1. bookTom 74 (2023): Zeszyt 1 (March 2023)
Archives of Industrial Hygiene and Toxicology's Cover Image
Archives of Industrial Hygiene and Toxicology
Informacje o czasopiśmie
License
Format
Czasopismo
eISSN
1848-6312
Pierwsze wydanie
26 Mar 2007
Częstotliwość wydawania
4 razy w roku
Języki
Angielski, Slovenian
Otwarty dostęp

The effects of simvastatin and fenofibrate on malondialdehyde and reduced glutathione concentrations in the plasma, liver, and brain of normolipidaemic and hyperlipidaemic rats

Antonija Vukšić,
Antonija Vukšić,
Dubravka Rašić,
Dubravka Rašić,
Suzana Žunec,
Suzana Žunec,
Tamara Božina,
Tamara Božina,
Paško Konjevoda,
Paško Konjevoda,
Jasna Lovrić,
Jasna Lovrić,
Marinko Bilušić oraz
Marinko Bilušić oraz
Vlasta Bradamante
Vlasta Bradamante
Data publikacji: 04 Apr 2023
Tom & Zeszyt: Tom 74 (2023) - Zeszyt 1 (March 2023)
Zakres stron: 34 - 41
Otrzymano: 01 Dec 2022
Przyjęty: 01 Mar 2023
Archives of Industrial Hygiene and Toxicology's Cover Image
Archives of Industrial Hygiene and Toxicology
Informacje o czasopiśmie
License
Format
Czasopismo
eISSN
1848-6312
Pierwsze wydanie
26 Mar 2007
Częstotliwość wydawania
4 razy w roku
Języki
Angielski, Slovenian

Statins are usually used to treat patients with elevated cholesterol to prevent cardiovascular diseases (1, 2) and fibrates to treat patients with elevated triglyceride. Regardless of their antilipid effects, both groups of drugs have additional pleiotropic effects such as anti-inflammatory, antiplatelet, improved glucose tolerance, reduced vascular smooth muscle inflammation, and lower plasma fibrinogen (3–6). There are adverse effects too. Statin side effects include muscle pain and damage, liver damage, increased blood sugar, or type 2 diabetes (7). Additionally, according to Okuyama et al. (8), statins may stimulate atherogenesis by suppressing vitamin K2 synthesis and cause heart failure by depleting the myocardium of coenzyme Q10. Fibrates can also cause side effects such as high liver enzymes and serum creatinine, myopathy, and less commonly rhabdomyolysis. These side effects can be serious if fibrates are co-administered with statins (4).

Many of these positive and negative pleiotropic effects are mediated by the interaction of statins and fibrates with peroxisome proliferator-activated receptors (PPARs), especially PPAR-α (9, 10). PPAR-α receptors are expressed in the brain, heart, liver muscle, and other organs and play a significant role in oxidative stress, energy homeostasis, mitochondrial fatty acid metabolism, and inflammation (11). According to new data, PPAR-α receptors in the brain are important for statins and fibrates to act as neuroprotectors and treat various neurodegenerative disorders, such as multiple sclerosis, stroke, and Parkinson’s and Alzheimer’s disease (12–15). Animal studies have also shown neuroprotective effects of fenofibrate alone or in combination with simvastatin in animals with traumatic brain injury (16, 17).

Both antilipid drugs also affect two important parameters of oxidative stress, namely malondialdehyde (MDA) and reduced glutathione (GSH) (18, 19). GSH is synthesised in the liver but also in the brain, where it plays an important role maintaining the homeostasis of cell functions (19, 20). However, studies of the effects of simvastatin and fenofibrate on MDA and GSH report inconsistent findings. Macan et al. (21) and Mohamadin et al. (22) reported that simvastatin reduced MDA concentrations in normolipidaemic and diabetic rats, whereas Zeng and Liu (23) reported a prooxidative effect of atorvastatin. Fenofibrate, in turn, was reported to significantly reduce plasma MDA in rats (24), whereas gemfibrozil was reported to increase it significantly in the plasma, liver, and kidney in Wistar and Fisher rats (25). Ciriolo et al. (26, 27) reported that clofibrate or fenofibrate caused lipid peroxidation in rat liver homogenates.

As far as reduced glutathione is concerned, simvastatin has been reported to significantly deplete its cellular reservoirs and to increase the levels of its oxidised form (28, 29), whereas fenofibrate has been reported to increase GSH in experimental animals with diabetic nephropathy (30).

In view of these inconsistent reports of preclinical and clinical studies about simvastatin and fenofibrate effects on MDA and GSH, we decided to investigate how two different doses of simvastatin and fenofibrate would affect plasma, liver, and brain MDA and GSH concentrations in normolipidaemic rats and if the effects would be dose-dependent. We also wanted to see if the same doses of simvastatin or fenofibrate would have the same or comparable effects in normolipidaemic and hyperlipidaemic rats.

MATERIAL AND METHODS
Test substances and dose selection

Simvastatin and fenofibrate were chosen for this investigation, because both agents cross the blood-brain barrier (31, 32). Simvastatin (CAS-79902-63-9) (Lipex®, Merck Sharp & Dohme, Haarlem, The Netherlands) (simvastatin) and fenofibrate (CAS-49562-28-9) (Tricor®, Recipharm Fontaine, Fontaine-lès-Dijon, France) (fenofibrate) tablets were suspended in 5 mL/kg saline and administered daily (at 9.00–10.00 a.m.) by gavage. Our choice of fenofibrate doses of 30 and 50 mg/kg/day and of simvastatin doses of 10 and 50 mg/kg/day is based on literature data (33–36) from different experiments on rats.
Treatment of animals

This study included male 10-week-old normolipidaemic (N=72) and hyperlipidaemic rats (N=21). The normolipidaemic rats were the Wistar strain and weighed 250–300 g (University of Zagreb School of Medicine, Department of Pharmacology, Zagreb, Croatia). The hyperlipidaemic rats were the HsdOla: Zucker-Lepr fa-fa strain (Harlan Laboratories srl, Udine, Italy) and weighed 270–300 g. The animals were kept in macrolone cages at controlled room temperature (22 °C) and 12:12 h day/night cycles and had free access to standard pellet diet. Animal handling and treatment followed the national (37) and European (38) guidelines and recommendations for the use of laboratory animals. The experiments were approved by the ethics committee of the University of Zagreb School of Medicine (approval No. 380-59-10106-23-111/33).

The experiment lasted 21 days (3 weeks). Normolipidaemic rats were randomly divided into four experimental (N=10) and four control groups (N=8). The first experimental group was receiving simvastatin 10 mg/kg/day and the second simvastatin 50 mg/kg/day. The third experimental group was receiving fenofibrate 30 mg/kg/day and the fourth fenofibrate 50 mg/kg/day. Corresponding control groups were given saline (0.9 % NaCl solution) 5 mL/kg b.w. daily by gavage.

Hyperlipidaemic Zucker rats were divided in two experimental and one control group. The first experimental group (N=7) was receiving simvastatin 50 mg/kg/day and the second (N=8) fenofibrate 30 mg/kg/day. The control group (N=6) was receiving saline as described above.

