Protective effect of trifluoperazine on MRL/LPR mice by upregulating FoxO1 expression / 中华风湿病学杂志

Objective:To investigate the effect of trifluoperazine (TFP) on the proliferation of mesangial cells through FoxO1 pathway and its protective effect on lupus nephritis (LN) mice.Methods:In vitro, MTT assay was used to detect the effect of different concentrations of trifluoperazine on the proliferation of mesangial cells. Flow cytometry was used to detect the effect of different concentrations of TFP on the mesangial cell cycle. Western blotting method (WB method) was used to detect the effect of different concentrations of TFP on the expression of FoxO1 and cyclinD1 proteins in mesangial cells, and the expression of TFP on mesangial cells, cyclinD1 and P21 after enhancing or inhibiting the expression of FoxO1. The effect of TFP on the proliferation of MRL/LPR mouse mesangial cells and the expression of FoxO1 was detected by HE staining, immunohistochemistry and WB method, and the effect of TFP on renal function in LN mice was detected by ELISA method in vivo. WB method was used to detect the effect of TFP on mesangial cell fibrosis, that is, the protein expression levels of FN and Col1. Repeated measures analysis of variance and One-way analysis of variance were used to compare measurement data between groups, and further pairwise comparisons were made using the Bonferroni method. Results:Trifluoperazine inhibits the proliferation of mesangial cells, and the interaction effects was concentration dependence and were statistically signifiant between groups, time ( Fgroup=162.58, Ftime=50.84, Finteraction=19.12, P<0.001). Flow cytometry results showed that after mesangial cells were treated with trifluoperazine at different concentrations, the percentage of cells in the G 0/G 1 phase gradually increased, while the cells in the S phase gradually decreased. This effect was dose-dependent, the difference was statistically significant ( P<0.05). Results of WB test proved that trifluoperazine inhibited the expression of cyclinD1 protein (2.17±0.34, 1.49±0.20, 1.11±0.27, 0.15±1.55, F=33.60 , P<0.001) and up-regulated the expression of FoxO1 (0.81±0.45, 2.31±0.81, 3.51±0.52, 5.13±10.07, F=35.63, P<0.001), and also in a dose-dependent patten. In vivo experimental results showed that trifluoperazine could inhibit the proliferation of mesangial cells and promote the expression of FoxO1 in mice with lupus nephritis, and the difference wsa statistically significant ( F=8.47, P=0.007). ELISA test results showed that trifluoperazine had a protective effect on renal function [serum creatinine: normal group(144±23)μmol/L, LN group (237±14)μmol/L, LN+TFP(211±36)μmol/L, Fvalue=20.47, P<0.001, urea nitrogen: normal group (22.84±0.56)μmol/L, LN group (19.99±0.92)μmol/L, LN+TFP (13.57±0.25)μmol/L, F=331.96, P<0.001] and it was proved by WB method that trifluoperazine could inhibit Fn and Col1 expression, the difference was statistically significant ( FFN=1 312.83, FCol1=171.16, P<0.001). Conclusion:Trifluoperazine blocks the mesangial cell cycle in G 0/G 1 phase by increasing the expression of FoxO1 and inhibits cell proliferation, which may have a therapeutic effect on lupus nephritis nephritis.

An unusual case of trifluoperazine induced hypoglycemia.

Hypoglycemia is a serious condition which if not diagnosed and treated urgently may cause irreversible damage to the brain and may be life threatening. There are various causes attributed to hypoglycemia, but drugs are one of the most important one of them. Various drugs are documented to cause hypoglycemia but we present a rare case report of a 52-year-old male patient with schizoaffective disorder on trifluoperazine who presented in emergency department with documented hypoglycemia and this hypoglycemic episode improved when the drug was withdrawn. When WHO causality assessment scale was applied, trifluoperazine was found as the probable cause of the episodes of hypoglycemia. Therefore, this possibility of hypoglycemia should always be kept in mind while prescribing trifluoperazine.

