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PubMed2003

Thiram and ziram stimulate non-selective cation channel and induce apoptosis in PC12 cells.

The neurotoxicity of dithiocarbamates has been previously reported, however, the detailed mechanism underlying the neurotoxicity is still not fully understood. Among the dithiocarbamates, we investigated thiram and ziram in a neuronal-like pheochromocytoma (PC12) cells. Thiram and ziram strongly induced cell death in both dose- and time-dependent manners with the LC(50) of 0.3 and 2 microM, respectively. The cell death showed typical apoptotic features, such as DNA fragmentation and an increase of subdiploidy nuclei. Interestingly, both thiram and ziram induced rapid and sustained increases of intracellular Ca(2+) in PC12 cells, which were almost completely blocked by flufenamic acid (FFA), an inhibitor of non-selective cation channel. BAPTA-AM, an intracellular Ca(2+) chelator, inhibited the thiram- and ziram-induced apoptotic cell death. These results suggest that thiram and ziram induce apoptotic neuronal cell death by Ca(2+) influx through non-selective cation channels. The present study may provide a clue for understanding the mechanism of neurotoxicity of thiram and ziram.

Animals↗
PubMed2000

Implications of Ca(2+)-activated Cl(-) channels in the delta-opioid receptor-mediated antinociception in the mouse spinal cord.

The present study was designed to investigate the role of Ca(2+)-activated Cl(-) channels in the spinal opioid receptor-mediated antinociception using the mouse tail-flick assay. The antinociception induced by intrathecal (i.t.) administration of a selective delta-opioid receptor agonist [D-Ala(2)]deltorphin II (10 microgram, i.t.) was significantly attenuated by i.t.-pretreatment with selective Ca(2+)-activated Cl(-) channel blockers, IAA-94, flufenamic acid and niflumic acid. By contrast, IAA-94 had no effect on the antinociception induced by i.t.-treated with either the selective mu-opioid receptor agonist [D-Ala(2),N-MePhe(4), Gly-ol(5)]enkephalin or the kappa-opioid receptor agonist U-50,488H. The present results provide evidence for the first time that the Ca(2+)-activated Cl(-) channel is, at least in part, implicated in the delta-, but not the mu- and kappa-opioid receptor-mediated antinociception in the mouse spinal cord.

Analgesia↗
PubMed1997

A role for chloride in the suppressive effect of acetylcholine on afferent vestibular activity.

Afferents of the frog semicircular canal (SCC) respond to acetylcholine (ACh) application (0.3-1.0 mM) with a facilitation of their activity while frog saccular afferents respond with suppression (Guth et al., 1994). All recordings are of resting (i.e., non-stimulated) multiunit activity as previously reported (Guth et al., 1994). Substitution of 80% of external chloride (Cl-) by large, poorly permeant anions of different structures (isethionate, methanesulfonate, methylsulfate, and gluconate) reduced the suppressive effect of ACh in the frog saccular afferents. This substitution did not affect the facilitatory response of SCC afferents to ACh. Chloride channel blockers were also used to test further whether Cl- is involved in the ACh suppressive effect. These included: niflumic and flufenamic acids, picrotoxin, 5-nitro-2-(-3-phenylpropylamino)benzoic acid (NPPB), and 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS). As with the Cl- substitutions, all of these agents reduced the suppressive response to ACh in the saccule, but not the facilitatory response seen in the SCC. The suppressive effect of ACh on saccular afferents is considered to be due to activation of a nicotinic-like receptor (Guth et al., 1994; Guth and Norris, 1996). Taking into account the effects of both Cl- substitutions and Cl- channel blockers, we conclude that changes in Cl- availability influence the suppressive effect of ACh and that therefore Cl- may be involved in this effect.

Acetylcholine↗
PubMed2002

A validated high-performance liquid chromatographic method for the determination of glibenclamide in human plasma and its application to pharmacokinetic studies.

