• The Korean Journal of Physiology and Pharmacology
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• v.9 no.4
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• pp.247-253
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• 2005

The present study assessed the effect of calmodulin antagonists trifluoperazine and W-7 against the cytotoxicity of $MPP^+$ and 6-bydroxydoparnine (6-OHDA) in relation to the mitochondrial dysfunction and cell death in PC12 cells. Trifluoperazine (an inhibitor of the mitochondrial permeability transition and calmodulin antagonist) and W-7 (a specific calmodulin antagonist) significantly attenuated the $MPP^+-induced$ cell viability loss in PC12 cells with a maximum inhibition at $0.5{\sim}1{\mu}M$; beyond these concentrations the inhibitory effect declined. Both compounds at this concentration range did not cause cell death significantly. In contrast to $MPP^+$, the trifluoperazine and W-7 did not depress the cytotoxic effect of 6-OHDA. Addition of trifluoperazine and W-7 inhibited the cytosolic accumulation of cytochrome c and caspase-3 activation in PC12 cells treated with $MPP^+$ and attenuated the formation of reactive oxygen species and the depletion of GSH, whereas both compounds did not reduce the effect of 6-OHDA. The results show that trifluoperazine and W-7 may attenuate the cytotoxicity of $MPP^+$ by inhibition of the mitochondrial permeability transition and calmodulin. Meanwhile, the cytotoxic effect of 6-OHDA seems to be mediated by the actions, which are different from $MPP^+$.

• Animal cells and systems
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• v.16 no.1
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• pp.20-26
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• 2012

Drug-induced parkinsonism has been associated with an increased risk for Parkinson's disease. Antipsychotic drugs have long been known to cause parkinsonian symptoms. However, it remains unclear whether antipsychotics can directly damage the nigrostriatal pathway. In the present study, we investigated the toxicity mechanism of two typical antipsychotics, perphenazine and trifluoperazine, in a human dopaminergic cell line, SH-SY5Y. Perphenazine and trifluoperazine induced mitochondrial damage as evidenced by fragmentation of mitochondria, activation of Bax, cytochrome c release and a decrease in cellular ATP level. In addition, activation of caspase-3 and apoptotic nuclei were observed following the drug treatment. However, pan-caspase inhibitor did not suppress the cell death induced by the antipsychotics, suggesting that the initiated apoptosis was possibly shifted to necrosis upon caspase inhibition. Damaged mitochondria may have induced oxidative stress since the drug-induced cell death was partially suppressed by an antioxidant. Taken together, our results suggest that perphenazine and trifluoperazine can induce apoptotic cell death in a dopaminergic cell line via mitochondrial damage accompanied by oxidative stress.

• BMB Reports
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• v.29 no.4
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• pp.314-320
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• 1996

The effects of non-cytotoxic concentrations of tamoxifen, verapamil, and trifluoperazine on doxorubicin cytotoxicity in five human breast cancer cell lines were studied. A non-cytotoxic concentration of tamoxifen resulted in enhanced doxorubicin cytotoxicity in HTB-123, HTB-26, and MCF-7. In these three cell lines, a combination of tamoxifen with verapamil resulted in even more increased doxorubicin cytotoxicity. Addition of verapamil or trifluoperazine alone did not influence the doxorubicin cytotoxicity significantly. Only in HTB-19 did coincubation with verapamil increase the doxorubicin cytotoxicity. In HTB-123, combination of tamoxifen with trifluoperazine increased the doxorubicin cytotoxicity significantly. In the cell lines where co-incubation with tamoxifen increased doxorubicin sensitivity, high estrogen receptor expression was detected. However, HTB-20, where tamoxifen did not enhance doxorubicin action, was also estrogen receptor positive. None of the cell lines had multidrug resistance related drug efflux and drug retention was not increased by the treatment with tamoxifen and verapamil. Cell cycle traverses were not altered by incubation with tamoxifen, verapamil or combinations thereof. These observatlons suggest mechanism of non-cytotoxic concentrations of tamoxifen and verapamil on doxorubicin cytotoxicity may involve one or more other cellular processes besides those of interference of estrogen binding to its receptor, cell cycle perturbation, or drug efflux blocking.

