Trimetazidine Pretreatment Research Articles

Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy.

Mitochondrial oxidative status exerts an important role in modulating glia–neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mechanistic rationale behind its anti-seizure potential has not been fully elucidated yet. Herein, the impact of TMZ against mitochondrial oxidative damage as well as glutamate homeostasis disruption in the hippocampus has been investigated in rats with lithium/pilocarpine (Li/PIL) seizures. Animals received 3 mEq/kg i.p. LiCl3 followed by PIL (single i.p.; 150 mg/kg) 20 h later for induction of seizures with or without TMZ pretreatment (25 mg/kg; i.p.) for five consecutive days. Seizure score and seizure latency were observed. Mitochondrial redox status as well as ATP and uncoupling protein 2 was recorded. Moreover, glutamate homeostasis was unveiled. The present findings demonstrate the TMZ-attenuated Li/PIL seizure score and latency. It improved mitochondrial redox status, preserved energy production mechanisms, and decreased reactive astrocytes evidenced as decreased glial fibrillary acidic protein immune-stained areas in hippocampal tissue. In addition, it modulated phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and p-AMP–activated protein kinase (p-AMPK) signaling pathways to reflect a verified anti-apoptotic effect. Consequently, it upregulated mRNA expression of astroglial glutamate transporters and reduced the elevated glutamate level. The current study demonstrates that TMZ exhibits robust anti-seizure and neuroprotective potentials. These effects are associated with its ability to modulate mitochondrial redox status, boost p-ERK1/2 and p-AMPK signaling pathways, and restore glutamate homeostasis in hippocampus.

Trimetazidine Protects from Mercury-Induced Kidney Injury

Introduction: The presence of mercury in the environment is a worldwide concern. Inorganic mercury is present in industrial materials, is employed in medical devices, is widely used in batteries, is a component of fluorescent light bulbs, and it has been associated with human poisoning in gold mining areas. The nephrotoxicity induced by inorganic mercury is a relevant health problem mainly in developing countries. The primary mechanism of mercury toxicity is oxidative stress. Trimetazidine (TMZ) is an anti-ischemic drug, which inhibits cellular oxidative stress, eliminates oxygen-free radicals, and improves lipid metabolism. The aim of this study was to evaluate whether the administration of TMZ protects against mercuric chloride (HgCl₂) kidney damage. Methods: Adult male Wistar rats received only HgCl₂ (4 mg/kg bw, sc) (Hg group, n = 5) or TMZ (3 mg/kg bw, ip) 30 min before HgCl₂ administration (4 mg/kg bw, sc) (TMZHg group, n = 7). Simultaneously, a control group of rats (n = 4) was studied. After 4 days of HgCl₂ injection, urinary flow, urea and creatinine (Cr) plasma levels, Cr clearance, urinary glucose, and sodium-dicarboxylate cotransporter 1 (NaDC1) in urine were determined. Lipid peroxidation (MDA) and glutathione (GSH) levels were measured in kidney homogenates. Results: Rats only treated with HgCl₂ showed an increase in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, and NaDC1 urinary excretion as compared with the control group and a decrease in Cr clearance. TMZHg group showed a decrease in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, NaDC1 urinary excretion, and an increase in Cr clearance when compared to the Hg group. Moreover, MDA and GSH levels observed in Hg groups were decreased and increased, respectively, by TMZ pretreatment. Conclusion: TMZ exerted a renoprotective action against HgCl₂-induced renal injury, which might be mediated by the reduction of oxidative stress. Considering the absence of toxicity of TMZ, its clinical application against oxidative damage due to HgCl₂-induced renal injury should be considered. The fact that TMZ is commercially available should simplify and accelerate the translation of the present data “from bench to bedside.” In this context, TMZ become an interesting new example of drug repurposing.