Glibenclamide is a potent second generation oral sulfonylurea antidiabetic agent widely used for the treatment of type II diabetes melitus. A rapid, sensitive, precise, accurate and specific HPLC assay for the determination of glibenclamide in human plasma was developed and validated. After addition of flufenamic acid as internal standard, the analytes were isolated from human plasma by liquid-liquid extraction. The method was linear in the 10-400 ng/ml concentration range (r > 0.999). Recovery for glibenclamide was greater than 91.5% and for internal standard was 93.5%. Within-day and between-day precision, expressed as the relative standard deviation (RSD%), ranged from 1.4 to 5.9% and 5.8 to 6.6%, respectively. Assay accuracy was better than 93.4%. The assay was used to estimate the pharmacokinetics of glibenclamide after oral administration of a 5 mg tablet of glibenclamide to 18 healthy volunteers.

Area Under Curve↗
PubMed2000

D609-phosphatidylcholine-specific phospholipase C inhibitor attenuates thapsigargin-induced sodium influx in human lymphocytes.

Previously, we reported that the phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor tricyclodecan-9-yl xanthogenate (D609) potentiates thapsigargin-induced Ca(2+) influx in human lymphocytes. In the present study we examined the effect of D609 on the thapsigargin-induced Na(+) entry. We found that the early phase of the thapsigargin-induced increase in the intracellular Na(+) concentration (approx. 1-2 min after stimulation) was attenuated after preincubation of lymphocytes with D609. By contrast, thapsigargin-induced Na(+) influx was not affected in the presence butan-1-ol, which inhibits phosphatidylcholine-specific phospholipase D (PC-PLD). The thapsigargin-induced Na(+) influx could be mimicked by PC-PLC exogenously added to the lymphocyte suspension, whereas addition of PC-PLD had no effect. In addition, thapsigargin stimulated formation of the physiological PC-PLC products, diacylglycerol. Cell-permeable diacylglycerol analogue, dioctanoyl-glycerol (DOG), produced time- and concentration-dependent increase in the intracellular Na(+) concentration. Both thapsigargin- and DOG-induced Na(+) increases were not affected in the presence of Na(+)/H(+) antiport inhibitor, HOE609, or Na(+)/Ca(2+) antiport inhibitor, dimethylthiourea, as well as in the presence of Co(2+) and Ni(2+), which block store-operated Ca(2+) entry. By contrast, markedly reduced thapsigargin- and DOG-induced Na(+) influx were noted in the presence of flufenamic acid, which blocks the non-selective cation current (I(CRANC)). In conclusion, our results suggest that diacylglycerol released due to the PC-PLC activation contributes to the thapsigargin-induced Na(+) entry.

Biological Transport↗
PubMed2004

Astrocytic connectivity in the hippocampus.

Little is known about the functional connectivity between astrocytes in the CNS. To explore this issue we photo-released glutamate onto a single astrocyte in murine hippocampal slices and imaged calcium responses. Photo-release of glutamate causes a metabotropic glutamate receptor (mGluR)-dependent increase in internal calcium in the stimulated astrocyte and delayed calcium elevations in neighboring cells. The delayed elevation in calcium was not caused by either neuronal activity following synaptic transmission or by glutamate released from astrocytes. However, it was reduced by flufenamic acid (FFA), which is consistent with a role for adenosine triphosphate (ATP) release from astrocytes as an intercellular messenger. Exogenous ligands such as ATP (1 mircoM) increased the number of astrocytes that were recruited into coupled astrocytic networks, indicating that extracellular accumulation of neurotransmitters modulates neuronal excitability, synaptic transmission and functional coupling between astrocytes.

Journal Article↗
PubMed1993

3,4-Dihydroxychalcones as potent 5-lipoxygenase and cyclooxygenase inhibitors.