• The Korean Journal of Physiology
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• v.19 no.1
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• pp.25-33
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• 1985

Renal arterial infusion of renotropic agents has been a very useful technique in the renal function studies. This type of experiments have usually been conducted in the large animals such as dogs and sheep. In these animals a catheter can be placed in the site without much disturbances of renal blood flow. Rabbits as an experimental model, however, caused a disturbances of renal blood flow by a catheterization of renal artery by its properties. Therefore we have developed a new technique that allows a simple and selective access to one side of renal arteries and the other as a control, without any disturbances of renal function. The distance between the both bifurcations of renal arteries on abdominal aorta is about 7 mm. To locate the tip of catheter on one side renal artery, ascending cannulation performed via femoral artery was done. We did an experiment with the technique to clarify the effect of calmodulin inhibitor on the renal function. One of the phenothiazine derivatives, trifluoperazine known as a powerful calmodulin inhibitor. Trifluoperazine, actual dose ranges of $2.76-5.20\;ug\;{\cdot}\;kg^{-1}\;{\cdot}\;min^{-1}$, increased urine volume and glomerular filtration rate significantly. Significant increases in urinary excretion of sodium, chloride and potassium were found. Fractional excretion of sodium and free water clearance increased significantly. These data suggest that this new technique is very useful in field of renal physiology and that striking effect of trifluoperazine on the renal function may be caused by increasing the renal hemodynamics, and by the inhibition of sodium, chloride and potassium reabsorption in the renal tubules.

• Journal of Food Hygiene and Safety
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• v.9 no.1
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• pp.15-21
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• 1994

The mutagenic activity of four phenothiazine derivatives such as chlorpromazine, perphenazine, trifluoperazine and thioridazine in conjunction with UV-A irradiation or not based on the Ames plate incorporation test in the presence and absence of liver microsomal enzyme(S9 fraction). None of these compounds and their photo-excited were detected as mutagen in the Salmonella microsome assay with TA 98 and TA 100.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.1
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• pp.109-117
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• 1998

Role of $Ca^{2+}$/calmodulin complex in intracellular $Ca^{2+}$ mobilization in neutrophils has not been clearly elucidated. In this study, effects of chlorpromazine, trifluoperazine and imipramine on the intracellular $Ca^{2+}$ mobilization, including $Ca^{2+}$ influx, in C5a-activated neutrophils were investigated. Complement C5a- stimulated superoxide production and myeloperoxidase release in neutrophils were inhibited by chlorpromazine, trifluoperazine and imipramine, except no effect of imipramine on myeloperoxidase release. A C5a-elicited elevation of [$Ca^{2+}$]i in neutrophils was inhibited by chlopromazine, trifluoperazine, imipramine, staurosporine, genistein, EGTA, and verapamil but not affected by pertussis toxin. The intracellular $Ca^{2+}$ release in C5a-activated neutrophils was not affected by chlorpromazine and imipramine. Chlorpromazine and imipramine inhibited $Mn^{2+}$ influx by C5a-activated neutrophils. Thapsigargin-evoked $Ca^{2+}$ entry was inhibited by chlorpromazine, trifluoperazine, imipramine, genistein, EGTA and verapamil, while the effect of staurosporine was not detected. The results suggest that $Ca^{2+}$/calmodulin complex is involved in the activation process of neutrophils. The depressive action of calmodulin inhibitors on the elevation of cytosolic $Ca^{2+}$ level in C5a-activated neutrophils appears to be accomplished by inhibition of $Ca^{2+}$ influx from the extracellular medium.