Trifluoperazine decreases scar thickness in a rabbit model of hypertrophic scar ear / 中国组织工程研究

BACKGROUND:Conventional treatments for hypertrophic scars include excision, steroid hormones, anti-metabolite drugs, immunosuppressive agents and radiation therapy. Easy to relapse or serious reaction limits their clinical use. In recent years, application of calcium channel blockers in treatment of hypertrophic scars has made more good progresses, but little adverse reactions are obtained. OBJECTIVE:To explore the effects of calcium channel blocker trifluoperazine on hypertrophic scar of rabbit ears. METHODS:A total of 24 rabbits were enrol ed in this study. After 1 week of accommodation, models of rabbit ear scar were established in accordance with the method of Morris and Li et al. Rabbit models were randomly assigned to three group (n=8). At 30 days after model induction, when scar formed, trifluoperazine and triamcinolone acetonide groups received trifluoperazine and triamcinolone acetonide injection. Blank control group was left intact. Changes in hyperplastic scar, hypertrophic index, levels of matrix metal oproteinase-2, tissue inhibitor of metal oproteinase-2, transforming growth factorβ1,α-smooth muscle actin and proliferating cellnuclear antigen were compared and observed in each group. RESULTS AND CONCLUSION:At 10 and 20 days after treatment, in the three groups, skin bulge was visible in rabbit ears and no rabbit hair grew. Rabbit ears had obvious softening in the trifluoperazine group compared with the triamcinolone acetonide group, showing dark red. In the blank control group, rabbit ear scar was evident and showed red color. At 20 days after treatment, scar thickness and scar index were lower in the trifluoperazine and triamcinolone acetonide groups than in the blank control group. Matrix metal oproteinase 2 expression was significantly higher, but tissue inhibitor of metal oproteinase-2 and transforming growth factorβ1 levels were lower in the trifluoperazine and triamcinolone acetonide groups than in the blank control group. Results indicated that trifluoperazine obtained good proliferative effects on rabbit ear scar, and could decrease scar thickness.

Measurement of antioxidant activity with trifluoperazine dihydrochloride radical cation

A novel, rapid and cost-effective trifluoperazine dihydrochloride (TFPH) decolorization assay is described for the screening of antioxidant activity. A chromogenic reaction between TFPH and potassium persulfate at low pH produces an orange-red radical cation with maximum absorption at 502 nm in its first-order derivative spectrum. TFPH was dissolved in distilled water to give a 100 mM solution. The TFPH radical cation solution was made by reacting 0.5 mL of the solution with K2S2O8 (final concentration: 0.1 mM) and diluting to 100 mL with 4 M H2SO4 solution. A linear inhibition of color production was observed with linearly increasing amounts of antioxidants, with correlation coefficients (R²) ranging from 0.999 to 0.983. The antioxidant capacity of standard solutions of an antioxidant was evaluated by comparing with the inhibition curve using Trolox as the standard. Comparison of antioxidant capacity determined with this newly developed TFPH assay and with the well-known 2,2'-azinobis-[3-ethylbenzthiazoline-6-sulfonic acid] (ABTS)-persulfate decolorization assay indicated the efficacy and sensitivity of the procedure. The proposed assay is less expensive (costs about US$4 per 100 assays) and requires only 20 min for preparation of radical cation solution in comparison with ABTS assay, in which almost 12-16 h are required for preparation of a stable ABTS radical cation solution. The present assay has the advantage over ABTS assay that it can be used to measure the antioxidant activity of the samples, which are naturally found at a pH as low as 1, because the radical cation itself has been stabilized at low pH.

Differential Inhibition of MPP+- or 6-Hydroxydopamine-induced Cell Viability Loss in PC12 Cells by Trifluoperazine and W-7

The present study assessed the effect of calmodulin antagonists trifluoperazine and W-7 against the cytotoxicity of MPP+ and 6-hydroxydopamine (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 0.5~1microM; 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+.

Implication of Egr-1 in trifluoperazine-induced growth inhibition in human U87MG glioma cells

The early growth response gene-1 (Egr-1) is a tumor suppressor which plays an important role in cell growth, differentiation and apoptosis. Egr-1 has been shown to be down-regulated in many types of tumor tissues. Trifluoperazine (TFP), a phenothiazine class of antipsychotics, restored serum-induced Egr-1 expression in several cancer cell lines. We investigated the effect of Egr-1 expression on the TFP-induced inhibition of cell growth. Ectopic expression of Egr-1 enhanced the TFP-induced antiproliferative activity and downregulated cyclin D1 level in U87MG glioma cells. Our results suggest that antipsychotics TFP exhibits antiproliferative activity through up-regulation of Egr-1.