A novel series of 3,4-dihydroxychalcones was synthesized to evaluate their effects against 5-lipoxygenase and cyclooxygenase. Almost all compounds exhibited potent inhibitory effects on 5-lipoxygenase with antioxidative effects, and some also inhibited cyclooxygenase. The 2',5'-disubstituted 3,4-dihydroxychalcones with hydroxy or alkoxy groups exhibited optimal inhibition of cyclooxygenase. We found that 2',5'-dimethoxy-3,4-dihydroxychalcone (37; HX-0836) inhibited cyclooxygenase to the same degree as flufenamic acid and 5-lipoxygenase, more than quercetin. Finally, these active inhibitors of 5-lipoxygenase inhibited arachidonic acid-induced mouse ear edema more than phenidone.

Administration, Topical↗
PubMed1980

Antiinflammatory effects of some copper complexes.

Copper complexes of a range of ligands have been prepared and evaluated for antiinflammatory activity and irritancy after oral, subcutaneous, and local administration in rats and guinea pigs. The antiinflammatory activities were found to depend on the species used and the route of administration. When nonantiinflammatory ligands were used, the response was generally dose dependent. With D-penicillamine and when the ligands were themselves antiinflammatory in animal models of inflammation--as was the case with flufenamic acid, levamisole, aspirin, L-histidine, and 2-amino-2-thiazoline--differences in antiinflammatory activity were observed between the copper complexes and the free ligands. In some cases, the copper complexes were the more effective. There was a weak correlation between local (subplantar) irritation and the dose of copper but, for four compounds studied in more detail, the response in the local subplantar test and degree of antiinflammatory activity were not related, suggesting that the action of copper is not solely by a counterirritant mechanism. No obvious differences between the activities of copper(I) and copper(II) compounds were observed, suggesting that a common metabolite may be involved in the antiinflammatory action of copper.

Administration, Oral↗
PubMed2005

Understanding solid-state reactions of organic crystals with density functional theory-based concepts.

Solid-state reactions are commonly observed in organic crystals, including pharmaceutical and agricultural materials, fine chemicals, dyes, explosives, optics, and many other substances. The fact that these reactions are in general highly anisotropic with regard to the initiation and propagation in a crystal has led to this study for investigating the effect of crystal packing on the reaction mechanism and kinetics of organic crystals. We have used electron density-based concepts, including nuclear Fukui function, developed from density functional theory, for elucidating the effect of electronic structures of different polymorphs on the difference in their chemical reactivity. Two polymorphs of flufenamic acid were studied. The calculation results on major reacting faces of the two forms support their reactivity difference with ammonia gas. In addition, we calculated surface energies of reacting faces to discuss how the mechanical difference may affect the propagation of solid-state reaction.

Crystallization↗
PubMed2002

An improved resazurin-based cytotoxicity assay for hepatic cells.

A simple resazurin-based cytotoxicity assay is presented for screening of cytotoxicity in hepatocytes and liver cell lines. Human hepatoma (HepG2) cells in 96-well culture plates were exposed to known toxic (cisplatin, 5-fluorouracil, ethionine, flufenamic acid, and diflunisal) and control (transplatin, 5-chlorouracil, methionine, and acetylsalicylic acid) compounds for 1-3 days, and resazurin (5 micromol/L) was added. A conventional short-term (1 h) assay was first performed, where cytotoxicity is indicated by decreased reduction of resazurin to its fluorescent product resorufin. Our improved assay consists of additionally measuring fluorescence 2-4 days later, when cytotoxicity is indicated by a striking increase in the concentration of resorufin, resulting from two distinct processes. First, viable liver-derived cells slowly convert resorufin to nonfluorescent metabolites. Fluorescence of control cell wells decreased to background during a 2- to 4-day exposure to resazurin. This metabolism of resorufin was largely blocked by dicumarol and to lesser extents by disulfiram and SKF525a. Second, dead or dying cells slowly convert resazurin to resorufin but do not further metabolize resorufin; thus this fluorescent metabolite accumulates to high levels in wells with dead cells by 2 to 4 days. A similar increase in fluorescence associated with cytotoxicity was observed in primary cultures of rat hepatocytes using the long-term resazurin-based assay. In addition to an improved signal relative to the short-term assay, the inversion of the fluorescent signal from high = alive short-term to high = dead long-term allows determination of two independent cytotoxicity endpoints after addition of one innocuous vital dye.

