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ABSTRACT: During prolonged depolarization, voltage-gated K(+) (Kv) channels display C-type inactivation, a process which is due to selectivity filter destabilization and serves to limit K(+) flux. Here we reported that coumarsabin, a coumarin derivative isolated from Juniperus Sabina, could hasten C-type inactivation and thus cause block of Kv channels in neuronal NG108-15 cells and Kv1.2 channels heterologously expressed in lung epithelial H1355 cells. In NG108-15 cells, extracellular, but not intracellular, coumarsabin (30μM) strongly speeded up Kv current decay and caused a left-shift in the steady-state inactivation curve. Coumarsabin inhibited end-of-pulse Kv currents with an IC(50) of 13.4μM. The kinetics and voltage-dependence of activation were not affected by coumarsabin. The degree of block by coumarsabin was not enhanced by a reduction in intracellular K(+) concentration. Data reveal that coumarsabin was a closed channel blocker and it displayed a frequency-independent mode of inhibition. Coumarsabin did not accelerate current decay in a Kv1.2 mutant (V370G) defective in C-type inactivation. Taken together, our data suggest that Kv channel inhibition by coumarsabin did not appear to result from a direct obstruction of the outer pore but relied on C-type inactivation.
European journal of pharmacology 02/2013; · 2.59 Impact Factor
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ABSTRACT: Flecainide, quinidine, and mexiletine have been shown to be sodium channel blockers and local anesthetics. The purpose of this study was to examine the interaction of the traditional local anesthetic bupivacaine with flecainide, quinidine, or mexiletine on spinal blockades. To obtain the 50% effective dose (ED(50)) of drugs, dose-dependent responses of spinal blockades of motor and sensory functions with intrathecal flecainide, quinidine, mexiletine, and bupivacaine in rats were constructed. Using a continuum of different fixed drug dose ratios, the interactions of bupivacaine with drugs (flecainide, quinidine, or mexiletine) were evaluated by an isobolographic analysis. Our resulting data showed that flecainide, quinidine, and mexiletine, as well as local anesthetic bupivacaine produced dose-dependent spinal blockades in motor function and nociception. Flecainide had the most potent spinal antinociceptive effect (P<0.01) among these three class I antiarrhythmic drugs. Co-administration of bupivacaine with flecainide, quinidine, or mexiletine displayed an additive effect on spinal blockades of motor function and nociception. We concluded that bupivacaine combined with flecainide, quinidine, or mexiletine exhibited an additive effect on spinal blockades of motor function and nociception. Using such a combination strategy to produce antinociception may potentially provide an improved therapeutic separation from myocardial toxicity occurred after spinal bupivacaine.
Neuroscience Letters 09/2012; 528(1):46-50. · 2.11 Impact Factor
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ABSTRACT: The purpose of the study is to find subcutaneous equianalgesic doses of memantine, amantadine and bupivacaine and use these doses to quantify the cardiovascular and central nervous system toxicity of these agents after intravenous administration. Memantine, amantadine and bupivacaine, a local anesthetic, in a dose-related fashion were determined for cutaneous analgesia by a block of the cutaneous trunci muscle reflex in rats, and equipotent doses were calculated. Following rapid intravenous infusion of equianalgesic bupivacaine, memantine, amantadine and saline (vehicle) in rats, we observed the onset time of seizure, apnea and impending death, and monitored mean arterial blood pressure and heart rate. Memantine and amantadine elicited dose-dependent cutaneous analgesia. At the 50% effective dose (ED(50)), the rank of potencies was bupivacaine [1.8 (1.7-2.0)]>memantine [19.1 (17.6-21.8)]>amantadine [36.1 (32.0-40.3)] (P<0.05). On ED(25), ED(50) and ED(75) basis, the duration caused by bupivacaine was similar to that caused by memantine or amantadine. At equianalgesic doses, the infusion time of memantine or amantadine required to induce seizure, impending death, and apnea was longer than that of bupivacaine during rapid intravenous infusion (P<0.01). The decreasing slope in mean arterial blood pressure and heart rate was slower with memantine and amantadine when compared with bupivacaine at equivalent doses (P<0.01). Our data showed that memantine and amantadine (i) were equal to bupivacaine at producing durations of cutaneous analgesia but (ii) were less likely than bupivacaine to cause cardiovascular and central nervous system toxicity.