Trimetazidine alleviates hypoxia/reoxygenation-induced apoptosis in neonatal mice cardiomyocytes via up-regulating HMGB1 expression to promote autophagy

Previous studies demonstrated the effect of Trimetazidine (TMZ) on alleviating cardiomyocytes Hypoxia/Reoxygenation (H/R) injuries and the protective effect of autophagy on Ischemia-Reperfusion (I/R) cell injuries. However, whether the protection mechanism of TMZ was also involved in autophagy remained unclear. Our study introduces the role of HMGB1 to examine the regulation of TMZ on autophagy against cardiomyocytes H/R injuries. After cell extraction and identification through anti-α-actin staining, the cardiomyocytes were made hypoxic and reoxygenated, each for 3 h, and then treated with various concentrations of TMZ and transfected with siHMGB1. Cell viability and apoptosis were measured by the MTS method and flow cytometry, respectively. The expressions of autophagy-related factors (LC3-I, LC3-II, Beclin-1) and HMGB1 were detected by Western blot and qPCR. Lactate dehydrogenase (LDH) release was assessed by ELISA kit. The cardiomyocytes were extracted. H/R decreased the cell viability and increased the LDH level and apoptosis of cardiomyocytes. TMZ had no effect on untreated cardiomyocytes, but it reversed the adverse impact of H/R on cardiomyocytes. The expressions of LC3-II, Beclin-1, and HMGB1 and the ratio of LC3-II/LC3-I were increased in H/R-processed cardiomyocytes and further raised by TMZ pretreatment. However, siHMGB1 transfection aggravated the impact of H/R on cardiomyocytes and suppressed the protective effects of TMZ on H/R damaged cardiomyocytes by increasing the LDH level and apoptosis and reducing the viability of cardiomyocytes. Autophagy was inhibited by siHMGB1 in TMZ-pretreated and H/R-processed cardiomyocytes. TMZ protected cardiomyocytes against H/R injuries may through regulating HMGB1 to increase the impact of autophagy.

Effects of Trimetazidine Pretreatment on Endothelial Dysfunction and Myocardial Injury in Unstable Angina Patients Undergoing Percutaneous Coronary Intervention.

Objectives Trimetazidine is an anti-ischemic medication licensed for the treatment of angina pectoris. However, the molecular mechanisms underlying its action remain incompletely elucidated. In this study, therefore, we examined the potential beneficial effects of trimetazidine on myocardial injury and endothelial dysfunction in patients with unstable angina in the perioperative period of percutaneous coronary intervention (PCI). Methods A total of 97 patients with unstable angina were randomly divided into trimetazidine (n = 48) and control (n = 49) groups. All subjects received standard medical therapy. The trimetazidine group additionally received 20 mg trimetazidine three times daily 24 hours before and after PCI. Serum levels of creatine kinase-muscle/brain (CK-MB), cardiac troponin I (cTnI), heart-type fatty acid-binding protein (h-FABP), von Willebrand factor (vWF), and nitric oxide (NO) were measured before and the morning following PCI. Results In the control group, levels of CK-MB, cTnI, and vWF were significantly elevated (P < 0.05) and NO level was decreased after PCI (P < 0.05). By contrast, no significant changes in the levels of these proteins were observed in the trimetazidine group after PCI (P > 0.05). Moreover, h-FABP levels were not significantly altered after PCI whether in the control or in the trimetazidine group (P > 0.05). Finally, a time-dependent increase in the levels of h-FABP from 0 to 6 hours after PCI, followed by a progressive decline, was observed (P < 0.05). Conclusions PCI induces endothelial dysfunction and myocardial damage in patients with unstable angina. Trimetazidine therapy in the perioperative period can reduce this damage.

Protective effects of trimetazidine and coenzyme Q10 on cisplatin-induced cardiotoxicity by alleviating oxidative stress and mitochondrial dysfunction.

Objective:The objective of this study was to investigate the effects of trimetazidine (TMZ) and coenzyme Q10 (CoQ10) on cisplatin-induced cardiotoxicity in rat cardiomyocytes.Methods:Rat cardiomyocytes were isolated and subjected to cisplatin (200 µM) treatment with and without TMZ (200 µM) and CoQ10 (200 mg/L) pretreatment. The cell viability, apoptosis, oxidant and antioxidant indicators, and mitochondrial dysfunction were examined.Results:TMZ or CoQ10 significantly attenuated cisplatin-induced cell viability inhibition (p<0.01) and apoptosis (p<0.001), and the combined use of TMZ and CoQ10 pretreatment exerted a pronounced effect compared to the effects of using each of these agents individually (p<0.05). TMZ or CoQ10 inhibited the levels of reactive oxidative species (ROS, p<0.01) and malondialdehyde (MDA, p<0.001 and p<0.01, respectively), elevated the activities of antioxidant enzymes superoxide dismutase (SOD, p<0.01) and catalase (CAT, p<0.01 and p<0.05, respectively), evidently enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2, p<0.05), alleviated mitochondrial membrane potential (ΔΨm) loss (p<0.05), and down-regulated the release of cytochrome c (cyto-c) into the cytosol (p<0.01) in cisplatin-treated cells. The combined use of TMZ and CoQ10 treatment was more effective than using either agent alone (p<0.01 for ROS, MDA, CAT, and cytosolic cyto-c; p<0.05 for SOD, nuclear Nrf2, and ΔΨm loss).Conclusion:TMZ and CoQ10 showed protective effects against cisplatin-induced cardiotoxicity via attenuating oxidative stress.