Animals↗
PubMed2000

Rational design of potent human transthyretin amyloid disease inhibitors.

The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases.

Amino Acid Sequence↗
PubMed2002

Disparate effects of non-steroidal anti-inflammatory drugs on apoptosis in guinea-pig gastric mucous cells: inhibition of basal apoptosis by diclofenac.

Non-steroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in gastrointestinal cancer cell lines. Similar actions on normal gastric epithelial cells could contribute to NSAID gastropathy. The present work therefore compared the actions of diclofenac, ibuprofen, indomethacin, and the cyclo-oxygenase-2 selective inhibitor, NS-398, on a primary culture of guinea-pig gastric mucous epithelial cells. Cell number was assessed by staining with crystal violet. Apoptotic activity was determined by condensation and fragmentation of nuclei and by assay of caspase-3-like activity. Necrosis was evaluated from release of cellular enzymes. Ibuprofen (250 microM for 24 h) promoted cell loss, and apoptosis, under both basal conditions and when apoptosis was increased by 25 microM N-Hexanoyl-D-sphingosine (C(6)-ceramide). Diclofenac (250 microM for 24 h) reduced the proportion of apoptotic nuclei from 5.2 to 2.1%, and caused inhibition of caspase-3-like activity, without causing necrosis under basal conditions. No such reduction in apoptotic activity was evident in the presence of 25 microM C(6)-ceramide. The inhibitory effect of diclofenac on basal caspase-3-like activity was also exhibited by the structurally similar mefenamic and flufenamic acids (1 - 250 microM), but not by niflumic acid. Inhibition of superoxide production by the cells increased caspase-3-like activity, but the inhibitory action of diclofenac on caspase activity remained. Diclofenac did not affect superoxide production. Diclofenac inhibited caspase-3-like activity in cell homogenates and also inhibited human recombinant caspase-3. In conclusion, NSAIDs vary in their effect on apoptotic activity in a primary culture of guinea-pig gastric mucous epithelial cells, and the inhibitory effect of diclofenac on basal apoptosis could involve an action on caspase activity.

Animals↗
PubMed2001

A diacylglycerol-activated Ca2+ channel in PC12 cells (an adrenal chromaffin cell line) correlates with expression of the TRP-6 (transient receptor potential) protein.

The structures, and mechanisms of activation, of plasma membrane intracellular-messenger-activated, non-selective cation channels in animal cells are not well understood. The PC12 adrenal chromaffin cell line is a well-characterized example of a nerve cell. In PC12 cells, 1-oleolyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analogue of diacylglycerol, initiated the inflow of Ca(2+), Mn(2+) and Sr(2+). Acetylcholine and thapsigargin initiated the inflow of Ca(2+) and Mn(2+), but not of Sr(2+). The activation of bivalent cation inflow by OAG: (i) was mimicked by another membrane-permeant diacylglycerol analogue, 1,2-dioctanoyl-sn-glycerol, but not by the membrane-impermeant analogue 1-stearoyl-2-arachidonyl-sn-glycerol; (ii) was not blocked by staurosporin or chelerythrine, inhibitors of protein kinase C; (iii) was enhanced by RHC80267 and R50922, inhibitors of diacylglycerol lipase and diacylglycerol kinase respectively; and (iv) was inhibited by extracellular Ca(2+). When OAG was added after acetylcholine, the effect of OAG on Ca(2+) inflow was over-and-above that induced by acetylcholine. 2-Aminoethyl diphenylborate (2-APB) inhibited Ca(2+) inflow initiated by either acetylcholine or thapsigargin, but not that initiated by OAG. Flufenamic acid inhibited OAG-initiated, but not acetylcholine-initiated, Ca(2+) and Mn(2+) inflow. OAG-initiated Ca(2+) inflow was less sensitive to inhibition by SK&F96365 than acetylcholine-initiated Ca(2+) inflow. In polyadenylated RNA prepared from PC12 cells, mRNA encoding TRP (transient receptor potential) proteins 1-6 was detected by reverse transcriptase (RT)-PCR, and in lysates of PC12 cells the endogenous TRP-6 protein was detected by Western blot analysis. It is concluded that PC12 cells express a diacylglycerol-activated, non-selective cation channel. Expression of this channel function correlates with expression of the TRP-3 and TRP-6 proteins, which have been shown previously to be activated by diacylglycerol when expressed heterologously in animal cells [Hofmann, Obukhov, Schaefer, Harteneck, Gudermann, and Schultz (1999) Nature (London) 397, 259-263].