European journal of pharmacology 08/2012; 693(1-3):25-30. · 2.59 Impact Factor
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ABSTRACT: The aim of this study was to examine whether thioxanthine-type antipsychotics (chlorprothixene and cis(z)-flupenthixol) and phenothiazine-type antipsychotics (chlorpromazine and fluphenazine) produced spinal anesthesia. Using a rat model of intrathecal injection, we evaluated spinal anesthesia of antipsychotic drugs (chlorprothixene, cis(z)-flupenthixol, chlorpromazine, and fluphenazine) and bupivacaine, a known local anesthetic. At a same dose of 2.31μmol/kg, chlorprothixene had the most potent spinal blockades (P<0.001) and the longest duration of action (P<0.001) of motor function and nociception among those antipsychotic drugs. On the 50% effective dose (ED(50)) basis, the ranks of potencies were chlorprothixene=bupivacaine>cis(z)-flupenthixol>chlorpromazine>fluphenazine (P<0.01 for the differences) in dose-response studies. At an equianesthetic basis (ED(25), ED(50), and ED(75)), the spinal block duration caused by chlorprothixene, cis(z)-flupenthixol, chlorpromazine or fluphenazine was longer than that caused by bupivacaine (P<0.05). These results showed that chlorprothixene produced a similar potency and longer duration of spinal anesthesia than did bupivacaine, whereas several other antipsychotics produced less potency than did bupivacaine.
European journal of pharmacology 08/2012; 693(1-3):31-6. · 2.59 Impact Factor
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ABSTRACT: Although nisoxetine has been shown to elicit cutaneous (peripheral) anesthesia, spinal (central) anesthesia with nisoxetine was not exposed. The aim of this study was to examine spinal anesthesia of nisoxetine and its influence on the antinociceptive action of mepivacaine. We compared nisoxetine with an established local anesthetic mepivacaine for spinal anesthesia after rats were intrathecally injected with drugs. The drugs were spinally administered alone as well as in combination, and their potencies were compared via dose-response curves and isobolographic analysis. We showed that nisoxetine, as well as mepivacaine elicited spinal anesthesia in dose-dependent manners. On a 50% effective dose (ED(50) ) basis, the spinal block effect of nisoxetine in motor function, proprioception, and nociception [0.99 (0.91-1.10), 0.85 (0.76-0.95), 0.82 (0.74-0.89)] was more potent (P < 0.05) than that of mepivacaine [1.28 (1.21-1.34), 1.14 (1.07-1.22), 0.99 (0.93-1.05)], respectively. Furthermore, the nociceptive/sensory blockade (ED(50) ) was greater than the motor blockade in both nisoxetine and mepivacaine groups (P < 0.05). Saline group (vehicle) produced no spinal anesthesia. Coadministration of nisoxetine with mepivacaine displayed an additive effect. Our data reported nisoxetine produced significant anesthesia at spinal level, and additive interaction with the local anesthetic, mepivacaine. Intrathecal nisoxetine elicited more potent spinal anesthesia than mepivacaine.
Fundamental and Clinical Pharmacology 07/2012; · 1.80 Impact Factor
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ABSTRACT: Prenyl-phloroglucinol derivatives from hop plants have been shown to have anticancer activities. This study is the first to investigate the anticancer effects of the new phloroglucinol derivative (2,4-bis(4-fluorophenylacetyl)phloroglucinol; BFP). BFP induced cell death and anti-proliferation in three glioma, U251, U87 and C6 cells, but not in primary human astrocytes. BFP-induced concentration-dependently cell death in glioma cells was determined by MTT and SRB assay. Moreover, BFP-induced apoptotic cell death in glioma cells was measured by Hochest 33258 staining and fluorescence-activated cell sorter (FACS) of propidine iodine (PI) analysis. Treatment of U251 human glioma cells with BFP was also found to induce reactive oxygen species (ROS) generation, which was detected by a fluorescence dye used FACS analysis. Treatment of BFP also increased a number of signature endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP)-78, GRP-94, IRE1, phosphorylation of eukaryotic initiation factor-2α (eIF-2α) and up-regulation of CAAT/enhancer-binding protein homologous protein (CHOP). Moreover, treatment of BFP also increased the down-stream caspase activation, such as pro-caspase-7 and pro-caspase-12 degradation, suggesting the induction of ER stress. Furthermore, BFP also induced caspase-9 and caspase-3 activation as well as up-regulation of cleaved PARP expression. Treatment of antioxidants, or pre-transfection of cells with GRP78 or CHOP siRNA reduced BFP-mediated apoptotic-related protein expression. Taken together, the present study provides evidences to support that ROS generation, GRP78 and CHOP activation are mediating the BFP-induced human glioma cell apoptosis.