Psychocardiological disorder and brain serotonin after comorbid myocardial infarction and depression: an experimental study

Objectives We investigated whether trimetazidine pretreatment can regulate central and peripheral serotonin (5-HT) in rats of myocardial infarction (MI) combined with depression.Methods Forty rats were randomly assigned to a sham operation group (n = 10) and a disease model group (n = 30). The sham operation group was pretreated with normal saline for 4 weeks. The disease model group was randomly assigned further into a negative control subgroup, a positive control subgroup, and a treatment subgroup — the groups received saline, sertraline, and trimetazidine pretreatment, respectively, for 4 weeks, then the rats were subjected to MI combined with depression. 5-HT concentrations in the serum, platelet lysate, and cerebral cortex lysate were analyzed with ELISA.Results The levels of serum 5-HT and platelet 5-HT were significantly lower in negative control subgroup than the sham operation group (P < 0.05), but there was no significant difference in brain 5-HT (P > 0.05). Compared with the negative control subgroup, the levels of serum 5-HT and platelet 5-HT in the positive control subgroup and treatment subgroup were significantly higher (P < 0.05). The levels of 5-HT in brain of the positive control subgroup and treatment subgroup were significantly lower than those in the negative control subgroup (P < 0.05).Conclusions Trimetazidine pretreatment can increase serum and platelet 5-HT levels in rats with MI and depression and decrease 5-HT levels in brain tissue. This regulatory effect on central and peripheral 5-HT suggests a role for trimetazidine in the treatment of psychocardiological diseases.

Beneficial effects of trimetazidine on expression of serotonin and serotonin transporter in rats with myocardial infarction and depression.

BackgroundTrimetazidine is an anti-ischemic drug that can inhibit platelet aggregation and regulate serotonin (5-hydroxytryptamine [5-HT]) release. The purpose of this study was to investigate the therapeutic effects of trimetazidine on 5-HT and serotonin transporter (SERT) expression in experimentally induced myocardial infarction (MI), depression, and MI + depression.Materials and methodsEighty Sprague Dawley (SD) rats were randomly divided into a trimetazidine group and a saline group of 40 rats each. The trimetazidine group was given trimetazidine pretreatment for 4 weeks, while the saline group received saline for 4 weeks. Both groups were then subdivided into four subgroups (n=10), which were each subjected to a unique disease condition: sham surgery, MI, depression, or MI + depression. All rats were sacrificed 3 days thereafter, and serum and platelet levels of 5-HT and SERT were assessed. In addition, we experimented with trimetazidine posttreatment. Twenty SD rats underwent MI surgery, and were then randomly divided into a treatment and a saline group (n=10 each). For 4 weeks post-surgery, the trimetazidine group was given trimetazidine, while the saline group received saline. Serum and platelet levels of 5-HT and SERT were assessed.ResultsPretreatment with trimetazidine: in the nontreatment saline group, MI, depression, and MI + depression showed significant declines (P<0.05) in both serum and platelet 5-HT levels compared to sham. Trimetazidine treatment significantly increased serum and platelet 5-HT levels in the MI, depression, and MI + depression (P<0.05) subgroups compared to their counterparts in the saline group. Results for SERT were heterogeneous between serum and platelets. Trimetazidine treatment significantly decreased serum levels of SERT in the sham surgery subgroup (P<0.05), while significantly increasing levels in depression rats, compared to control (P<0.05). In platelets, trimetazidine significantly decreased SERT in sham surgery, MI, depression, and MI + depression rats, compared to control (P<0.05). This contrast suggests that trimetazidine has opposite effects in serum and platelet SERT levels for the three disease models. Post-surgery trimetazidine: increased serum 5-HT (P<0.05) and serum SERT (P<0.05) were observed, compared to control. In platelets, trimetazidine decreased both 5-HT and SERT compared to control, significantly (P<0.05) for 5-HT, but not significantly for SERT (P>0.05).ConclusionTrimetazidine has a regulatory effect on 5-HT and SERT in the serum and platelets. Because of the downstream effects of this regulation on blood vessel function and myocardial protection, trimetazidine may be a therapeutic or preventive agent in several disease processes, including MI, depression, and the comorbidity between these two diseases. Further investigation, aimed at exploring the clinical potential of trimetazidine, is therefore warranted.