Acetylcholine↗
PubMed1975

Effects of inhaled prostaglandins E1, E2, and F2alpha on the airway resistance of healthy and asthmatic man.

1. Changes in specific airway conductance after the inhalation of aerosols of prostaglandins (PG) E1, E2, and F2alpha were investigated in healthy and asthmatic subjects. 2. Inhalation of 155 nmol (55 mug) of PGE1 or 156 nmol (55 mug) of PGF2 resulted in consistent minor bronchodilatation in healthy subjects, but in asthmatic patients airway conductance increased significantly, along with subjective improvement. Isoprenaline (988 nmol; 550 mug) inhalation resulted in a similar increase in conductance to that obtained after these two prostaglandins, whereas a control aerosol had no effect. In contrast to the isoprenaline aerosol, both PGE1 and PGF2 were highly irritant to inhale. It was concluded that this made them unsuitable for therapeutic use. 3. Prostaglandin F2alpha inhalation resulted in a dose-related bronchoconstriction in healthy and asthmatic subjects. Asthmatics were approximately 150 than were the healthy subjects but there was very wide and significant variantion in the sensitivity of the asthmatic subjects. In contrast the asthmatic subjects were only 8-5 times more sensitive to histamine than the healthy subjects with less variation in response of individual subjects. The reasons for the hyper-reactivity of asthmatic subjects to PGF2alpha is unknown and no correlation could be drawn between increased sensitivity and age, type of asthma, or treatment. 4. The effects of disodium cromoglycate, flufenamic acid, atropine methonitrate, PGF2 and isoprenaline on PGF2alpha-induced bronchoconstriction were investigated in healthy subjects. Prostaglandin E2 reversed PGF2alpha-induced bronchoconstriction, as did isoprenaline, but prior treatment with the other drugs had no effect in preventing bronchoconstriction.

Adolescent↗
PubMed1999

Muscarinic receptors regulate two different calcium-dependent non-selective cation currents in rat prefrontal cortex.

Pyramidal neurons of layer V in rat prefrontal cortex display a prominent fast afterdepolarization (fADP) and a muscarinic-induced slow afterdepolarization (sADP). We have shown previously that both of these ADPs are produced by the activation of calcium-dependent non-selective cation currents. In the present report we examine whether they represent two distinct currents. In most pyramidal neurons recorded with caesium gluconate-based intracellular solution, a calcium spike is followed by a fast decaying inward aftercurrent (IfADP). The decay of IfADP is monoexponential with a time constant (t) of approximately 35 ms. Administration of carbachol (10-30 microm) increases the time constant of this decay by approximately 80% and induces the appearance of a much slower inward aftercurrent (IsADP). IfADP recorded in control conditions and in the presence of carbachol increases linearly with membrane hyperpolarization. In contrast, the carbachol-induced IsADP decreases with membrane hyperpolarization. When the sodium driving force across the cell membrane was reduced, IfADP was found to reverse at around -40 mV whereas IsADP remain inward over the same voltage range tested. Finally, bath administration of flufenamic acid (100 microm-1 mm) selectively blocks the carbachol-induced IsADP without a significant effect on the amplitude of IfADP. These differences in the electrical and pharmacological properties of IfADP and IsADP suggest that they were mediated by two distinct non-selective cation currents.

Animals↗
PubMed2003

Calcium-activated cationic channel in rat sensory neurons.