Determinación de la disolución en tabletas de trifluoperazina 1 mg por el método de colorantes ácidos

Se desarrolló un procedimiento espectrofotométrico por un método de colorantes ácidos con tropeolina OO para la determinación de la solución en tabletas de trifluoperazina 1 mg en las condiciones de disolución de la USP 23. El valor del pH seleccionado para la máxima partición del complejo colorante-trifluoperazina en cloroformo fue de 2,5, en el cual el complejo presentó una absorbancia máxima a 408 nm. La linealidad, precisión, exactitud y robustez del método se evaluaron en soluciones modelos de trifluoperazina de concentraciones exactamente conocidas, que permitieron demostrar la fiabilidad del procedimiento analítico desarrollado y determinaron su adopción como método alternativo de control de calidad del producto.

As spectrophotometric procedure was developed by using a methods of acid coloring matters with tropeolin 00 for the determination of the solution in trifluoperazine 1 mg tablets under the conditions of dissolution of the USP 23. The value of the ph selected for the maximun partition of the coloring matter-trifluoperazine complex in chloroform was of 2.5, in which the complex had a maximum absorbency at 408 nm. The lineality, accuracy, exactitude and robustness of the method were evaluated in model solutions of trifluoperazine of exactly known concentrations that allowed to demonstrate the reliability of the analytical process developed, and to determine its adoption as an alternative method to control the quality of the product.

Effects of sodium azide and trifluoperazine on growth, development and monolayer cell differentiation in Dictyostelium discoideum.

The effects of sodium azide and trifluoperazine on growth, cAMP-chemotaxis, morphogenesis and cell differentiation in the slime mould Dictyostelium discoideum were examined. Growth rate of cells pretreated with low chemical concentrations was reduced directly after the treatment but was partially recovered within two to three hours. The levels of growth inhibition were directly proportional to the chemical concentrations. Low concentrations of trifluoperazine (1 μΜ) had no clear effect on the morphogenesis of the wild type strain HM27, but induced partial phenotype correction in the final fruiting body of the sporogenous mutant HM28. On the other hand, all relatively non toxic treatments with sodium azide had no effect on morphogenesis of both strains and on cell differentiation of the wild type strain HM27. Both trifluoperazine and sodium azide shifted cell differentiation of the sporogenous mutant HM28 in monolayers from spore- to stalk-pathway. Higher concentrations of both chemicals inhibited cell differentiation in all strains completely. The results indicated that these chemicals influenced the effects of the sporogenous locus which plays a role in the spore/stalk determination mechanism in the sporogenous mutant HM28.

Trifluoperazine attenuates naloxone-precipitated symptoms in morphine-dependent rats and mice / 中国药理学通报

AIM To investigate the effects of trifluoperazine on naloxone precipitated withdrawal symptoms in morphine dependent rats and mice, and its pharmacological mechanisms. METHODS\ Naloxone precipitated tests in morphine dependent rats and mice were used. RESULTS\ Trifluoperazine(2～20 mg?kg -1 ) dose dependently inhibited naloxone precipitated withdrawal jumping, wet dog shakes, paw tremor and weight loss in morphine dependent mice. With ip trifluoperazine (5～20 mg?kg -1 ), most of positive withdrawal symptoms, including jumping, wet dog shakes, defeacation, weight loss, teeth chattering, salivation, diarrhea, ptosis and irritating, induced by naloxone in morphine dependent rats were significantly reduced. Apomorphine (2～8 mg?kg -1 ), a mixed DA 1/DA 2 receptor agonist, did not affect inhibition of trifluoperazine on naloxone precipitated withdrawal symptoms in morphine dependent mice. However, nifedipine(5～20 mg?kg -1 ), a L type voltage sensitive calcium channel blocker, enhanced a pharmacological action of trifluoperazine against naloxone precipitated symptoms in morphine dependent mice. CONCLUSION\ Trifluoperazine attenuates naloxone precipitated withdrawal symptoms in morphine dependent rats and mice by inhibiting the activity of post receptor calmodulin, but it does not antagonizes DA 2 receptor, in central nervous system.