Trimetazidine Protects Cardiomyocytes Against Hypoxia/Reoxygenation Injury by Promoting AMP-activated Protein Kinase-dependent Autophagic Flux.

Trimetazidine (TMZ), a metabolic agent, may protect against myocardial ischemia/reperfusion injury. Because of the critical role of autophagy in cardioprotection, we aimed to evaluate whether autophagy was involved in TMZ-induced protection during hypoxia/reoxygenation (H/R). Neonatal rat cardiomyocytes were subjected to H/R injury, and they were divided into 7 groups: control, control+TMZ, control+chloroquine (Cq)/compound C (com C), H/R, H/R+TMZ, H/R+Cq/com C, and H/R+TMZ+Cq/com C. Autophagic flux was primarily assessed by Western blot and tandem fluorescent mRFP-GFP-LC3. Assays for MTS, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and lactate dehydrogenase release were performed to assess cell injury. Our results showed that TMZ pretreatment had a cardioprotective effect against H/R injury. The H/R+TMZ group had an increased ratio of LC3-II to LC3-I and increased autophagic flux (degradation of p62 and increases in autophagosomes and autolysosomes). TMZ also reduced apoptosis and enhanced cell survival while inducing autophagy. Correspondingly, autophagy inhibition with Cq blocked this protective effect. Furthermore, TMZ-induced enhancement of autophagy could be related to increased AMP-activated protein kinase (AMPK) phosphorylation and decreased Mammalian target of rapamycin (mTOR) phosphorylation, which was abolished by an AMPK-specific inhibitor (com C). Our data provide evidence that TMZ pretreatment protects against H/R injury by promoting autophagic flux through the AMPK signaling pathway.

Impact of trimetazidine pre-treatment on 5-hydroxytryptamine and serotonin transporter in rats with experimental myocardial infarction and depression

Objective: To explore the effect of trimetazidine pre-treatments on serum 5-hydroxytryptamine (5-HT) and serotonin transporter (SERT), platelet 5-HT and SERT in the Sprague Dawley rats with myocardial infarction(MI), depression, and myocardial infarction co-exist with depression (MI+ depression) and in sham operated rats. Methods: Eighty rats were divided into treatment group and placebo (saline) group by the random number table method (n=40 each group). After 4 weeks' treatment with trimetazidine, or saline, these rats were assigned to respective sham subgroup, depression subgroup, MI subgroup, MI + depression subgroup (n=10 each subgroup). All rats were sacrificed 3 days later. 5-HT in serum and platelet, and SERT in serum and platelet of the rats were tested by enzyme linked immunosorbent assay (ELISA). Data were analyzed by SPSS 17.0. Results: In saline group, serum and platelet 5-HT levels were significantly lower in MI, depression and MI+ depression subgroup compared to sham subgroup (all P<0.01). In trimetazidine pre-treatment group, serum and platelet 5-HT levels were significantly higher in the depression subgroup, MI subgroup, MI + depression subgroup than respective subgroups of saline pretreated rats (all P<0.01). In saline group, SERT in serum and platelet were higher in MI, depression, MI+ depression subgroup than the sham subgroup and statistical significance was found between MI+ depression subgroup and sham subgroups. Serum SERT level was significantly lower in the treatment group compared to saline group for sham rats (P<0.01). In treatment group, serum SERT level was higher in MI, depression and MI+ depression subgroups compared to respective subgroup treated with saline while the statistical significance was found in depression subgroup between trimetazidine pre-treatment and saline control groups. Platelet SERT was higher in MI, depression and MI+ depression subgroups compared to sham subgroup post saline treatment. Platelet SERT was significantly lower in MI, depression and MI+ depression subgroups post trimetazidine pre-treatment than in respective subgroups post saline treatment (all P<0.01). Conclusions: Our study results indicate that trimetazidine pretreatment could increase the levels of 5-HT and SERT in serum and 5-HT in platelet, and decrease the level of SERT in platelet in the rat MI and depression model.

Effects of Trimetazidine on PDCD4/NF-κB/TNF-α Pathway in Coronary Microembolization

Background/Aims: The local inflammatory response caused by coronary microembolization (CME) is the primary cause of progressive cardiac dysfunction. The PDCD4/NF-κB/TNF-α signaling pathway plays a significant role in CME-induced myocardial Inflammation. Trimetazidine (TMZ) reduces myocardial injury, caused by percutaneous coronary intervention, through relieving the CME-induced myocardial systolic dysfunction. Therefore, the present study investigated the role of TMZ pre-treatment in the protection of myocardium after CME and PDCD4/NF-κB/TNF-α in mini pigs. Methods: 20 Bama mini pigs were randomized into sham operation (sham), microembolization (CME), TMZ, and siRNA-PDCD4 groups (n = 5). The CME model was established by injecting polyethylene microspheres via microcatheter into the left anterior descending coronary artery. The TMZ group was injected 2.5 mg/kg drug via ear vein 30 min before CME; whereas, the siRNA-PDCD4 group was transfected with PDCD4 siRNA at the left anterior descending coronary artery via microcatheter 72h before CME. Cardiac function indexes were measured using cardiac echocardiography. The mRNA expression of PDCD4 and TNF-α in the myocardium was detected by quantitative fluorescence PCR, and the protein expression of PDCD4, NF-κB (p65), and TNF-α by Western blot. Results: Echocardiographic parameters showed lower cardiac function and higher serum cTnI level in the CME group than sham, which was manifested as reduced left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS), cardiac output (CO), and increased left ventricular diastolic diameter (LVEDd). Compared to the CME group, the CME-induced cardiac function injury was reduced, and the serum cTnI level was decreased in the TMZ and siRNA-PDCD4 groups. The expressions of PDCD4, NF-κB (p65), and TNF-α were significantly increased in the CME than the sham groups (P < 0.05), and significantly decreased in the TMZ and siRNA-PDCD4 groups than the CME group (P < 0.05). Conclusion: TMZ pretreatment effectively reduced the myocardial damage caused by CME via inhibiting the PDCD4/NF-κB/ TNF-α pathway in cardiomyocytes.

Trimetazidine Pretreatment Inhibits Myocardial Apoptosis and Improves Cardiac Function in a Swine Model of Coronary Microembolization

Objective: Trimetazidine (TMZ) is a well-known anti-ischemic agent; however, its efficacy and mechanism of cardioprotection on coronary microembolization (CME) are largely unknown. The present study was undertaken to determine whether TMZ pretreatment could attenuate myocardial apoptosis and improve cardiac function in a swine model of CME. Methods: Fifteen swine were randomly and equally divided into a sham-operated (control) group, CME group and CME plus TMZ (TMZ) group. CME was induced by injecting inert plastic microspheres (42 μm in diameter) into the left anterior descending artery. For the control group, the same dose of normal saline was substituted for the microspheres, and the TMZ group was pretreated with TMZ 30 min before microsphere injection. Cardiac function was assessed by echocardiography, myocardial apoptosis was detected by TUNEL staining, and the expression levels of cleaved caspase-9/3 were measured by Western blot 12 h after operation. Results: Compared to the control group, cardiac function in the CME group was significantly decreased (p < 0.05); however, TMZ pretreatment showed significantly improved cardiac function as compared to the CME group (p < 0.05). The myocardial apoptotic rate and the expression levels of cleaved caspase-9/3 increased remarkably in CME group as compared with the control group (p < 0.001). Again, TMZ pretreatment significantly reduced the apoptotic rate and also the expression levels of cleaved caspase-9/3 (p < 0.001). Conclusion: The present study demonstrated that TMZ pretreatment could significantly inhibit CME-induced myocardial apoptosis and improve cardiac function, and that the cardioprotective effect appeared to be mediated by the blockade of the mitochondrial apoptotic pathway. These results emphasize the importance of TMZ pretreatment in the therapy of CME-induced myocardial injury.

Effect of trimetazidine pretreatment on myocardial injury induced by propofol in rats

Objective To evaluate the effect of trimetazidine pretreatment on myocardial injury induced by propofol in rats.Methods Forty healthy Sprague-Dawley rats,weighing 240-250 g,aged 2.5 months,were randomly divided into 4 groups (n =10 each):fat emulsion group (group L),propofol group (group P),and different doses of trimetazidine groups (TL and TH groups).In group L,10％ fat emulsion was infused intravenously for 12 h at a rate of 30 mg·kg-1 ·h-1.In group P,1％ propofol was infused intravenously for 12 h at a rate of 30 mg·kg-1 ·h-1.In TL and TH groups,trimetazidine 2 and 5 mg/kg were injected intravenously,respectively,and 1.5 h later propofol was infused intravenously for 12 h at a rate of 30 mg·kg-1 ·h-1.At 6 and 12 h after beginning of administration,blood samples from the internal jugular vein were taken for determination of the levels of serum creatine kinase (CK),creatine kinase isoenzyme-MB (CK-MB),lactate dehydrogenase (LDH),α-hydroxybutyric acid dehydrogenase (α-HBDH),cardiac troponin Ⅰ (cTnⅠ),triglycerides (TG),low-density lipoprotein (LDL) and high-density lipoprotein (HDL).After blood sampling at 12 h after beginning of administration,myocardial specimens were obtained for microscopic examination of the pathological changes with light and electron microscope.Results Compared with group L,the serum CK,CK-MB,LDH,α-HBDH,cTnⅠ and TG levels were significantly increased,HDL was decreased,and no significant changes were found in LDL concentrations in P and TL groups,and the serum TG,HDL and LDL were increased,and no significant changes were found in the other parameters in group TH.Compared with group P,the serum CK,CK-MB,LDH,α-HBDH,and cTnⅠ levels were significantly decreased in TL and TH groups,the serum TG level was increased in TL group,and the serum TG,HDL and LDL levels were increased in TH group.Compared with group TL,the serum CK,CK-MB,LDH,α-HBDH and cTnⅠ levels were significantly decreased,and the serum TG,HDL and LDL levels were increased in group TH.Conclusion Trimetazidine pretreatment can attenuate myocardial injury induced by propofol,but it induces increase in blood lipids. Key words: Trimetazidine; Propofol; Myocardial

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model

Acute renal failure (ARF) is often the consequence of an ischemia-reperfusion injury (IRI) and associated with high mortality. Warm ischemia (WI) is a crucial factor of tissue damage, and tissue destruction led by ischemia-reperfusion (I/R) can impact the early and long-term functional outcome. Trimetazidine (TMZ) is an anti-ischemic drug. Previously, we already verified its protective effect on a cold-ischemic pig kidney model by directly adding TMZ into the preservation solution (Faure JP, Baumert H, Han Z, Goujon JM, Favreau F, Dutheil D, Petit I, Barriere M, Tallineau C, Tillement JP, Carretier M, Mauco G, Papadopoulos V, Hauet T. Biochem Pharmacol 66: 2241-2250, 2003; Faure JP, Petit I, Zhang K, Dutheil D, Doucet C, Favreau F, Eugene M, Goujon JM, Tillement JP, Mauco G, Vandewalle A, Hauet T. Am J Transplant 4: 495-504, 2004). In this study, we aimed to study the potential effect of TMZ pretreatment (5 mg/kg iv 24 h before WI) on the injury caused by WI for 45, 60, and 90 min and reperfusion in a WI pig kidney model. Compared with sham-operated (control) and uninephrectomized animals (UNX), TMZ pretreatment significantly reduced deleterious effects after 45 min, and particularly 60 and 90 min, of WI by improving the recovery of renal function and minimizing the inflammatory response commonly prevalent in ischemic kidney injury. Compared with controls (control group and UNX group), it was observed that 1) hypoxia-inducible factor-1 (HIF-1alpha) expression occurred earlier and with a higher intensity in the TMZ-treated groups; 2) the reduction of IRI during the first week following reperfusion was correlated with an earlier and greater expression of stathmin, which is involved in the process of tubular repair; and 3) the tubulointerstitial fibrosis was reduced, particularly after 60 and 90 min of WI. In conclusion, TMZ made the warm-ischemic kidneys more resistant to the deleterious impact of a single episode of I/R and reduced early and long-term subsequent damage.

Trimetazidine inhibits cardiomyocyte apoptosis in a rabbit model of ischemia-reperfusion

The effects of trimetazidine on cardiomyocyte apoptosis and hemodynamics in a rabbit model of ischemia-reperfusion were determined. Thirty male New Zealand white rabbits were randomly divided into sham, control, and treated groups (n = 10). Trimetazidine (2 mg/kg(-1)/day(-1)) was fed for 2 weeks to treated animals before the procedure. Control and treated groups were subjected to a 30-min coronary occlusion followed by a 2-h reperfusion. Mean arterial pressure, left ventricular systolic pressure, and maximum rate of left ventricular pressure rise were significantly higher in the treated group than in the controls (P < 0.01, < 0.01, and < 0.05, respectively), whereas left ventricular end-diastolic pressure was significantly lower in the treated group than in the controls (P < 0.01). As compared with the sham group, controls had a significantly higher apoptotic index (22.10% +/- 2.85% vs 0.51% +/- 0.31%, P < 0.01) and malondialdehyde (MDA) concentration (18.52 +/- 1.51 vs 5.75 +/- 0.95 micromol/, P < 0.01), and significantly lower serum superoxide dismuase (SOD) levels (66.40 +/- 7.92 vs 89.25 +/- 1.36 microU/L, P < 0.01). Trimetazidine pretreatment apparently decreased apoptotic index (11.37% +/- 2.53%, P < 0.01 vs the sham or control) and MDA concentration (5.49 +/- 0.74 micromol/L, P > 0.05 vs sham, P < 0.01 vs control), and increased SOD levels (88.81 +/- 2.81 microU/L, P > 0.05 vs sham, P < 0.01 vs control). The caspase-3 activation and mitochondrial cytochrome c release were also higher in controls than in the treated group (P < 0.01). The apoptotic indices were negatively correlated with SOD and positively correlated with MDA in the groups, suggesting that trimetazidine may be a useful drug in preventing cardiomyocyte apoptosis and ischemia-reperfusion injury.

Effects of trimetazidine in ethanol‐ and acetic acid‐induced colitis: oxidant/anti‐oxidant status

There is overwhelming evidence in favour of a significant role of reactive oxygen metabolites (ROM) in the pathophysiology of inflammatory bowel disease (IBD) in man and in experimental animal models. This study was undertaken to investigate the possible protective effects of pretreatment with trimetazidine (TMZ) on the oxidant-anti-oxidant balance in ethanol- and acetic acid-induced colonic damage in rats. TMZ was chosen because of its various cytoprotective features (preserving cellular ATP levels, limiting intracellular acidosis and limiting inorganic phosphate, Na(+) and Ca(2+) accumulation) and anti-oxy characteristics which were previously reported. A total of 80 rats were randomized into eight major groups each consisting of 10 animals. Animals in groups 1, 2 and 3 served as models of ethanol-induced colitis (0.25 ml of 30% (v/v) ethanol), while group 4 served as their control. Animals in groups 5, 6 and 7 served as models of acetic acid-induced colitis (1 ml of 4% (v/v) acetic acid), while group 8 served as their control. TMZ was administered 5 mg/kg by intrarectal (i.r.) and intraperitoneal (i.p.) routes to groups 1, 2, 5 and 6. Intraperitoneal administration of TMZ was used in order to evaluate its systemic effect while i.r. administration was used to determine its local effect. After decapitation, colon mucosa samples were obtained and evaluated macroscopically and microscopically. Myeloperoxidase (MPO) activities as markers for inflammation, malondialdehyde (MDA) levels as markers for oxidant stress and reduced glutathione (GSH) and oxidized glutathione (GSSG) levels as markers for anti-oxidant status were determined. Acute colitis was observed in macroscopic and microscopic evaluation in ethanol- and acetic acid-administered groups compared with controls (P = 0.000). The macroscopic and microscopic scores in colitis groups were correlated with MPO activities (r = 0.5365, P = 0.000 and r = 0.5499, P = 0.000, respectively). MDA and GSSG levels in the acetic acid-induced colitis group were higher compared with ethanol-induced colitis group (P < 0.008 and P < 0.005, respectively), while GSH levels were significantly lower (P < 0.05). While TMZ pretreatment did not improve the oxidant state, it preserved the GSH levels significantly (P < 0.05). In conclusion, ethanol- and acetic acid-induced colitis models are appropriate experimental colitis models which in many ways manifest the characteristics seen in tissue injury related to colitis in humans. Of these two, the acetic acid-induced colitis model proved more suitable than the ethanol model for investigating the alterations in long-term and in more severe tissue injury. While TMZ pretreatment via i.p. or i.r. route did not improve the oxidative-inflammative state in either of these models, it did contribute significantly to the preservation of the anti-oxidant pool via the conservation of intracellular GSH levels. This conserving effect of TMZ was substantially more pronounced in the i.p. route compared with the i.r. route. Based on our results, we conclude that the 'GSH-preservation' role of TMZ can be the mode of action it manifests as an anti-oxy compound.

TRIMETAZIDINE AMELIORATES THE HEPATIC INJURY ASSOCIATED WITH ISCHAEMIA–REPERFUSION IN RATS

Ischaemia–reperfusion induces structural and functional damage to hepatocytes. The purpose of this study was to evaluate the protective effect of trimetazidine, an anti- ischaemic drug, in a rat liver model of ischaemia–reperfusion. Male Wistar rats were divided into groups pretreated with different doses of trimetazidine (1, 5, 10 or 20 mg kg−1day−1) or saline for 7 days. Liver ischaemia was induced for 120 min and blood reflow was subsequently restored for 30, 60, 90 or 120 min. The activities of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) as well as the bile flow and the liver ATP content were determined. Ischaemia–reperfusion induced major alterations of hepatic functions involving increases of ASAT and ALAT activities, a drop of ATP content and a sharp decrease in bile flow. Trimetazidine pretreatment reduced the liver injury. Indeed, it lowered the increase in ALAT and ASAT activities observed immediately after reperfusion and maintained higher concentrations of hepatic ATP. Simultaneously, bile flow was increased. These effects were dose-dependent and 5 mg kg−1day−1seemed to be the lowest effective dose. In this experimental model trimetazidine pretreatment reduced the liver damage induced by ischaemia–reperfusion. Our data suggest that trimetazidine may be a useful drug in liver surgery to prevent ischaemia–reperfusion injury.

Effects of trimetazidine on ischemic contracture in isolated perfused rat hearts.

Trimetazidine (1-[2,3,4-trimethoxibenzyl)]-piperazine, TMZ) is a drug with a proposed metabolically based antiischemic action. Because ischemic contracture is a serious complication of ischemia and is considered metabolic in origin, we studied the effect of trimetazidine (TMZ) on development of ischemic contracture in experimental low-flow ischemia. TMZ was either added to the perfusion fluid or given as pretreatment to the donor rats. Langendorff-perfused isolated rat hearts were submitted to 30-min subtotal global ischemia (residual flow = 0.2 ml/min, n = 6 per group) (normal flow = 12.4 +/- 0.8 ml/min, heart fresh weight = 0.9 +/- 0.3 g). Ischemic contracture was measured by a water-filled intraventricular balloon. Thereafter, the hearts were reperfused for 20 min and recovery of intraventricular pressure was monitored. Furthermore, because the mechanisms of action of TMZ may involve cellular energy metabolism, we assessed throughout glycolytic flux by collecting the coronary effluent every 5 min during control perfusion, ischemia, and reperfusion periods. Animals from the pretreated groups received TMZ [3 mg/kg orally (p.o.) twice daily] for 5 days. Animals from the control group received placebo for the same time period. Concentrations of 10(-6) and 10(-4) M were used when the drug was added to the perfusate. In our experimental conditions, TMZ pretreatment alone had no measurable cardioprotective effect, but addition to the perfusate of TMZ 10(-6) M, approximately a therapeutic concentration in humans, reduced ischemic contracture in both pretreated and control groups and improved postischemic recovery of developed pressure.(ABSTRACT TRUNCATED AT 250 WORDS)