• Journal of Food Hygiene and Safety
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• v.7 no.4
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• pp.143-147
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• 1992

This study was conducted to investigate the effects of ascorbic add on their phototoxicity of four phenothiazine derivatives such as chloropromazine, perphenazine, trifluoperazine and thioridazine. Effects of the test compounds on RBes were monitored with a spectrophotometer by the method of Kahan et al. The extent of photohemolysis by chlorpromazine, perphenazine and thioridazine were decreased with the use of ascorbic acid. It was observed that toxic photoproducts were formed by chlorpromazine and thioridazine with preirtadiated. Although red blood cell hemolysis by preirradiated chlorpromazine was decreased with the use of ascorbic acid but thioridazine was not changed.

• Journal of Chest Surgery
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• v.23 no.1
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• pp.1-8
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• 1990

This experiment was carried out under the postulation that activation of an intracellular calcium-calmodulin complex may play an important role in myocardial injury induced by ischemia and reperfusion. Trifluoperazine[TFP], a calmodulin antagonist, was added to the potassium cardioplegic solution and used just before ischemia, and its protective effect from ischemic injury was investigated, using Langendorff rat heart model. TFP group had better post-ischemic functional recovery and lower post-ischemic contracture after 30 minutes of normothermic ischemia. Creatine kinase leakage was also decreased in TFP group but there was no statistical difference between control group and TFP group. We concluded that TFP has some protective effect from myocardial ischemic injury and its effect might be due to prevention of activation of intracellular calcium-calmodulin complex.

• Bulletin of the Korean Chemical Society
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• v.35 no.2
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• pp.419-424
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• 2014

The pro-apoptotic BCL-2 family protein BID activates BAK and/or BAX, which form oligomeric pores in the mitochondrial outer membrane. This results in the release of cytochrome c into the cytoplasm, initiating the apoptotic cascade. Here, we utilized liposomes encapsulating sulfo-rhodamine at a controlled temperature to improve upon a previously reported assay system with enhanced sensitivity and specificity for measuring membrane permeabilization by BID-dependent BAK activation. BAK activation was inhibited by BCL-$X_L$ protein but not by a mutant protein with impaired anti-apoptotic activity. With the assay system, we screened a chemical library and identified several compounds including trifluoperazine, a mitochondrial apoptosis-induced channel blocker. It inhibited BAK activation by direct binding to BAK and blocking the oligomerization of BAK.

• The Korean Journal of Pharmacology
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• v.31 no.1 s.57
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• pp.123-133
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• 1995

A number of tricyclic antidepressants appear to have inhibitory action on calmodulin. Although amitriptyline, imipramine and doxepine have been shown to inhibit calcium uptake, oxidative phosphorylation and ATPase activities, effects of amitriptyline, imipramine and doxepine on functional responses of human neutrophils have not been elucidated. In this study, effects amitriptyline, imipramine and doxepine on superoxide and hydrogen peroxide generation, myeloperoxidase release, leukocriene B4 formation and intracellular calcium level were investigated. Superoxide and hydrogen peroxide production in heat aggregated IgG-activated neutrophils were inhibited by amitriptyline, imipramine and doxepine. EDTA, EGTA, verapamil and bepredil inhibited heat aggregated IgG-induced superoxide production. Chlorpromazine, trifluoperazine, staurosporine and H-7 also inhibited it. PMA-induced superoxide production was inhibited by amitriptyline, imipramine, doxepine, chlorpromazine and H-7. Amitriptyline, imipramine, chlorpromazine and trifluoperazine inhibited the myeloperoxidase release by heat aggregated IgG. Productions of $LTB_4$, and 5-HETE in heat aggregated IgG-activated neutrophils were inhibited by amitriptyline, imipramine and doxepine. In neutrophils, elevation of intracellular calcium induced by heat aggregated IgG was inhibited by amitriptyline, imipramine, doxepine, chlorpromazine and EGTA, while verapamil slightly inhibited increase of intracellular calcium and H-7 did not inhibit it. These results suggest that the inhibitory effect of amitriptyline, imipramine and doxepine on respiratory burst, myeloperoxidase release and LTB4 production in heat aggregated IgG-activated neutrophils appears to be ascribed to the inhibition of calcium mobilization, calmodulin and protein kinase C.