Ion channels in sensory neurons are molecular sensors that detect external stimuli and transduce them to neuronal signals. Although Ca2+-activated nonselective cation (CAN) channels were found in many cell types, CAN channels in mammalian sensory neurons are not yet identified. In the present study, we describe an ion channel that is activated by intracellular Ca2+ in cultured rat sensory neurons. Half-maximal concentration of Ca2+ in activating the CAN channel was approximately 780 micro m. The current-voltage relationship of this channel was linear with a unit conductance of 28.8 +/- 0.4 pS at -60 mV in symmetrical 140 mm Na+ solution. The CAN channel was permeable to monovalent cations such as Na+, K+, Cs+, and Li+, but poorly permeable to Ca2+. The CAN channel in mammalian sensory neurons was reversibly blocked by intracellular adenine nucleotides, such as ATP, ADP, and AMP. Interestingly, single-channel currents activated by Ca2+ were blocked by fenamates, such as flufenamic acid, a class of nonsteroidal anti-inflammatory drugs. Thus, these results suggest that CAN channels in mammalian sensory neurons would participate in modulating nociceptive neural transmission in response to ever-changing intracellular Ca2+ in the local microenvironment.

Adenine Nucleotides↗
PubMed2001

Nonselective cation channels as effectors of free radical-induced rat liver cell necrosis.

Necrosis, as opposed to apoptosis, is recognized as a nonspecific cell death that induces tissue inflammation and is preceded by cell edema. In non-neuronal cells, the latter has been explained by defective outward pumping of Na(+) caused by metabolic depletion or by increased Na(+) influx via membrane transporters. Here we describe a novel mechanism of swelling and necrosis; namely the influx of Na(+) through oxidative stress-activated nonselective cation channels. Exposure of liver epithelial Clone 9 cells to the free-radical donors calphostin C or menadione induced the rapid activation of an approximately 16-pS nonselective cation channel (NSCC). Blockage of this conductance with flufenamic acid protected the cells against swelling, calcium overload, and necrosis. Protection was also achieved by Gd(3+), an inhibitor of stretch-activated cation channels, or by isosmotic replacement of extracellular Na(+) with N-methyl-D-glucamine. It is proposed that NSCCs, which are ubiquitous although largely inactive in healthy cells, become activated under severe oxidative stress. The ensuing influx of Na(+) initiates a positive feedback of metabolic and electrolytic disturbances leading cells to their necrotic demise.

Animals↗
PubMed2006

Fluorogenic metabolic probes for direct activity readout of redox enzymes: Selective measurement of human AKR1C2 in living cells.

The current arsenal of tools and methods for the continuous monitoring and imaging of redox metabolic pathways in the context of intact cells is limited. Fluorogenic substrates allow for direct measurement of enzyme activity in situ; however, in contrast to proteases and exo-glycosidases, there are no simple guidelines for the design of selective probes for redox metabolic enzymes. Here, we introduce redox probe 1 and demonstrate its high selectivity in living cells for human hydroxysteroid dehydrogenases (HSDs) of the aldo-keto reductase (AKR) superfamily. AKR1C isoforms perform multiple functions among which the metabolism of potent steroid hormones is well documented. Moreover, expression of these enzymes is responsive to cellular stress and pathogenesis, including cancer. Our probe design is based on redox-sensitive optical switches, which couple a ketone-alcohol redox event to a profound change in fluorescence. The high selectivity of phenyl ketone 1 for AKR1C2 over the many endogenous reductases present in mammalian cells was established by a quantitative comparison of the metabolic rates between null control cells (COS-1) and AKR1C2-transfected cells. Phenyl ketone 1 is a cell-permeable fluorogenic probe that permits a direct, real-time, and operationally simple readout of AKR1C2 enzyme activity in intact mammalian cells. Furthermore, it was demonstrated that probe 1 enables the quantitative examination of physiological substrate 5alpha-dihydrotestosterone ("dark substrate") in situ by means of a two-substrate competitive assay. Similarly, inhibitor potency of physiological (ursodeoxycholate) and synthetic inhibitors (flufenamic acid, ibuprofen, and naproxen) was also readily evaluated.

Animals↗