On day 22 of the study, after an overnight fast of 12 h, all rats were sacrificed under diethyl ether anaesthesia. Blood samples were taken by cardiac puncture and frozen at -20 °C immediately after sampling. Liver and brain tissues were also taken immediately after sacrifice. Liver was rinsed with saline in situ via the superior vena cava to remove blood. The brain was also rinsed with saline. The whole brain and a part of the liver were homogenised in saline in the 1:4 ratio and centrifuged at 3500 g for 20 min. The separated supernatants were frozen at -80 °C.
Measurement of malondialdehyde in plasma

The samples were prepared by pipetting 100 µL of plasma and 500 µL of precipitation reagent into labelled, light-protected vials, which were vortexed and then centrifuged at 8125 g for 5 min. The obtained supernatant (500 µL) was then transferred to a labelled derivatisation vial and added 100 µL of derivatisation reagent. The vials were capped, briefly vortexed, and incubated at 95 °C for 60 min. Followed abrupt cooling under a stream of cold water, and then we added 500 µL of neutralisation buffer to the cooled mixture and injected 20 µL of the prepared sample into the column.

Plasma MDA concentrations were determined with a high performance liquid chromatograph (HPLC) (Nexera, Shimadzu Corporation, Kyoto, Japan) using a commercially available kit (Cat. No. 67000, Chromsystems Instruments and Chemicals GmbH, Gräfelfing, Germany), according to the manufacturer’s instructions. Sample preparation was based on protein precipitation followed by derivatisation. The HPLC system consisted of a fluorescent detector (RF-20AXS), isocratic pump (LC-20ADXR), column thermostat (CTO-20A), autoinjector (SIL-30AC), degasser (DGU-20A5), and control unit (CBM-20A). Chromatographic conditions were as follows: isocratic mobile phase flow 1.0 mL/min; pressure ~125 bar; wavelength 515 nm (excitation) and 553 nm (emission); column temperature 25 °C; analysis time 5 min; injection volume 20 µL.

Data from the detector were collected and processed with the Shimadzu LabSolutions software, and the measured plasma MDA concentrations are expressed in micromoles per litre (µmol/L).
Measurement of malondialdehyde in the liver and brain

Brain and liver tissue MDA concentrations were measured using a modified method described by Drury et al. (39), which is based on MDA binding to 2-thiobarbituric acid (TBA) to form a pink compound that absorbs light at the wavelength of 538 nm. For the standard calibration curve we used 1,1,3,3-tetraethoxy propane. Further oxidation was prevented by adding butylated hydroxytoluene (BHT).

The sample solution contained 50 µL of the brain or liver tissue supernatant, 5 µL of BHT (0.2 %, w/v), 750 µL of phosphoric acid (1 %, v/v), 250 µL of TBA (0.6 %, w/v), and 445 µL of ultrapure water (18 MΩ; obtained from a Thermo Scientific Smart2Pure 3 UV/UF water purification system, Thermo Fisher Scientific Inc., Waltham, MA, USA). We stirred it and incubated in a boiling water bath for 30 min, then stopped the reaction by cooling in water, and then injected 20 µL of the prepared solution into a HPLC consisting of a degasser, isocratic pump, thermostated column space, and UV detector (LC-20AD, Shimadzu). The pre-column and analytical column were C-18 reverse phases (LiChrospher, Merck, Darmstadt, Germany) with 5 µm particles. The dimensions of the pre-column were 4.0 × 4.0, and of the columns 4.0 x 125.0 mm.

Mobile phase consisted of 50 mmol/L KH2PO4 and methanol (60:40, v/v, pH 6.8). The flow rate was 1 mL/min. MDA was measured with a UV detector at 532 nm and column temperature was 32 °C. Under these conditions, the MDA retention time was 2.5 min. Its brain and liver tissue concentrations are expressed as micromoles per litre (µmol/L).
Measurement of reduced glutathione in plasma, liver, and brain

Rat plasma, brain, and liver GSH concentrations were measured according to the Ellman’s spectrophotometric method (40), which is based on glutathione (thiol) coupling with 5,5’-dithiobis-(2-nitrobenzoic acid) (DTNB). In this rapid reaction, a disulphide bond is cleaved to form 2-nitro-5-thiobenzoate (NTB), which is ionised to NTB2- and whose yellow colour is read at 412 nm. We added 100 µL of trichloroacetic acid (TCA, 5 % solution) to 300 µL of supernatant and first stirred the mixture with a shaker and then centrifuged it at 10,000 g for 10 min. Reaction mixtures consisted of 850 µL of phosphate buffer and 50 µL of DTNB added to100 µL H2O for the blank sample or to 100 µL standards for standard samples or to 100 µL of tissue or plasma supernatant and were measured at 412 nm using a Cecil 9000 spectrophotometer (Cecil Instruments Limited, Cambridge, UK). All measurements were done in triplicate. The concentration of GSH was calculated from the calibration diagram and is expressed as micrograms per millilitre (µg/mL).
Statistical analysis

All data were analysed with the GraphPAD Prism software, version 6 (GraphPAD Software, San Diego, CA, USA). For normolipidaemic rats, the results are shown as arithmetic means ± standard deviations (x̄±SD) and p-values. For hyperlipidaemic rats the results are shown as arithmetic means ± standard deviations and p-values of Dunnett’s multiple comparison test, which is considered optimal for comparison of different drug doses with a single control group. All applied tests were two-way. P values of less than 0.05 are considered statistically significant (41).
RESULTS
MDA and GSH concentrations in normolipidaemic rats after simvastatin treatment

Table 1 shows MDA and GSH concentrations in the plasma, liver, and brain of normolipidaemic rats receiving either of the two simvastatin doses. Compared to control, only the higher dose (50 mg/kg/day) significantly lowered MDA concentrations (20 %; p=0.044) in the plasma, neither dose lowered it significantly in the liver, and only the lower dose (10 mg/kg/day) decreased it significantly in the brain 59 % (p<0.001).

The effects of simvastatin (10 mg/kg and 50 mg/kg daily for 3 weeks) on MDA and GSH levels in the plasma, liver, and brain of normolipidaemic rats

VariableSourceControlaSimvastatina(10 mg/kg/day)P valueb(95 % CI)cControlaSimvastatina(50 mg/kg/day)P valueb(95 % CI)c
MDA (μmol/L)Plasma0.26±0.051(n=8)0.24±0.046(n=8)0.471(-0.05–0.08)0.30±0.236(n=7)0.24±0.036(n=6)0.044(-0.14–0.06)
Liver105.2±15.12(n=6)92.3±19.26(n=10)0.166(-33.31–6.32)103.6±17.94(n=8)104.8±22.54(n=8)0.909(-20.65–23.04)
Brain2.67±0.204(n=8)1.11±0.231(n=10)<0.001(-1.77–1.33)2.28±0.508(n=8)1.80±0.218(n=6)0.050(-0.97–0.01)
GSH (μg/mL)Plasma57.3±17.68(n=6)47.4±15.81(n=9)0.324(-30.81–10.96)51.0±17.68(n=8)47.7±26.80(n=7)0.778(-28.32–21.61)
Liver133.5±21.24(n=6)218.1±43.03(n=5)0.002(39.80–129.6)229.0±36.05(n=6)258.0±135.2(n=6)0.623(-96.57–43.02)
Brain17.2±4.61(n=8)22.1±9.08(n=10)0.179(-2.52–12.47)20.2±4.23(n=8)23.6±5.01(n=9)0.152(-1.41–8.24)

GSH – reduced glutathione; MDA – malondialdehyde. Bold P values are significant at the <0.05 level.

a mean ± SD.

b P value of independent two-sample t-test.

c 95 % confidence interval for difference between means

GSH concentrations increased significantly (63 %; p=0.002) only in the liver of rats receiving the lower simvastatin dose (10 mg/kg/day).
MDA and GSH concentrations in normolipidaemic rats after fenofibrate treatment

Table 2 shows MDA and GSH concentrations in the plasma, liver, and brain of normolipidaemic rats receiving either fenofibrate dose (30 or 50 mg/kg/day). Both significantly lowered MDA concentrations in the plasma [39 % (p=0.017) and 42 % (p<0.001), respectively], but neither changed them significantly in the liver or brain.

