Effects of trimetazidine on heart failure with reduced ejection fraction and associated clinical outcomes: a systematic review and meta-analysis.

BACKGROUND: Despite maximal treatment, heart failure (HF) remains a major clinical challenge. Besides neurohormonal overactivation, myocardial energy homoeostasis is also impaired in HF. Trimetazidine has the potential to restore myocardial energy status by inhibiting fatty acid oxidation, concomitantly enhancing glucose oxidation. Trimetazidine is an interesting adjunct treatment, for it is safe, easy to use and comes at a low cost. OBJECTIVE: We conducted a systematic review to evaluate all available clinical evidence on trimetazidine in HF. We searched Medline/PubMed, Embase, Cochrane CENTRAL and ClinicalTrials.gov to identify relevant studies. METHODS: Out of 213 records, we included 28 studies in the meta-analysis (containing 2552 unique patients), which almost exclusively randomised patients with HF with reduced ejection fraction (HFrEF). The studies were relatively small (median study size: N=58) and of short duration (mean follow-up: 6 months), with the majority (68%) being open label. RESULTS: Trimetazidine in HFrEF was found to significantly reduce cardiovascular mortality (OR 0.33, 95% CI 0.21 to 0.53) and HF hospitalisations (OR 0.42, 95% CI 0.29 to 0.60). In addition, trimetazidine improved (New York Heart Association) functional class (mean difference: -0.44 (95% CI -0.49 to -0.39), 6 min walk distance (mean difference: +109 m (95% CI 105 to 114 m) and quality of life (standardised mean difference: +0.52 (95% CI 0.32 to 0.71). A similar pattern of effects was observed for both ischaemic and non-ischaemic cardiomyopathy. CONCLUSIONS: Current evidence supports the potential role of trimetazidine in HFrEF, but this is based on multiple smaller trials of varying quality in study design. We recommend a large pragmatic randomised clinical trial to establish the definitive role of trimetazidine in the management of HFrEF.

Influence of trimetazidine on myocardial injury in mice with diabetic cardiomyopathy.

INTRODUCTION: The prevalence of diabetes mellitus is increasing year by year globally, and diabetic cardiomyopathy (DCM), as the most common complication of type 2 diabetes mellitus, seriously affects the prognosis of patients. Trimetazidine (TMZ), as a drug affecting myocardial energy metabolism, mainly reduces the oxidation rate of ß-oxidation by inhibiting 3-ketoacyl-CoA thiolase (3-KAT), a key enzyme in ß-oxidation of free fatty acid (FFA), so that the energy metabolism substrate of cardiomyocytes preferentially selects glucose rather than fatty acids, increases the content of intracellular adenosine triphosphate (ATP), enhances the contractile function of cardiomyocytes, and improves the state of cellular ischemia and hypoxia. Previous studies have shown that TMZ is closely related to the activation and induction of apoptosis of the MAPK pathway and AMPK pathway, and plays a role in the treatment of diabetic cardiomyopathy, but the specific mechanism is still unclear. OBJECTIVE: This study aims to investigate the impact of TMZ on myocardial damage in mice exhibiting diabetic cardiomyopathy (DCM), and to furnish a laboratory foundation for the clinical treatment of diabetic cardiomyopathy. METHOD: Male db/db mice (6 weeks old, n = 21) and male wild-type (wt) (6 weeks old, n = 20) mice were selected for the study. The wt mice were randomly assigned to the wt group (n = 10) and wt + TMZ group (n = 10), while the remaining db/db mice were randomly allocated to the db/db group (n = 11) and db/db + TMZ group (n = 10). Following 8 weeks of feeding, the wt + TMZ group and db/db + TMZ group received TMZ via gavage, whereas the remaining groups were administered physiological saline. Periodic measurements of blood glucose, blood lipids, and myocardial enzymes were conducted in mice, with samples obtained after the 12th week for subsequent biochemical analysis, myocardial pathology assessment, immunohistochemistry, western blot analysis, and TUNEL staining (TdT-mediated dUTP Nick-End Labeling). RESULT: GLU, TC, TG, LDL-C, and CK-MB levels were significantly higher in db/db mice compared to wt mice (GLU: M ± SD wt 5.94 ± 0.37, db/db 17.63 ± 0.89, p < 0.05, ES = 0.991; TC: M ± SD wt 3.01 ± 0.32, db/db 6.97 ± 0.36, p < 0.05, ES = 0.972; TG: M ± SD wt 0.58 ± 0.2, db/db 1.75 ± 0.14, p < 0.05, ES = 0.920; LDL-C: M ± SD wt 1.59 ± 0.12, db/db 3.87 ± 0.14, p < 0.05, ES = 0.989; CK-MB: M ± SD wt 0.12 ± 0.01, db/db 0.31 ± 0.04, p < 0.05, ES = 0.928). HDL-C levels were significantly lower in db/db mice (M ± SD wt 1.89 ± 0.08, db/db 0.64 ± 0.09, p < 0.05, ES = 0.963). Histopathological analysis confirmed myocardial damage in db/db mice. Treatment with TMZ reduced GLU, TC, TG, LDL-C, and CK-MB levels (p < 0.05, ES > 0.9) and increased HDL-C levels compared to untreated db/db mice. Additionally, TMZ treatment significantly decreased myocardial cell apoptosis (p < 0.05, ES = 0.980). These results demonstrate the efficacy of TMZ in reversing myocardial injury in DCM mice. CONCLUSION: TMZ can mitigate myocardial damage in db/db mice by downregulating the expression of caspase-12, a protein associated with the endoplasmic reticulum stress (ERS) cell apoptosis pathway, consequently diminishing cell apoptosis. This underscores the protective efficacy of TMZ against myocardial damage in mice afflicted with DCM.