Phytomedicine: international journal of phytotherapy and phytopharmacology 07/2012; 19(12):1093-100. · 2.17 Impact Factor
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ABSTRACT: Although diphenidol has long been deployed as an anti-emetic and anti-vertigo drug, its mechanism of action remains unclear. In particular, little is known as to how diphenidol affects neuronal ion channels. Recently, we showed that diphenidol blocked neuronal voltage-gated Na(+) channels, causing spinal blockade of motor function, proprioception and nociception in rats. In this work, we investigated whether diphenidol could also affect voltage-gated K(+) and Ca(2+) channels.
Electrophysiological experiments were performed to study ion channel activities in two neuronal cell lines, namely, neuroblastoma N2A cells and differentiated NG108-15 cells.
Diphenidol inhibited voltage-gated K(+) channels and Ca(2+) channels, but did not affect store-operated Ca(2+) channels.
Diphenidol is a non-specific inhibitor of voltage-gated ion channels in neuronal cells.
Pharmacological reports: PR 05/2012; 64(3):739-44. · 2.44 Impact Factor
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ABSTRACT: Substantiating evidence for the inflammation theory of depression is that interferon-alpha (IFN-α) induces clinical depression. Despite numerous researches on neurochemical and neuroendocrinological mechanisms from human and animal studies, the direct mechanisms of IFN-α at cellular levels are still lacking. In this study, we aimed to identify the cellular mechanisms for IFN-α-induced neuroinflammatory response with the murine BV-2 microglia cell line. IFN-α potently induced nitric oxide synthase (iNOS) and nitric oxide (NO) release and down-regulated haem oxygenase-1 (HO-1) expression, which could be dampened by Janus kinase 1 (JAK1) and c-Jun NH2-terminal kinase (JNK) inhibition, respectively. IFN-α activated JAK1, JNK, signal transducers and activators of transcription (STAT)1 and STAT3, but not extracellular signal-regulated kinases (ERK) and phosphoinositide 3 (PI3) kinase, signal pathways. The transfection with STAT1 and STAT3 siRNA also inhibited IFN-α-induced iNOS/NO expression and HO-1 down-regulation. The HO-1 activator, CoppIX, reversed iNOS/NO up-regulation and HO-1 down-regulation induced by IFN-α. On the other hand, a knockdown of HO-1 expression enhanced IFN-α-induced iNOS/NO expression. The effects of IFN-α-induced iNOS/NO up-regulation and HO-1 down-regulation in microglia are associated with JAK1/JNK/STAT1 and STAT3 signalling pathways. The different effects between IFN-α and IFN-γ on HO-1 regulation and ERK phosphorylation might provide a possible explanation of different risk in their induction of neuropsychiatric adverse effects in clinical and animal studies. The results from this study add the missing part of direct cellular mechanisms for IFN-α-induced depression.
The International Journal of Neuropsychopharmacology 04/2012; · 4.58 Impact Factor
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ABSTRACT: Magnolol, a polyphenolic compound isolated from Houpu, a Chinese herb from the bark of Magnolia officinalis, has been reported to have in vitro and in vivo neuroprotective effects. In spite of these reported beneficial effects, studies on the direct impact of magnolol on neuronal ion channels have been scarce. Whether magnolol affects voltage-gated Na(+) channels (VGSC) and voltage-gated K(+) (Kv) channels is unknown. Using the whole-cell voltage-clamp method, we studied the effects of magnolol on voltage-gated ion channels in neuronal NG108-15 cells. Magnolol inhibited VGSC channels with mild state-dependence (IC(50) of 15 and 30 μM, at holding potentials of -70 and -100 mV, respectively). No frequency-dependence was observed in magnolol block. Magnolol caused a left-shift of 18 mV in the steady-state inactivation curve but did not affect the voltage-dependence of activation. Magnolol inhibited Kv channels with an IC(50) of 21 μM, and it caused a 20-mV left-shift in the steady-state inactivation curve without affecting the voltage-dependence of activation. In conclusion, magnolol is an inhibitor of both VGSC and Kv channels and these inhibitory effects may in part contribute to some of the reported neuroprotective effects of magnolol.
European journal of pharmacology 02/2012; 682(1-3):73-8. · 2.59 Impact Factor
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ABSTRACT: P2X7 receptor (P2X7R) activation by extracellular ATP triggers influx of Na(+) and Ca(2+), cytosolic Ca(2+) overload and consequently cytotoxicity. Whether disturbances in endoplasmic reticulum (ER) Ca(2+) homeostasis and ER stress are involved in P2X7R-mediated cell death is unknown. In this study, a P2X7R agonist (BzATP) was used to activate P2X7R in differentiated NG108-15 neuronal cells. In a concentration-dependent manner, application of BzATP (10-100 µM) immediately raised cytosolic Ca(2+) concentration ([Ca(2+)]i) and caused cell death after a 24-h incubation. P2X7R activation for 2 h did not cause cell death but resulted in a sustained reduction in ER Ca2+ pool size, as evidenced by a diminished cyclopiazonic acid-induced Ca(2+) discharge (fura 2 assay) and a lower fluorescent signal in cells loaded with Mag-fura 2 (ER-specific Ca(2+)-fluorescent dye). Furthermore, P2X7R activation (2 h) led to the appearance of markers of ER stress [phosphorylated α subunit of eukaryotic initiation factor 2 (p-eIF2α) and C/EBP homologous protein (CHOP)] and apoptosis (cleaved caspase 3). Xestospongin C (XeC), an antagonist of inositol-1,4,5-trisphosphate (IP3) receptor (IP3R), strongly inhibited BzATP-triggered [Ca(2+)]i elevation, suggesting that the latter involved Ca(2+) release via IP3R. XeC pretreatment not only attenuated the reduction in Ca(2+) pool size in BzATP-treated cells, but also rescued cell death and prevented BzATP-induced appearance of ER stress and apoptotic markers. These novel observations suggest that P2X7R activation caused not only Ca(2+) overload, but also Ca(2+) release via IP3R, sustained Ca(2+) store depletion, ER stress and eventually apoptotic cell death.
Journal of Cellular Biochemistry 12/2011; 113(4):1377-85. · 2.87 Impact Factor
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ABSTRACT: Apocynum venetum Linn. (Apocynaceae family), also called Luobuma, is a shrub which grows widely in the Xinjiang Autonomous Region of China. Its leaves are used in herbal tea for the treatment of hypertension, anxiety and depression. Animal studies have also shown that Apocynum venetum leaf extract (AVLE) also exerts anti-depressant and anti-anxiety activities. The effects of AVLE on neuronal tissues in vitro are not fully understood.
Using the whole-cell voltage-clamp method, we studied the effects of AVLE on ion channels in cultured mouse neuroblastoma N2A cells.
AVLE inhibited voltage-gated inward Na(+) current in a reversible and concentration-dependent manner (half-inhibitory concentration was 18 μg/ml and maximum inhibition at 100 μg/ml). AVLE specifically promoted steady-state inactivation of Na(+) channels but did not affect voltage-dependence of activation. The inhibitory effect was not use-dependent and was not affected by 300μM L-NAME, suggesting that NO was not involved in the action of AVLE in neuronal cells. AVLE also had a mild inhibitory effect on voltage-gated K(+) channels, but did not affect ATP-sensitive K(+) channels.
Since voltage-gated Na(+) and K(+) channels are associated with neuronal excitability and therefore affect neurotransmission, the modulation of neuronal ion channels by AVLE may exert neuropharmacological effects. In particular, the inhibition of voltage-gated Na(+) currents by AVLE may in part account for the psychopharmacological effects of this herbal remedy.
Journal of ethnopharmacology 06/2011; 136(1):149-55. · 2.32 Impact Factor
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ABSTRACT: Neuritogenesis is essential in establishing the neuronal circuitry. An important intracellular signal causing neuritogenesis is cAMP. In this report, we showed that an increase in intracellular cAMP stimulated neuritogenesis in neuroblastoma N2A cells via a PKA-dependent pathway. Two voltage-gated K(+) (Kv) channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA), inhibited cAMP-stimulated neuritogenesis in N2A cells in a concentration-dependent manner that remarkably matched their ability to inhibit Kv currents in these cells. Consistently, siRNA knock down of Kv1.1, Kv1.4, and Kv2.1 expression reduced Kv currents and inhibited cAMP-stimulated neuritogenesis. Kv1.1, Kv1.4, and Kv2.1 channels were expressed in the cell bodies and neurites as shown by immunohistochemistry. Microfluorimetric imaging of intracellular [K(+)] demonstrated that [K(+)] in neurites was lower than that in the cell body. We also showed that cAMP-stimulated neuritogenesis may not involve voltage-gated Ca(2+) or Na(+) channels. Taken together, the results suggest a role of Kv channels and enhanced K(+) efflux in cAMP/PKA-stimulated neuritogenesis in N2A cells.
Journal of Cellular Physiology 04/2011; 226(4):1090-8. · 3.87 Impact Factor
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ABSTRACT: Individual activation of nicotinic acetylcholine receptor (nAChR) or nitric oxide (NO) synthase in the dorsal facial area (DFA) increases blood flow of common carotid artery (CCA) supplying intra- and extra-cranial tissues. We investigated whether the activation of nAChR initiated the activation of NO synthase and guanylyl cyclase to increase CCA blood flow in anesthetized cats. Microinjections of nicotine (a non-selective nAChR agonist), or choline (a selective α7-nAChR agonist) in the DFA produced increases in CCA blood flow ipsilaterally. These increases were significantly reduced by pretreatment with NG-nitro-arginine methyl ester (l-NAME, a non-specific NO synthase inhibitor), 7-nitroindazole (7-NI, a relatively selective neuronal NO synthase inhibitor) or methylene blue (MB, a guanylyl cyclase inhibitor) but not by that with N5-(1-iminoethyl)-l-ornithine (l-NIO, a potent endothelial NO synthase inhibitor). Control microinjection with d-NAME (an isomer of l-NAME), artificial cerebrospinal fluid or DMSO (a solvent for 7-NI) did not affect resting CCA blood flow, nor did they affect nicotine- or choline-induced response. In conclusion, activation of nAChR, at least α7-nAChR, led to the activation of neuronal NO synthase and guanylyl cyclase in the DFA, which induced an increase in CCA blood flow.
Neuroscience Letters 12/2010; 486(3):122-6. · 2.11 Impact Factor
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ABSTRACT: Lignans are natural phytochemicals which exhibit multiple pharmacological effects such as anti-inflammation, antivirus and anti-tumor activities. Whether they have effects on neural tissues and ion channels is still unknown. The effects of several arylnaphathalene lignans purified from Taiwania cryptomerioides on voltage-gated K(+) (Kv) channels in mouse neuroblastoma N2A cells were examined. These lignans included Taiwanin E, helioxanthin (HXT) and diphyllin. All lignans showed inhibitory effects on Kv channels and HXT was the most potent compound (IC(50)=1.7 μM). The mechanism of HXT block was further investigated. Its action was found to be extracellular but not intracellular. HXT accelerated current decay, caused a left-shift in steady-state inactivation curve but had no effect on voltage-dependence of activation. HXT block was unaffected by intracellular K(+) concentrations. Further, it did not affect ATP-sensitive K(+) channels. Our data therefore suggest that HXT is a potent and specific blocker of Kv channels, possibly with an inhibitory mechanism involving acceleration of slow inactivation.
Phytomedicine: international journal of phytotherapy and phytopharmacology 12/2010; 18(1):46-51. · 2.17 Impact Factor
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ABSTRACT: Interaction between the selectivity filter and the adjacent pore helix of voltage-gated K(+) (Kv) channels controls pore stability during K(+) conduction. Kv channels, having their selectivity filter destabilized during depolarization, are said to undergo C-type inactivation. We examined the functionality of a residue at the pore helix of the Kv1.2 channel (V370), which reportedly affects C-type inactivation. A mutation into glycine (V370G) caused a shift in reversal potential from around -72 to -9 mV. The permeability ratios (P(Na)/P(K)) of the wild type and V370G mutant are 0.04 and 0.76, respectively. In the wild-type, P(Rb)/P(K), P(Cs)/P(K) and P(Li)/P(K) are 0.78, 0.10 and 0.05, respectively. Kv1.2 V370G channels had enhanced permeability to Rb(+) and Cs(+) (P(Rb)/P(K) and P(Cs)/P(K) are 1.63 and 1.18, respectively); however, Li(+) permeability was not significantly augmented (P(Li)/P(K) is 0.13). Therefore, in addition to its known effect on pore stability, V370 of Kv1.2 is also crucial in controlling ion selectivity.
The Journal of Physiological Sciences 11/2010; 60(6):441-6. · 1.61 Impact Factor
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ABSTRACT: Malignant gliomas are the most common primary brain tumors in adults and the second most common tumor in children. Gliomas are associated high morbidity and mortality because these tumors are highly invasive into surrounding brain tissue, making complete surgical resection impossible. Glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor in a variety of neuronal cell populations. However, the molecular mechanisms and pathologic roles underlying GDNF-induced glioma migration remain unclear. In this study, we found that application of recombinant human GDNF enhances the migration of U87 and U251 cells but not C6 cells. In addition, we found that the expression of matrix metalloproteinase-13 (MMP-13) mRNA, protein and secretion increase in response to GDNF stimulation. The GDNF-induced increase in cell migration was antagonized by MMP-13 neutralizing antibody or silencing MMP-13. We then examined the involvement of mitogen-activated protein kinases (MAPKs) in glioma cell migration induced by GDNF. GDNF-induced MMP-13 expression and glioma migration were attenuated by MEK/extracellular signal-regulating kinase (ERK) and c-Jun N-terminal protein kinase (JNK) inhibitors, as well as ERK and JNK dominant-negative mutants. Treatment with GDNF-induced MEK/ERK and JNK/c-Jun activation and increased AP-1 DNA binding activity in a time-dependent manner. Treatment with AP-1 inhibitors (tanshinone IIA and curcumin) also reduced GDNF-induced glioma cell migration. In migration-prone sublines, cells with greater migration ability had higher GDNF expression. These results indicate that GDNF enhances migration of glioma cells through the increase of MMP-13 production and is mainly regulated by the MEK/ERK and JNK, c-Jun and AP-1 pathways.
Biochemical pharmacology 10/2010; 80(8):1201-9. · 4.25 Impact Factor
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ABSTRACT: Accumulating evidence suggests that the pathophysiology of depression might be associated with neuroinflammation, which could be attenuated by pharmacological treatment for depression. Omega-3 polyunsaturated fatty acids (PUFAs) are anti-inflammatory and exert antidepressant effects. The aim of this study was to identify the molecular mechanisms through which docosahexaenoic acid (DHA), the main omega-3 PUFA in the brain, modulates oxidative reactions and inflammatory cytokine production in microglial and neuronal cells. The results of this study showed that DHA reduced expressions of tumor necrosis factor-α, interleukin-6, nitric oxide synthase, and cyclo-oxygenase-2, induced by interferon-γ, and induced upregulation of heme oxygenase-1 (HO-1) in BV-2 microglia. The inhibitory effect of DHA on nitric oxide production was abolished by HO-1 inhibitor zinc protoporphyrin IX. In addition, DHA caused AKT and ERK activation in a time-dependent manner, and the DHA-induced HO-1 upregulation could be attenuated by PI-3 kinase/AKT and MEK/ERK inhibitors. DHA also increased IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation, whereas both nuclear factor-κB and IκB protease inhibitors could inhibit DHA-induced HO-1 expressions. The other major n-3 PUFA, eicosapentaenoic acid, showed similar effects of DHA on inflammation and HO-1 in repeated key experiments. In connecting with inflammation hypothesis of depression and clinical studies supporting the antidepressant effects of omega-3 PUFAs, this study provides a novel implication of the antidepressant mechanisms of DHA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2010; 35(11):2238-48. · 6.99 Impact Factor
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ABSTRACT: Bradykinin is produced and acts at the site of injury and inflammation. Recent reports have also shown that bradykinin selectively modulates blood-tumor barrier permeability. However, the molecular mechanisms and pathologic roles underlying bradykinin-induced glioma migration remain unclear. Glioma is the most common primary adult brain tumor, with a poor prognosis because of the ease with which tumor cells spread to other regions of the brain. In this study, we found that bradykinin increases the cell migration and expression of cyclo-oxygenase-2 (COX-2) in glioma cells. Bradykinin-mediated migration was attenuated by the selective COX-2 inhibitor NS-398. Moreover, increased motility of glioma cells and expression of COX-2 were mimicked by a bradykinin B1 receptor (B1R) agonist and markedly inhibited by a B1R antagonist. Bradykinin-mediated migration was attenuated by phosphoinositide 3-kinase (PI-3 kinase)/AKT inhibitors LY 294002 and wortmannin. Bradykinin stimulation also increased the phosphorylation of the p85 subunit of PI-3 kinase and serine 473 of AKT. Treatment of bradykinin with AP-1 inhibitors Tanshinone IIA and curcumin also reduced COX-2 expression and glioma cell migration. Moreover, treatment of bradykinin also induced phosphorylation of c-Jun in glioma cells. AP-1 promoter analysis in the luciferase reporter construct showed that bradykinin increased AP-1 transcription activity and was inhibited by LY 294002 and wortmannin. One mechanism underlying bradykinin-directed migration is transcriptional up-regulation of COX-2 and activation of the B1R receptor, PI-3 kinase, AKT, c-Jun, and AP-1 pathways.
Journal of Cellular Biochemistry 05/2010; 110(1):141-50. · 2.87 Impact Factor
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Yuk-Man Leung
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ABSTRACT: A manifestation in neurodegeneration is apoptosis of neurons. Neurons undergoing apoptosis may lose a substantial amount of cytosolic K+ through a number of pathways including K+ efflux via voltage-gated K+ (Kv) channels. The consequent drop in cytosolic [K+] relieves inhibition of an array of pro-apoptotic enzymes such as caspases and nucleases. Blocking Kv channels has been known to prevent neuronal apoptosis by preventing K+ efflux. Some neural diseases such as epilepsy are caused by neuronal hyperexcitability, which eventually may lead to neuronal apoptosis. Reduction in activities of A-type Kv channels and Kv7 subfamily members is amongst the etiological causes of neuronal hyperexcitation; enhancing the opening of these channels may offer opportunities of remedy. This review discusses the potential uses of Kv channel modulators as neuroprotective drugs.
Life sciences 04/2010; 86(21-22):775-80. · 2.56 Impact Factor
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ABSTRACT: Mercury, one of the widespread pollutants in the world, induces oxidative stress and dysfunction in many cell types. Alveolar type II epithelial cells are known to be vulnerable to oxidative stress. Alveolar type II epithelial cells produce and secrete surfactants to maintain morphological organization, biophysical functions, biochemical composition, and immunity in lung tissues. However, the precise action and mechanism of mercury on alveolar type II epithelial cell damage remains unclear. In this study, we investigate the effect and possible mechanism of methylmercury chloride (MeHgCl) on the human lung invasive carcinoma cell line (Cl1-0) and mouse lung tissue. Cl1-0 cells were exposed to MeHgCl (2.5-10 microM) for 24-72 h. The results showed a decrease in cell viability and an increase in malondialdehyde (MDA) level and ROS production at 72 h after MeHgCl exposure in a dose-dependent manner. Caspase-3 activity, sub-G1 contents and annexin-V binding were dramatically enhanced in Cl1-0 cells treated with MeHgCl. MeHgCl could also activate Bax, release cytochrome c, and cleave poly(ADP-Ribose) polymerase (PARP), and decrease surfactant proteins mRNA levels. Moreover, in vivo study showed that mercury contents of blood and lung tissues were significantly increased after MeHgCl treatment in mice. The MDA levels in plasma and lung tissues were also dramatically raised after MeHgCl treatment. Lung tissue sections of MeHgCl-treated mice showed pathological fibrosis as compared with vehicle control. The mRNA levels of proteins in apoptotic signaling, including p53, mdm-2, Bax, Bad, and caspase-3 were increased in mice after exposure to MeHgCl. In addition, the mRNA levels of surfactant proteins (SPs), namely, SP-A, SP-B, SP-C, and SP-D (alveolar epithelial cell functional markers) were significantly decreased. These results suggest that MeHgCl activates an oxidative stress-induced mitochondrial cell death in alveolar epithelial cells.
Toxicology Letters 02/2010; 194(3):70-8. · 3.23 Impact Factor