The effects of fenofibrate (30 mg/kg and 50 mg/kg daily for 3 weeks) on MDA and GSH levels in the plasma, liver, and brain of normolipidaemic rats

VariableSourceControlaFenofibratea(30 mg/kg/day)P valueb(95 % CI)cControlaFenofibratea(50 mg/kg/day)P valueb(95 % CI)c
MDA (μmol/L)Plasma0.33±0.127(n=5)0.20±0.033(n=8)0.017(-0.23–0.03)0.31±0.048(n=8)0.18±0.022(n=8)<0.001(-0.17–0.08)
Liver62.2±14.43(n=7)62.4±15.37(n=10)0.971(-34.18–14.22)85.0±10.70(n=8)71.1±11.95(n=8)0.188(-23.18–7.57)
Brain3.51±0.596(n=8)3.30±0.40(n=10)0.404(-0.69–0.29)2.89±1.018(n=8)2.20±0.13(n=7)0.120(-1.30–0.09)
GSH (μ/mL)Plasma69.6±20.85(n=5)76.5±15.63(n=4)0.602(-22.93–36.68)70.4±12.23(n=6)92.4±18.32(n=7)0.030(2.60–41.41)
Liver71.8±36.16(n=8)33.3±17.71(n=9)0.013(-67.33–9.57)72.6±16.31(n=6)29.2±10.27(n=10)<0.001(-57.51–29.24)
Brain16.7±2.54(n=7)15.2±3.54(n=9)0.349(-4.95–1.87)20.6±5.58(n=8)23.5±2.57(n=10)0.169(-1.34–7.03)

GSH – reduced glutathione; MDA – malondialdehyde. Bold P values are significant at the <0.05 level.

a mean ± SD.

b P value of independent two-sample t-test.

c 95 % confidence interval for difference between means

The higher fenofibrate dose significantly increased plasma GSH (31 %; p=0.03), and both doses significantly lowered it in the liver [54 % (p=0.013) and 60 % (p<0.001), respectively]. Neither dose significantly affected brain GSH concentrations.
MDA and GSH concentrations in hyperlipidaemic rats after simvastatin and fenofibrate treatment

Table 3 shows plasma, liver, and brain MDA and GSH concentrations in hyperlipidaemic rats receiving either the higher simvastatin (50 mg/kg/day) or lower fenofibrate dose (30 mg/kg/day). Compared to control, simvastatin did not significantly affect MDA concentrations in any of the organs, but fenofibrate significantly lowered them in the plasma (33 %; p=0.009) and increased them in the brain (39 %; p=0.032). It did not change MDA concentrations in the liver.

The effects of simvastatin (50 mg/kg daily for 3 weeks) and fenofibrate (30 mg/kg daily for 3 weeks) on MDA and GSH levels in the plasma, liver, and brain of hyperlipidaemic rats

VariableSourceControlaSimvastatina(50 mg/kg/day)P valueb(95 % CI)cFenofibratea(30 mg/kg/day)P valueb(95 % CI)c
MDA (μmol/L)Plasma0.39±0.114(n=6)0.40±0.036(n=6)0.960(-0.11–0.09)0.26±0.036(n=7)0.009(0.04–0.24)
Liver92.1±30.00(n=6)100.4±19.45(n=6)0.828(-46.89–30.43)82.8±31.26(n=7)0.774(-27.96–46.55)
Brain9.7±1.67(n=6)8.6±2.42(n=6)0.641(-2.32–4.61)13.5±3.08(n=6)0.032(-7.26–0.33)
GSH (μ/mL)Plasma251.7±127.4(n=4)224.2±57.58(n=5)0.845(-117.2–172.2)304.6±0.033(n=4)0.593(-205.5–99.61)
Liver59.4±22.00(n=6)33.0±24.04(n=5)0.045(0.57–52.34)12.2±5.98(n=8)0.001(24.13–70.30)
Brain8.9±1.73(n=6)9.1±1.80(n=6)0.876(-3.26–2.28)9.1±2.30(n=7)0.847(-3.19–2.14)

GSH – reduced glutathione; MDA – malondialdehyde. Bold P values are significant at the <0.05 level.

a mean ± SD.

b P value of Dunnett’s multiple comparison test with control.

c 95 % confidence interval for difference between means

As for GSH concentrations, both drugs had a significant (lowering) effect only in the liver (45 % and 80 % vs control, respectively).
DISCUSSION

Our results show that the effects of simvastatin on either MDA or GSH concentrations are dose-independent and confirm earlier reports that simvastatin can have antioxidative properties. The effect of lowering MDA in the plasma and tissues may be owed to statins’ potential to suppress specific oxidation pathways and reduce lipid peroxidation, upregulate antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase), or downregulate key prooxidant enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (42–44). We believe that in normolipidaemic rats this effect is owed to lower lipid peroxidation in the presence of statins. One systematic review (45) with a meta-analysis has shown that statins significantly increase glutathione peroxidase and superoxide dismutase levels in patients.

The antioxidative properties of simvastatin are also supported by our GSH findings in normolipidaemic rats, which confirm earlier reports (22, 46).

The dose-independent lowering effects of fenofibrate on plasma, liver, and brain MDA concentrations in normolipidaemic rats are similar to those of simvastatin (Table 2) and are also supported by other studies in vivo (24, 47–49). However, Beltowski et al. (24) report a dose-dependent effect and suggest that fenofibrate, as a peroxisome proliferator, can increase the concentrations of hydrogen peroxide and oxidative stress locally, but without increasing lipid peroxidation products in the plasma. Aberg et al. (48) and Arnaiz et al. (49) propose that clofibrate and fenofibrate increase the concentrations of ubiquinols as the only liposoluble endogenous antioxidants in several animal tissues that inhibit lipid peroxidation (48, 49). In humans, Tkác et al. (50) reported that fenofibrate treatment increased glutathione peroxidase activity in patients with combined dyslipidaemia.

However, we have also observed a significant decrease in liver GSH in normolipidaemic rats, which begs the question if fenofibrate can also produce prooxidant effects, as some studies suggest (27, 51). We, however, believe that this drop in liver GSH has to do with its binding with one or more fenofibrate metabolites, as demonstrated by Shore et al. (52) for one metabolite (1-O-clofibryl glucuronide) of clofibrate, which belongs to the same class of antilipidaemic drugs.

As for the second aim of our study, our results show that the same doses of simvastatin and fenofibrate produce different effects on MDA and GSH concentrations in normolipidaemic and hyperlipidaemic rats. In hyperlipidaemic rats simvastatin (50 mg/kg/day) did not change MDA concentrations and significantly decreased liver GSH, which points to oxidative stress, as reported in some earlier studies (28, 29). Some recent studies, however, report antioxidant action of statins in hyperlipidaemic rats (22, 46). These discrepancies may be owed to differences in experimental methods, including rat strain, dosing, and duration of statin treatment.