Trimetazidine Improves Mitochondrial Dysfunction in SOD1G93A Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation.

Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1G93A-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1G93A, with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.

Biochemical Aspects That Lead to Abusive Use of Trimetazidine in Performance Athletes: A Mini-Review.

Trimetazidine (TMZ), used for treating stable angina pectoris, has garnered attention in the realm of sports due to its potential performance-enhancing properties, and the World Anti-Doping Agency (WADA) has classified TMZ on the S4 list of prohibited substances since 2014. The purpose of this narrative mini-review is to emphasize the biochemical aspects underlying the abusive use of TMZ among athletes as a metabolic modulator of cardiac energy metabolism. The myocardium's ability to adapt its energy substrate utilization between glucose and fatty acids is crucial for maintaining cardiac function under various conditions, such as rest, moderate exercise, and intense effort. TMZ acts as a partial inhibitor of fatty acid oxidation by inhibiting 3-ketoacyl-CoA thiolase (KAT), shifting energy production from long-chain fatty acids to glucose, reducing oxygen consumption, improving cardiac function, and enhancing exercise capacity. Furthermore, TMZ modulates pyruvate dehydrogenase (PDH) activity, promoting glucose oxidation while lowering lactate production, and ultimately stabilizing myocardial function. TMZs role in reducing oxidative stress is notable, as it activates antioxidant enzymes like glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). In conclusion, TMZs biochemical mechanisms make it an attractive but controversial option for athletes seeking a competitive edge.

Effects of trimetazidine on cardiac function in adult cyanotic congenital heart disease patients: Protocol for a 3-month multicenter, randomized, double-blind controlled trial.

BACKGROUND: Nearly 20% Patients with cyanotic congenital heart disease (CCHD) are not able to receive surgery. These patients experience a decline in cardiac function as they age, which has been demonstrated to be associated with changes in energy metabolism in cardiomyocytes. Trimetazidine (TMZ), a metabolic regulator, is supposed to alleviate such maladaptation and reserve cardiac function in CCHD patients. METHODS: This is a randomized, double-blind, placebo-controlled clinical trial. Eighty adult CCHD patients will be recruited and randomized to the TMZ (20 mg TMZ 3 times a day for 3 months) or placebo group (placebo 3 times a day for 3 months). The primary outcome is the difference in cardiac ejection fractions (EF) measured by cardiac magnetic resonance (MRI) between baseline and after 3 months of TMZ treatment. The secondary outcomes include TMZ serum concentration, rate of cardiac events, NYHA grading, fingertip SpO2, NT-proBNP levels, 6-minute walking test (6MWT), KCCQ-CSS questionnaire score, echocardiography, ECG, routine blood examination, liver and kidney function test, blood pressure and heart rate. DISCUSSION: This trial is designed to explore whether the application of TMZ in adult CCHD patients can improve cardiac function, reduce cardiac events, and improve exercise performance and quality of life. The results will provide targeted drug therapy for CCHD patients with hypoxia and support the application of TMZ in children with CCHD.

Comprehensive metabolite profiling of trimetazidine in camels using high-resolution accurate mass spectrometry: Implications for doping control.

RATIONALE: Trimetazidine and its metabolites are prohibited substances in sports. With a growing number of adverse findings in human athletes, it is crucial to develop doping control strategies that include screening for trimetazidine in animal sports. This study aims to detect and characterize trimetazidine and its metabolites for doping control in camel racing. METHODS: Camel urine and plasma samples were collected from four healthy animals following a single oral dose of trimetazidine. In vitro investigations were conducted using camel liver samples. Liquid-liquid extraction and solid-phase extraction techniques were employed for the extraction of trimetazidine metabolites from plasma and urine matrices. The metabolites were analyzed using a Thermo Orbitrap Exploris LC-MS system with optimized settings to achieve maximum sensitivity and accurate mass measurements. RESULTS: Comprehensive metabolite profiling of trimetazidine in camels revealed the identification of seven phase I and five phase II metabolites. Phase I metabolites were primarily formed through dealkylation, while phase II metabolites were dominated by glucuronide conjugation of demethylated trimetazidine. The findings provided insights into the distinct metabolic pathways and biotransformation patterns of trimetazidine in camels under the experimental conditions. CONCLUSION: The developed method enables detection and characterization of trimetazidine and its metabolites in camels. The identified metabolites have the potential to serve as marker metabolites for trimetazidine abuse in camel racing. This study provides valuable insights into the metabolism of trimetazidine in camels.

Evaluating the protective role of trimetazidine versus nano-trimetazidine in amelioration of bilateral renal ischemia/reperfusion induced neuro-degeneration: Implications of ERK1/2, JNK and Galectin-3 /NF-κB/TNF-α/HMGB-1 signaling.

BACKGROUND: Renal ischemia/reperfusion (I/R) is a primary culprit of acute kidney injury. