, have been shown to play important roles in the nervous system, including neuronal survival and synaptogenesis. However, the physiological functions of BMP signaling in the mammalian neuromuscular system are not well understood. In this study, we found that proteins of the type II bone morphogenetic receptors (BMPRII) were detected at the neuromuscular junction (NMJ), and one of its ligands, BMP4, was expressed by Schwann cells and skeletal muscle fibers. In double-ligated nerves, BMP4 proteins accumulated at the proximal and distal portions of the axons, suggesting that Schwann cell- and muscle fiber-derived BMP4 proteins were anterogradely and retrogradely transported by motor neurons. Furthermore, BMP4 mRNA was down-regulated in nerves but up-regulated in skeletal muscles following nerve ligation. The motor neuron-muscle interactions were also demonstrated using differentiated C2C12 muscle cells and NG108-15 neurons in vitro. BMP4 mRNA and immunoreactivity were significantly up-regulated in differentiated C2C12 muscle cells when the motor neuron-derived factor, agrin, was present in the culture. Peripherally-derived BMP4, on the other hand, promotes embryonic motor neuron survival and protects NG108-15 neurons from glutamate-induced excitotoxicity. Together, these data suggest that BMP4 is a peripherally-derived factor that may regulate the survival of motor neurons.
Ginseng on Hyperglycemia: Effects and Mechanisms  [PDF]
John Zeqi Luo,Luguang Luo
Evidence-Based Complementary and Alternative Medicine , 2009, DOI: 10.1093/ecam/nem178
Abstract: It has been reported that American ginseng attenuates hyperglycemia and may present itself as a supplement to diabetes therapy. However, the lack of standardization in the usage of ginseng root leads to inconclusive results when applied to diabetes treatment. The mechanisms of American ginseng root in the treatment of diabetes remains a mystery. This greatly limits the effective utilization of American ginseng in facilitating diabetic therapy. Initiating studies have shown that American ginseng increases insulin production and reduces cell death in pancreatic β-cells. Also, studies have revealed American ginseng's ability to decrease blood glucose in type II diabetes patients as well as in streptozotocin-induced diabetic animals (STZ-diabetic mice). These data suggest that effects of ginseng in improving hyperglycemia may alter mitochondrial function as well as apoptosis cascades to ensure cell viability in pancreatic islet cells. This review briefly summarizes current knowledge of ginseng components and clinical studies related to diabetes. Further research will be needed to explore and identify the component(s) of ginseng, which may be responsible for the beneficial effects observed in animal studies which could then be extrapolated to human islets.
Effects of nimesulide on kainate-induced in vitro oxidative damage in rat brain homogenates  [cached]
Candelario-Jalil Eduardo,Sonia León Olga
BMC Pharmacology , 2003, DOI: 10.1186/1471-2210-3-7
Abstract: Background The cyclooxygenase-2 inhibitor nimesulide is able to reduce kainate-induced oxidative stress in vivo. Here we investigate if this effect is mediated by the direct antioxidant properties of nimesulide using a well-characterized in vitro model of kainate toxicity. Results Exposure of rat brain homogenates to kainate (12 mM) caused a significant (p < 0.01) increase in the concentrations of malondialdehyde and 4-hydroxy-alkenals and a significant (p < 0.01) decrease in sulfhydryl levels. High concentrations of nimesulide (0.6–1.6 mM) reduced the extent of lipid peroxidation and the decline in both total and non-protein sulfhydryl levels induced by kainate in a concentration-dependent manner. Conclusions Our results suggest that the neuroprotective effects of nimesulide against kainate-induced oxidative stress in vivo are not mediated through its direct free radical scavenging ability because the concentrations at which nimesulide is able to reduce in vitro kainate excitotoxicity are excessively higher than those attained in plasma after therapeutic doses.
Wu-Chia-Pi Solution Attenuates Carbon Tetrachloride-Induced Hepatic Injury through the Antioxidative Abilities of Its Components Acteoside and Quercetin  [PDF]
Steven Kuan-Hua Huan,Kun-Teng Wang,Chia-Jung Lee,Chun-hsien Sung,Ting-Yi Chien,Ching-Chiung Wang
Molecules , 2012, DOI: 10.3390/molecules171214673
Abstract: Wu-Chia-Pi medicated wine, composed nine Chinese medicines soaked in 35% alcohol, is widely used in Asia for its health-promoting functions. However, long-term consumption of alcohol could result in liver dysfunction. In this study, Wu-Chia-Pi solution (WCPS) and extract (WCPE) were prepared by modification of the principals given by the Committee on Chinese Medicine and Pharmacy in Taiwan. The aim of this study was to explore the protective effect of WCPS against carbon tetrachloride (CCl4)-induced liver injury and to clarify its active component(s). Antioxidative effects of the test samples were evaluated via MDA inhibition, catalase activity and DPPH-scavenging assays. HPLC was used to analysis the active components. Results showed that WCPS (1 and 5 mL/kg) significantly prevented CCl4-induced liver injury without chronic liver toxicity. Referring to the antioxidative activities, WCPE displayed significant MDA inhibitory and DPPH-scavenging activities with IC50 values of 0.91 ± 0.03 and 0.60 ± 0.04 mg/mL, respectively. Catalase activity was also enhanced by treatment of WCPE, acteoside and quercetin. Therefore, we suggest that acteoside and quercetin are the major contributors to the antioxidative and hepatoprotective activities of WCPS, and a possible mechanism could be mediated through reduction of oxidative stress.
Ginseng- Multipurpose Herb  [PDF]
Chhotaram Seervi,Rupali Kirtawade,Pandurang Dhabale,Pallavi salve.
Journal of Biomedical Sciences and Research , 2010,
Abstract: Ginseng is the most popular herb. Ginseng is often referred as the ultimate tonic; the herb boosts general well-being, immune function, libido, and athletic performance. Ginseng is popularly used for its adaptogenic, antineoplastic, immunomodulatory, cardiovascular, CNS, endocrine, and ergogenic effects, but these uses have not been confirmed by clinical trials. A number of ginseng species used in herbal products grow around the world. Some of these plants include American ginseng, Korean ginseng, Sanchi ginseng, Chikusetsu ginseng. Ginseng is also known as Siberian ginseng, devil's shrub, eleuthero, touch-me-not, and wild pepper. Ginseng has been used to improve the body's resistance to stress and to increase vitality. However, the mechanisms underlying ginseng's effects remain to be investigated. Biological effects of ginseng are due to its anti-inflammatory effects, antineurological effect, hypoglycemia effect. Research has shown that drinking a cup of hot ginseng tea has an anti-inflammatory effect.
Nimesulide limits kainate-induced oxidative damage in the rat hippocampus  [PDF]
E. Candelario-Jalil,H. H. Ajamieh,S. Sam,G. Martinez,O. S. Leon
Quantitative Biology , 2007,
Abstract: Kainate induces a marked expression of cyclooxygenase-2 after its systemic administration. Because cyclooxygenase-2 activity is associated to the production of reactive oxygen species, we investigated the effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on kainate-induced in vivo oxidative damage in the rat hippocampus. A clinically relevant dose of nimesulide (6 mg/kg, i.p.) was administered three times following kainate application (9 mg/kg, i.p.). After 24 h of kainate administration, the drastic decrease in hippocampal glutathione content and the significant increase in lipid peroxidation were attenuated in nimesulide-treated rats, suggesting that the induction of cyclooxygenase-2 is involved in kainate-mediated free radicals formation.
The Role of -Containing Kainate Receptors in Entorhinal Cortex Gamma Frequency Oscillations  [PDF]
Heather L. Stanger,Rebekah Alford,David E. Jane,Mark O. Cunningham
Neural Plasticity , 2008, DOI: 10.1155/2008/401645
Abstract: Using in vitro brain slices of hippocampus and cortex, neuronal oscillations in the frequency range of 30–80 Hz (gamma frequency oscillations) can be induced by a number of pharmacological manipulations. The most routinely used is the bath application of the broad-spectrum glutamate receptor agonist, kainic acid. In the hippocampus, work using transgenic kainate receptor knockout mice have revealed information about the specific subunit composition of the kainate receptor implicated in the generation and maintenance of the gamma frequency oscillation. However, there is a paucity of such detail regarding gamma frequency oscillation in the cortex. Using specific pharmacological agonists and antagonists for the kainate receptor, we have set out to examine the contribution of kainate receptor subtypes to gamma frequency oscillation in the entorhinal cortex. The findings presented demonstrate that in contrast to the hippocampus, kainate receptors containing the GLUK5 subunit are critically important for the generation and maintenance of gamma frequency oscillation in the entorhinal cortex. Future work will concentrate on determining the exact nature of the cellular expression of kainate receptors in the entorhinal cortex.
Antioxidative defense  [PDF]
Stevanovi? Jelka,Borozan Sun?ica,Jovi? Slavoljub,Ignjatovi? Igor
Veterinarski Glasnik , 2011, DOI: 10.2298/vetgl1104247s
Abstract: Free radicals occur constantly during metabolism and take part in numerous physiological processes, such as: intra-cellular and inter-cellular signalization, gene expression, removal of damaged or senescent cells, and control of the tone of blood vessels. However, there is an increased quantity of free radicals in situations of so-called oxidative stress, when they cause serious damage to cellular membranes (peroxidation of their lipids, damage of membrane proteins, and similar), to interior cellular protein molecules, as well as DNA molecules and carbohydrates. This is precisely why the organism has developed numerous mechanisms for removing free radicals and/or preventing their production. Some of these are enzyme-related and include superoxide-dismutase, catalase, glutathione-peroxidase, and others. Other, non-enzyme mechanisms, imply antioxidative activities of vitamins E and C, provitamin A, coenzyme Q, reduced glutation, and others. Since free radicals can leave the cell that has produced them and become dispersed throughout the body, in addition to antioxidative defense that functions within cellular structures, antioxidant extra-cellular defense has also been developed. This is comprised by: transferrin, lactoferrin, haptoglobin, hemopexin, ceruloplasmin, albumins, extra-cellular isoform SOD, extracellular glutathione-peroxidase, glucose, bilirubin, urates, and many other molecules.
Excitotoxicity Triggered by Neurobasal Culture Medium  [PDF]
Joshua Hogins,Devon C. Crawford,Charles F. Zorumski,Steven Mennerick
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025633
Abstract: Neurobasal defined culture medium has been optimized for survival of rat embryonic hippocampal neurons and is now widely used for many types of primary neuronal cell culture. Therefore, we were surprised that routine medium exchange with serum- and supplement-free Neurobasal killed as many as 50% of postnatal hippocampal neurons after a 4 h exposure at day in vitro 12–15. Minimal Essential Medium (MEM), in contrast, produced no significant toxicity. Detectable Neurobasal-induced neuronal death occurred with as little as 5 min exposure, measured 24 h later. D-2-Amino-5-phosphonovalerate (D-APV) completely prevented Neurobasal toxicity, implicating direct or indirect N-methyl-D-aspartate (NMDA) receptor-mediated neuronal excitotoxicity. Whole-cell recordings revealed that Neurobasal but not MEM directly activated D-APV-sensitive currents similar in amplitude to those gated by 1 μM glutamate. We hypothesized that L-cysteine likely mediates the excitotoxic effects of Neurobasal incubation. Although the original published formulation of Neurobasal contained only 10 μM L-cysteine, commercial recipes contain 260 μM, a concentration in the range reported to activate NMDA receptors. Consistent with our hypothesis, 260 μM L-cysteine in bicarbonate-buffered saline gated NMDA receptor currents and produced toxicity equivalent to Neurobasal. Although NMDA receptor-mediated depolarization and Ca2+ influx may support survival of young neurons, NMDA receptor agonist effects on development and survival should be considered when employing Neurobasal culture medium.
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