Treatment with fenofibrate, in turn, yielded comparable plasma and liver MDA lowering in hyperlipidaemic and normolipidaemic rats. Its tendency to lower MDA was also reported in the plasma of rats with hypertriglyceridaemia (53). We believe that the decrease in plasma and liver MDA concentrations in hyperlipidaemic rats may be evidence that no lipid peroxidation occurs during fenofibrate treatment.

However, brain MDA concentrations in normolipidaemic rats dropped (although not significantly), whereas in hyperlipidaemic rats they significantly increased. Considering that we found no studies reporting fenofibrate effects on brain MDA in vivo, we find it difficult to explain our finding, especially in regard to recent studies reporting the neuroprotective, anti-inflammatory, and antioxidative effects of fenofibrate in some neurodegenerative diseases through their agonistic action mainly on PPAR-α receptors (11, 16). It is possible that higher brain MDA concentrations in hyperlipidaemic rats have something to do with changes in these receptors, as pointed out by Wójtowicz et al. (11). New preclinical studies might clear this out, especially in view of the fact that fenofibrate did not significantly increase brain GSH in either rat strain. Speaking of GSH, fenofibrate effects were similar between normolipidaemic and hyperlipidaemic rats only in the liver.
CONCLUSIONS

To conclude, our results show similar antioxidative but dose-independent effects of simvastatin and fenofibrate on MDA and GSH in the plasma and brain of normolipidaemic rats. However, these effects are not repeated in hyperlipidaemic rats, save for a significant decrease in liver GSH concentrations by fenofibrate in both rat strains, which points to GSH binding with the same fenofibrate metabolite in the liver.

Considering our findings and the current knowledge about the importance of oxidative stress parameters, GSH in particular, in different neurological and cardiovascular conditions and the widespread use of statins and fibrates, we believe that further preclinical and clinical research is needed to shed more light on their action on oxidative stress parameters.

The effects of simvastatin (10 mg/kg and 50 mg/kg daily for 3 weeks) on MDA and GSH levels in the plasma, liver, and brain of normolipidaemic rats

Variable Source Controla Simvastatina(10 mg/kg/day) P valueb(95 % CI)c Controla Simvastatina(50 mg/kg/day) P valueb(95 % CI)c
MDA (μmol/L) Plasma 0.26±0.051(n=8) 0.24±0.046(n=8) 0.471(-0.05–0.08) 0.30±0.236(n=7) 0.24±0.036(n=6) 0.044(-0.14–0.06)
Liver 105.2±15.12(n=6) 92.3±19.26(n=10) 0.166(-33.31–6.32) 103.6±17.94(n=8) 104.8±22.54(n=8) 0.909(-20.65–23.04)
Brain 2.67±0.204(n=8) 1.11±0.231(n=10) <0.001(-1.77–1.33) 2.28±0.508(n=8) 1.80±0.218(n=6) 0.050(-0.97–0.01)
GSH (μg/mL) Plasma 57.3±17.68(n=6) 47.4±15.81(n=9) 0.324(-30.81–10.96) 51.0±17.68(n=8) 47.7±26.80(n=7) 0.778(-28.32–21.61)
Liver 133.5±21.24(n=6) 218.1±43.03(n=5) 0.002(39.80–129.6) 229.0±36.05(n=6) 258.0±135.2(n=6) 0.623(-96.57–43.02)
Brain 17.2±4.61(n=8) 22.1±9.08(n=10) 0.179(-2.52–12.47) 20.2±4.23(n=8) 23.6±5.01(n=9) 0.152(-1.41–8.24)

The effects of fenofibrate (30 mg/kg and 50 mg/kg daily for 3 weeks) on MDA and GSH levels in the plasma, liver, and brain of normolipidaemic rats

Variable Source Controla Fenofibratea(30 mg/kg/day) P valueb(95 % CI)c Controla Fenofibratea(50 mg/kg/day) P valueb(95 % CI)c
MDA (μmol/L) Plasma 0.33±0.127(n=5) 0.20±0.033(n=8) 0.017(-0.23–0.03) 0.31±0.048(n=8) 0.18±0.022(n=8) <0.001(-0.17–0.08)
Liver 62.2±14.43(n=7) 62.4±15.37(n=10) 0.971(-34.18–14.22) 85.0±10.70(n=8) 71.1±11.95(n=8) 0.188(-23.18–7.57)
Brain 3.51±0.596(n=8) 3.30±0.40(n=10) 0.404(-0.69–0.29) 2.89±1.018(n=8) 2.20±0.13(n=7) 0.120(-1.30–0.09)
GSH (μ/mL) Plasma 69.6±20.85(n=5) 76.5±15.63(n=4) 0.602(-22.93–36.68) 70.4±12.23(n=6) 92.4±18.32(n=7) 0.030(2.60–41.41)
Liver 71.8±36.16(n=8) 33.3±17.71(n=9) 0.013(-67.33–9.57) 72.6±16.31(n=6) 29.2±10.27(n=10) <0.001(-57.51–29.24)
Brain 16.7±2.54(n=7) 15.2±3.54(n=9) 0.349(-4.95–1.87) 20.6±5.58(n=8) 23.5±2.57(n=10) 0.169(-1.34–7.03)

The effects of simvastatin (50 mg/kg daily for 3 weeks) and fenofibrate (30 mg/kg daily for 3 weeks) on MDA and GSH levels in the plasma, liver, and brain of hyperlipidaemic rats

Variable Source Controla Simvastatina(50 mg/kg/day) P valueb(95 % CI)c Fenofibratea(30 mg/kg/day) P valueb(95 % CI)c
MDA (μmol/L) Plasma 0.39±0.114(n=6) 0.40±0.036(n=6) 0.960(-0.11–0.09) 0.26±0.036(n=7) 0.009(0.04–0.24)
Liver 92.1±30.00(n=6) 100.4±19.45(n=6) 0.828(-46.89–30.43) 82.8±31.26(n=7) 0.774(-27.96–46.55)
Brain 9.7±1.67(n=6) 8.6±2.42(n=6) 0.641(-2.32–4.61) 13.5±3.08(n=6) 0.032(-7.26–0.33)
GSH (μ/mL) Plasma 251.7±127.4(n=4) 224.2±57.58(n=5) 0.845(-117.2–172.2) 304.6±0.033(n=4) 0.593(-205.5–99.61)
Liver 59.4±22.00(n=6) 33.0±24.04(n=5) 0.045(0.57–52.34) 12.2±5.98(n=8) 0.001(24.13–70.30)
Brain 8.9±1.73(n=6) 9.1±1.80(n=6) 0.876(-3.26–2.28) 9.1±2.30(n=7) 0.847(-3.19–2.14)

Parums DV. Editorial: The 2021 European Society of Cardiology (ESC) guidelines on the real-world prevention of atherosclerotic cardiovascular disease (ASCVD). Med Sci Monit 2021;27:e9351721–3. doi: 10.12659/MSM.935172 Parums DV . Editorial: The 2021 European Society of Cardiology (ESC) guidelines on the real-world prevention of atherosclerotic cardiovascular disease (ASCVD) . Med Sci Monit 2021 ; 27 : e9351721 – 3 . doi: 10.12659/MSM.935172 Otwórz DOISearch in Google Scholar

Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Muñoz D, Smith SC Jr, Virani SS, Williams KA Sr, Yeboah J, Ziaeian B. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;140(11):e596-e646. doi: 10.1161/CIR.0000000000000678 Arnett DK Blumenthal RS Albert MA Buroker AB Goldberger ZD Hahn EJ Himmelfarb CD Khera A Lloyd-Jones D McEvoy JW Michos ED Miedema MD Muñoz D Smith SC Jr Virani SS Williams KA Sr Yeboah J Ziaeian B . 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines . Circulation 2019 ; 140 ( 11 ): e596 - e646 . doi: 10.1161/CIR.0000000000000678 Otwórz DOISearch in Google Scholar

Bedi O, Dhawan V, Sharma PL, Kumar P. Pleiotropic effects of statins: new therapeutic targets in drug design. Naunyn Schmiedebergs Arch Pharmacol 2016;389:695–712. doi: 10.1007/s00210-016-1252-4 Bedi O Dhawan V Sharma PL Kumar P . Pleiotropic effects of statins: new therapeutic targets in drug design . Naunyn Schmiedebergs Arch Pharmacol 2016 ; 389 : 695 – 712 . doi: 10.1007/s00210-016-1252-4 Otwórz DOISearch in Google Scholar

Botta M, Audano M, Sahebkar A, Sirtori CR, Mitro N, Ruscica M. PPAR agonists and metabolic syndrome: an established role? Int J Mol Sci 2018;19(4):1197. doi: 10.3390/ijms19041197 Botta M Audano M Sahebkar A Sirtori CR Mitro N Ruscica M . PPAR agonists and metabolic syndrome: an established role? Int J Mol Sci 2018 ; 19 ( 4 ): 1197 . doi: 10.3390/ijms19041197 Otwórz DOISearch in Google Scholar

Ali FY, Armstrong PC, Dhanji AR, Tucker AT, Paul-Clark MJ, Mitchell JA, Warner TD. Antiplatelet actions of statins and fibrates are mediated by PPARs. Arterioscler Thromb Vasc Biol 2009;29:706–11. doi: 10.1161/ATVBAHA.108.183160 Ali FY Armstrong PC Dhanji AR Tucker AT Paul-Clark MJ Mitchell JA Warner TD . Antiplatelet actions of statins and fibrates are mediated by PPARs . Arterioscler Thromb Vasc Biol 2009 ; 29 : 706 – 11 . doi: 10.1161/ATVBAHA.108.183160 Otwórz DOISearch in Google Scholar

Sahebkar A, Serban MC, Mikhailidis DP, Toth PP, Muntner P, Ursoniu S, Mosterou S, Glasser S, Martin SS, Jones SR, Rizzo M, Rysz J, Sniderman AD, Pencina MJ, Banach M; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Head-to-head comparison of statins versus fibrates in reducing plasma fibrinogen concentrations: A systematic review and meta-analysis. Pharmacol Res 2016;103:236–52. doi: 10.1016/j.phrs.2015.12.001 Sahebkar A Serban MC Mikhailidis DP Toth PP Muntner P Ursoniu S Mosterou S Glasser S Martin SS Jones SR Rizzo M Rysz J Sniderman AD Pencina MJ Banach M Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group . Head-to-head comparison of statins versus fibrates in reducing plasma fibrinogen concentrations: A systematic review and meta-analysis . Pharmacol Res 2016 ; 103 : 236 – 52 . doi: 10.1016/j.phrs.2015.12.001 Otwórz DOISearch in Google Scholar

Navarese EP, Buffon A, Andreotti F, Kozinski M, Welton N, Fabiszak T, Caputo S, Grzesk G, Kubica A, Swiatkiewicz I, Sukiennik A, Kelm M, De Servi S, Kubica J. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am J Cardiol 2013;111:1123–30. doi: 10.1016/j.amjcard.2012.12.037 Navarese EP Buffon A Andreotti F Kozinski M Welton N Fabiszak T Caputo S Grzesk G Kubica A Swiatkiewicz I Sukiennik A Kelm M De Servi S Kubica J . Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus . Am J Cardiol 2013 ; 111 : 1123 – 30 . doi: 10.1016/j.amjcard.2012.12.037 Otwórz DOISearch in Google Scholar

Okuyama H, Langsjoen PH, Hamazaki T, Ogushi Y, Hama R, Kobayashi T, Uchino H. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol 2015;8:189–99. doi: 10.1586/17512433.2015.1011125 Okuyama H Langsjoen PH Hamazaki T Ogushi Y Hama R Kobayashi T Uchino H . Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms . Expert Rev Clin Pharmacol 2015 ; 8 : 189 – 99 . doi: 10.1586/17512433.2015.1011125 Otwórz DOISearch in Google Scholar

Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088–93. doi: 10.1161/01.cir.98.19.2088 Staels B Dallongeville J Auwerx J Schoonjans K Leitersdorf E Fruchart JC . Mechanism of action of fibrates on lipid and lipoprotein metabolism . Circulation 1998 ; 98 : 2088 – 93 . doi: 10.1161/01.cir.98.19.2088 Otwórz DOISearch in Google Scholar

Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart JC, Najib-Fruchart J, Glineur C, Staels B. Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I. J Clin Invest 2001;107:1423–32. doi: 10.1172/JCI10852 Martin G Duez H Blanquart C Berezowski V Poulain P Fruchart JC Najib-Fruchart J Glineur C Staels B . Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I . J Clin Invest 2001 ; 107 : 1423 – 32 . doi: 10.1172/JCI10852 Otwórz DOISearch in Google Scholar

Wójtowicz S, Strosznajder AK, Jeżyna M, Strosznajder JB. The novel role of PPAR alpha in the brain: promising target in therapy of Alzheimer’s disease and other neurodegenerative disorders. Neurochem Res 2020;45:972–88. doi: 10.1007/s11064-020-02993-5 Wójtowicz S Strosznajder AK Jeżyna M Strosznajder JB . The novel role of PPAR alpha in the brain: promising target in therapy of Alzheimer’s disease and other neurodegenerative disorders . Neurochem Res 2020 ; 45 : 972 – 88 . doi: 10.1007/s11064-020-02993-5 Otwórz DOISearch in Google Scholar

Hong K-S, Lee JS. Statins in acute ischemic stroke: a systematic review. J Stroke 2015;17:282–301. doi: 10.5853/jos.2015.17.3.282 Hong K-S Lee JS . Statins in acute ischemic stroke: a systematic review . J Stroke 2015 ; 17 : 282 – 301 . doi: 10.5853/jos.2015.17.3.282 Otwórz DOISearch in Google Scholar

Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014;383:2213–21. doi: 10.1016/S0140-6736(13)62242-4 Chataway J Schuerer N Alsanousi A Chan D MacManus D Hunter K Anderson V Bangham CR Clegg S Nielsen C Fox NC Wilkie D Nicholas JM Calder VL Greenwood J Frost C Nicholas R . Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial . Lancet 2014 ; 383 : 2213 – 21 . doi: 10.1016/S0140-6736(13)62242-4 Otwórz DOISearch in Google Scholar

Lee Y-C, Lin C-H, Wu R-M, Lin M-S, Lin J-W, Chang C-H, Lai M-S. Discontinuation of statin therapy associates with Parkinson disease: a population-based study. Neurology 2013;81:410–6. doi: 10.1212/WNL.0b013e31829d873c Lee Y-C Lin C-H Wu R-M Lin M-S Lin J-W Chang C-H Lai M-S . Discontinuation of statin therapy associates with Parkinson disease: a population-based study . Neurology 2013 ; 81 : 410 – 6 . doi: 10.1212/WNL.0b013e31829d873c Otwórz DOISearch in Google Scholar

Shinohara M, Sato N, Shimamura M, Kurinami H, Hamasaki T, Chatterjee A, Rakugi H, Morishita R. Possible modification of Alzheimer’s disease by statins in midlife: interactions with genetic and non-genetic risk factors. Front Aging Neurosci 2014;6:71. doi: 10.3389/fnagi.2014.00071 Shinohara M Sato N Shimamura M Kurinami H Hamasaki T Chatterjee A Rakugi H Morishita R . Possible modification of Alzheimer’s disease by statins in midlife: interactions with genetic and non-genetic risk factors . Front Aging Neurosci 2014 ; 6 : 71 . doi: 10.3389/fnagi.2014.00071 Otwórz DOISearch in Google Scholar

Losey P, Ladds E, Laprais M, Guevel B, Burns L, Bordet R, Anthony DC. The role of PPAR activation during the systemic response to brain injury. J Neuroinflammation 2015;12:99. doi: 10.1186/s12974-015-0295-7 Losey P Ladds E Laprais M Guevel B Burns L Bordet R Anthony DC . The role of PPAR activation during the systemic response to brain injury . J Neuroinflammation 2015 ; 12 : 99 . doi: 10.1186/s12974-015-0295-7 Otwórz DOISearch in Google Scholar

Chen XR, Besson VC, Beziaud T, Plotkine M, Marchand-Leroux C. Combination therapy with fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on experimental traumatic brain injury. J Pharmacol Exp Ther 2008;326:966–74. doi: 10.1124/jpet.108.140368 Chen XR Besson VC Beziaud T Plotkine M Marchand-Leroux C . Combination therapy with fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on experimental traumatic brain injury . J Pharmacol Exp Ther 2008 ; 326 : 966 – 74 . doi: 10.1124/jpet.108.140368 Otwórz DOISearch in Google Scholar

Frijhoff J, Winyard PG, Zarkovic N, Davies SS, Stocker R, Cheng D Knight AR, Taylor EL, Oettrich J, Ruskovska T, Gasparovic AC, Cuadrado A, Weber D, Poulsen HE, Grune T, Schmidt HH, Ghezzi P. Clinical relevance of biomarkers of oxidative stress. Antioxid Redox Signal 2015;23:1144–70. doi: 10.1089/ars.2015.6317 Frijhoff J Winyard PG Zarkovic N Davies SS Stocker R Cheng D Knight AR Taylor EL Oettrich J Ruskovska T Gasparovic AC Cuadrado A Weber D Poulsen HE Grune T Schmidt HH Ghezzi P . Clinical relevance of biomarkers of oxidative stress . Antioxid Redox Signal 2015 ; 23 : 1144 – 70 . doi: 10.1089/ars.2015.6317 Otwórz DOISearch in Google Scholar

Aoyama K. Glutathione in the brain. Int J Mol Sci 2021;22(9):5010. doi: 10.3390/ijms22095010 Aoyama K . Glutathione in the brain . Int J Mol Sci 2021 ; 22 ( 9 ): 5010 . doi: 10.3390/ijms22095010 Otwórz DOISearch in Google Scholar

Lu SC. Regulation of glutathione synthesis. Mol Aspects Med 2009;30:42–59. doi: 10.1016/j.mam.2008.05.005 Lu SC . Regulation of glutathione synthesis . Mol Aspects Med 2009 ; 30 : 42 – 59 . doi: 10.1016/j.mam.2008.05.005 Otwórz DOISearch in Google Scholar

Macan M, Vukšić A, Žunec S, Konjevoda P, Lovrić J, Kelava M, Štambuk N, Vrkić N, Bradamante V. Effects of simvastatin on malondialdehyde level and esterase activity in plasma and tissue of normolipidaemic rats. Pharmacol Rep 2015;67:907–13. doi: 10.1016/j.pharep.2015.02.005 Macan M Vukšić A Žunec S Konjevoda P Lovrić J Kelava M Štambuk N Vrkić N Bradamante V . Effects of simvastatin on malondialdehyde level and esterase activity in plasma and tissue of normolipidaemic rats . Pharmacol Rep 2015 ; 67 : 907 – 13 . doi: 10.1016/j.pharep.2015.02.005 Otwórz DOISearch in Google Scholar

Mohamadin AM, Elberry AA, Abdel Gawad HS, Morsy GM, Al-Abbasi FA. Protective effects of simvastatin, a lipid lowering agent, against oxidative damage in experimental diabetic rats. J Lipids 2011;2011:167958. doi: 10.1155/2011/167958 Mohamadin AM Elberry AA Abdel Gawad HS Morsy GM Al-Abbasi FA . Protective effects of simvastatin, a lipid lowering agent, against oxidative damage in experimental diabetic rats . J Lipids 2011 ; 2011 : 167958 . doi: 10.1155/2011/167958 Otwórz DOISearch in Google Scholar

Zeng H, Liu Z. Atorvastatin induces hepatotoxicity in diabetic rats via oxidative stress, inflammation, and anti-apoptotic pathway. Med Sci Monit 2019;25:6165–73. doi: 10.12659/MSM.915790 Zeng H Liu Z . Atorvastatin induces hepatotoxicity in diabetic rats via oxidative stress, inflammation, and anti-apoptotic pathway . Med Sci Monit 2019 ; 25 : 6165 – 73 . doi: 10.12659/MSM.915790 Otwórz DOISearch in Google Scholar

Bełtowski J, Wójcicka G, Mydlarczyk M, Jamroz A. The effect of peroxisome proliferator-activated receptors alpha (PPARalpha) agonist, fenofibrate, on lipid peroxidation, total antioxidant capacity, and plasma paraoxonase 1 (PON 1) activity. J Physiol Pharmacol 2002;53:463–75. PMID: 12369742 Bełtowski J Wójcicka G Mydlarczyk M Jamroz A . The effect of peroxisome proliferator-activated receptors alpha (PPARalpha) agonist, fenofibrate, on lipid peroxidation, total antioxidant capacity, and plasma paraoxonase 1 (PON 1) activity . J Physiol Pharmacol 2002 ; 53 : 463 – 75 . PMID: 12369742 Search in Google Scholar

Macan M, Konjevoda P, Lovrić J, Koprivanac M, Kelava M, Vrkić N, Bradamante V. The influence of gemfibrozil on malondialdehyde level and paraoxonase 1 activity in Wistar and fisher rats. Basic Clin Pharmacol Toxicol 2011;108:428–35. doi: 10.1111/j.1742-7843.2011. 00674.x Macan M Konjevoda P Lovrić J Koprivanac M Kelava M Vrkić N Bradamante V . The influence of gemfibrozil on malondialdehyde level and paraoxonase 1 activity in Wistar and fisher rats . Basic Clin Pharmacol Toxicol 2011 ; 108 : 428 – 35 . doi: 10.1111/j.1742-7843.2011. 00674.x Otwórz DOISearch in Google Scholar

Ciriolo MR, Mavelli I, Rotilio G, Borzatta V, Cristofari M, Stanzani L. Decrease of superoxide dismutase and glutathione peroxidase in liver of rats treated with hypolipidaemic drugs. FEBS Lett 1982;144:264–8. doi: 10.1016/0014-5793(82)80651-0 Ciriolo MR Mavelli I Rotilio G Borzatta V Cristofari M Stanzani L . Decrease of superoxide dismutase and glutathione peroxidase in liver of rats treated with hypolipidaemic drugs . FEBS Lett 1982 ; 144 : 264 – 8 . doi: 10.1016/0014-5793(82)80651-0 Otwórz DOISearch in Google Scholar

Ciriolo MR, Rossi L, Mavelli I, Rotilio G, Borzatta V, Cristofori M, Barbanti M. The effects of hypolipidaemic agents derived from procetofenic acid on the activity of superoxide dismutase and glutathione peroxidase and on malonyl dialdehyde production of rat liver. Arzneimittelforschung 1984;34:465–7. PMID: 6540105 Ciriolo MR Rossi L Mavelli I Rotilio G Borzatta V Cristofori M Barbanti M . The effects of hypolipidaemic agents derived from procetofenic acid on the activity of superoxide dismutase and glutathione peroxidase and on malonyl dialdehyde production of rat liver . Arzneimittelforschung 1984 ; 34 : 465 – 7 . PMID: 6540105 Search in Google Scholar

Abdoli N, Heidari R, Azarmi Y, Eghbal MA. Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes. J Biochem Mol Toxicol 2013;27:287–94. doi: 10.1002/jbt.21485 Abdoli N Heidari R Azarmi Y Eghbal MA . Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes . J Biochem Mol Toxicol 2013 ; 27 : 287 – 94 . doi: 10.1002/jbt.21485 Otwórz DOISearch in Google Scholar

Eghbal MA, Abdoli N, Azarmi Y. Efficiency of hepatocyte pretreatment with coenzyme Q10 against statin toxicity. Arh Hig Rada Toksikol 2014;65:101–8. doi: 10.2478/10004-1254-65-2014-2398 Eghbal MA Abdoli N Azarmi Y . Efficiency of hepatocyte pretreatment with coenzyme Q10 against statin toxicity . Arh Hig Rada Toksikol 2014 ; 65 : 101 – 8 . doi: 10.2478/10004-1254-65-2014-2398 Otwórz DOISearch in Google Scholar

Yaribeygi H, Mohammadi MT, Rezaee R, Sahebkar A. Fenofibrate improves renal function by amelioration of NOX-4, IL-18, and p53 expression in an experimental model of diabetic nephropathy. J Cell Biochem 2018;119:7458–69. doi: 10.1002/jcb.27055 Yaribeygi H Mohammadi MT Rezaee R Sahebkar A . Fenofibrate improves renal function by amelioration of NOX-4, IL-18, and p53 expression in an experimental model of diabetic nephropathy . J Cell Biochem 2018 ; 119 : 7458 – 69 . doi: 10.1002/jcb.27055 Otwórz DOISearch in Google Scholar

Wood WG, Eckert GP, Igbavboa U, Müller WE. Statins and neuroprotection: a prescription to move the field forward. Ann N Y Acad Sci 2010;1199:69–76. doi: 10.1111/j.1749-6632.2009.05359.x Wood WG Eckert GP Igbavboa U Müller WE . Statins and neuroprotection: a prescription to move the field forward . Ann N Y Acad Sci 2010 ; 1199 : 69 – 76 . doi: 10.1111/j.1749-6632.2009.05359.x Otwórz DOISearch in Google Scholar

Deplanque D, Gelé P, Pétrault O, Six I, Furman C, Bouly M, Nion S, Dupuis B, Leys D, Fruchart JC, Cecchelli R, Staels B, Duriez P, Bordet R. Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. J Neurosci 2003;23:6264–71. doi: 10.1523/JNEUROSCI.23-15-06264.2003 Deplanque D Gelé P Pétrault O Six I Furman C Bouly M Nion S Dupuis B Leys D Fruchart JC Cecchelli R Staels B Duriez P Bordet R . Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment . J Neurosci 2003 ; 23 : 6264 – 71 . doi: 10.1523/JNEUROSCI.23-15-06264.2003 Otwórz DOISearch in Google Scholar

Balakumar P, Varatharajan R, Nyo YH, Renushia R, Raaginey D, Oh AN, Akhtar SS, Rupeshkumar M, Sundram K, Dhanaraj SA. Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats. Pharmacol Res 2014;90:36–47. doi: 10.1016/j.phrs.2014.08.008 Balakumar P Varatharajan R Nyo YH Renushia R Raaginey D Oh AN Akhtar SS Rupeshkumar M Sundram K Dhanaraj SA . Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats . Pharmacol Res 2014 ; 90 : 36 – 47 . doi: 10.1016/j.phrs.2014.08.008 Otwórz DOISearch in Google Scholar

Fatani SH, Naderaralli EK, Panchiani S, Shah F, Wong C. The effects of dietary obesity on protein expressions of insulin signalling pathway in rat aorta. Drug Discov Ther 2008;2:256–61. PMID: 22504637 Fatani SH Naderaralli EK Panchiani S Shah F Wong C . The effects of dietary obesity on protein expressions of insulin signalling pathway in rat aorta . Drug Discov Ther 2008 ; 2 : 256 – 61 . PMID: 22504637 Search in Google Scholar

Nezić L, Skrbić R, Dobrić S, Stojiljković MP, Jaćević V, Stoisavljević Satara S, Milovanović ZA, Stojaković N. Simvastatin and indomethacin have similar anti-inflammatory activity in a rat model of acute local inflammation. Basic Clin Pharmacol Toxicol 2009;104:185–91. doi: 10.1111/j.1742-7843.2008.00302.x Nezić L Skrbić R Dobrić S Stojiljković MP Jaćević V Stoisavljević Satara S Milovanović ZA Stojaković N . Simvastatin and indomethacin have similar anti-inflammatory activity in a rat model of acute local inflammation . Basic Clin Pharmacol Toxicol 2009 ; 104 : 185 – 91 . doi: 10.1111/j.1742-7843.2008.00302.x Otwórz DOISearch in Google Scholar

Simsek Ozek N, Burak Bal I, Yildirim S, Rustu Inur, Severcan F. Structural and functional characterization of simvastatin-induced myotoxicity in different skeletal muscles. Biochim Biophys Acta 2014;1840:406–14. doi: 10.1016/j.bbagen.2013.09.010 Simsek Ozek N Burak Bal I Yildirim S Rustu Inur Severcan F. Structural and functional characterization of simvastatin-induced myotoxicity in different skeletal muscles . Biochim Biophys Acta 2014 ; 1840 : 406 – 14 . doi: 10.1016/j.bbagen.2013.09.010 Otwórz DOISearch in Google Scholar

Pravilnik o zaštiti životinja koje se koriste u znanstvene svrhe [Regulation of the protection of animals used for scientific purposes, in Croatian]. Narodne novine 55/2013. Pravilnik o zaštiti životinja koje se koriste u znanstvene svrhe [Regulation of the protection of animals used for scientific purposes, in Croatian] . Narodne novine 55 / 2013 . Search in Google Scholar

Guillen J. FELASA guidelines and recommendations. J Am Assoc Lab Anim Sci 2012;51:311–21. PMCID: PMC3358979 Guillen J . FELASA guidelines and recommendations . J Am Assoc Lab Anim Sci 2012 ; 51 : 311 – 21 . PMCID: PMC3358979 Search in Google Scholar

Drury JA, Nycyk JA, Cooke RW. Comparison of urinary and plasma malondialdehyde in preterm infants. Clin Chim Acta 1997;263:177–85. doi: 10.1016/s0009-8981(97)00051-x Drury JA Nycyk JA Cooke RW . Comparison of urinary and plasma malondialdehyde in preterm infants . Clin Chim Acta 1997 ; 263 : 177 – 85 . doi: 10.1016/s0009-8981(97)00051-x Otwórz DOISearch in Google Scholar

Ellman GL. A colorimetric method for determining low concentrations of mercaptans. Arch Biochem Biophys 1958;74:443–50. doi: 10.1016/0003-9861(58)90014-6 Ellman GL . A colorimetric method for determining low concentrations of mercaptans . Arch Biochem Biophys 1958 ; 74 : 443 – 50 . doi: 10.1016/0003-9861(58)90014-6 Otwórz DOISearch in Google Scholar

Rowe P. Essential Statistics for the Pharmaceutical Sciences. Chichester: Wiley; 2007. ISBN: 9780470034682 Rowe P . Essential Statistics for the Pharmaceutical Sciences . Chichester : Wiley ; 2007 . ISBN: 9780470034682 Search in Google Scholar

Bełtowski J, Wójcicka G, Mydlarczyk M, Jamroz A. Cerivastatin modulates plasma paraoxonase/arylesterase activity and oxidant-antioxidant balance in the rat. Pol J Pharmacol 2002;54:143–50. PMID: 12139111 Bełtowski J Wójcicka G Mydlarczyk M Jamroz A . Cerivastatin modulates plasma paraoxonase/arylesterase activity and oxidant-antioxidant balance in the rat . Pol J Pharmacol 2002 ; 54 : 143 – 50 . PMID: 12139111 Search in Google Scholar

Liang H, Feng Y, Cui R, Qiu M, Zhang J, Liu C. Simvastatin protects against acetaminophen-induced liver injury in mice. Biomed Pharmacother 2018;98:916–24. doi: 10.1016/j.biopha. 2017.12076 Liang H Feng Y Cui R Qiu M Zhang J Liu C . Simvastatin protects against acetaminophen-induced liver injury in mice . Biomed Pharmacother 2018 ; 98 : 916 – 24 . doi: 10.1016/j.biopha. 2017.12076 Otwórz DOISearch in Google Scholar

Zhang F, Sun D, Chen J, Guan N, Huo X, Xi H. Simvastatin attenuates angiotensin II-induced inflammation and oxidative stress in human mesangial cells. Mol Med Rep 2015;11:1246–51. doi: 10.3892/mmr.2014-2871 Zhang F Sun D Chen J Guan N Huo X Xi H . Simvastatin attenuates angiotensin II-induced inflammation and oxidative stress in human mesangial cells . Mol Med Rep 2015 ; 11 : 1246 – 51 . doi: 10.3892/mmr.2014-2871 Otwórz DOISearch in Google Scholar

Zinellu A, Mangoni AA. A systematic review and meta-analysis of the effect of statins on glutathione peroxidase, superoxide dismutase, and catalase. Antioxidants (Basel) 2021;10(11):1841. doi: 10.3390/antiox10111841 Zinellu A Mangoni AA . A systematic review and meta-analysis of the effect of statins on glutathione peroxidase, superoxide dismutase, and catalase . Antioxidants (Basel) 2021 ; 10 ( 11 ): 1841 . doi: 10.3390/antiox10111841 Otwórz DOISearch in Google Scholar

Verma K, Makwana S, Paliwal S, Paliwal V, Jain S, Paliwal S, Sharma S. Simvastatin ameliorates oxidative stress levels in HepG2 cells and hyperlipidaemic rats. Curr Res Pharmacol Drug Discov 2022;3:100088. doi: 10.1016/j.crphar.2022.100088 Verma K Makwana S Paliwal S Paliwal V Jain S Paliwal S Sharma S . Simvastatin ameliorates oxidative stress levels in HepG2 cells and hyperlipidaemic rats . Curr Res Pharmacol Drug Discov 2022 ; 3 : 100088 . doi: 10.1016/j.crphar.2022.100088 Otwórz DOISearch in Google Scholar

Wahba MGF, Messiha BAS, Abo-Saif AA. Protective effects of fenofibrate and resveratrol in an aggressive model of rheumatoid arthritis in rats. Pharm Biol 2016;54:1705–15. doi: 10.3109/13880209. 2015.1125931 Wahba MGF Messiha BAS Abo-Saif AA . Protective effects of fenofibrate and resveratrol in an aggressive model of rheumatoid arthritis in rats . Pharm Biol 2016 ; 54 : 1705 – 15 . doi: 10.3109/13880209. 2015.1125931 Otwórz DOISearch in Google Scholar

Aberg F, Appelkvist EL. Clofibrate and di(2-ethylhexyl) phthalate increase ubiquinone contents without affecting cholesterol levels. Acta Biochim Pol 1994;41:321–9. PMID: 7856403 Aberg F Appelkvist EL . Clofibrate and di(2-ethylhexyl) phthalate increase ubiquinone contents without affecting cholesterol levels . Acta Biochim Pol 1994 ; 41 : 321 – 9 . PMID: 7856403 Search in Google Scholar

Arnaiz LS, Travacio M, Monserrat AJ, Cutrín JC, Llesuy S, Boveris A. Chemiluminescence and antioxidant levels during peroxisome proliferation by fenofibrate. Biochim Biophys Acta 1997;1360:222–8. doi: 10.1016/s0925-4439(97)00004-5 Arnaiz LS Travacio M Monserrat AJ Cutrín JC Llesuy S Boveris A . Chemiluminescence and antioxidant levels during peroxisome proliferation by fenofibrate . Biochim Biophys Acta 1997 ; 1360 : 222 – 8 . doi: 10.1016/s0925-4439(97)00004-5 Otwórz DOISearch in Google Scholar

Tkác I, Molcányiová A, Javorský M, Kozárová M. Fenofibrate treatment reduces circulating conjugated diene level and increases glutathione peroxidase activity. Pharmacol Res 2006;53:261–4. doi: 10.1016/j.phrs.2005.12.002 Tkác I Molcányiová A Javorský M Kozárová M . Fenofibrate treatment reduces circulating conjugated diene level and increases glutathione peroxidase activity . Pharmacol Res 2006 ; 53 : 261 – 4 . doi: 10.1016/j.phrs.2005.12.002 Otwórz DOISearch in Google Scholar

Jiao H-L, Zhao B-L. Cytotoxic effect of peroxisome proliferator fenofibrate on human HepG2 hepatoma cell line and relevant mechanisms. Toxicol Appl Pharmacol 2002;185:172–9. doi: 10.1006/taap.2002.9538 Jiao H-L Zhao B-L . Cytotoxic effect of peroxisome proliferator fenofibrate on human HepG2 hepatoma cell line and relevant mechanisms . Toxicol Appl Pharmacol 2002 ; 185 : 172 – 9 . doi: 10.1006/taap.2002.9538 Otwórz DOISearch in Google Scholar

Shore LJ, Fenselau C, King AR, Dickinson RG. Characterization and formation of the glutathione conjugate of clofibric acid. Drug Metab Dispos 1995;23:119–23. PMID: 7720514 Shore LJ Fenselau C King AR Dickinson RG . Characterization and formation of the glutathione conjugate of clofibric acid . Drug Metab Dispos 1995 ; 23 : 119 – 23 . PMID: 7720514 Search in Google Scholar

Sun B, Xie Y, Jiang J, Wang Y, Xu X, Zhao C, Huang F. Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia. Lipids Health Dis 2015;14:27. doi: 10.1186/s12944-015-0032-3 Sun B Xie Y Jiang J Wang Y Xu X Zhao C Huang F . Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia . Lipids Health Dis 2015 ; 14 : 27 . doi: 10.1186/s12944-015-0032-3 Otwórz DOISearch in Google Scholar

    Polecane artykuły z Trend MD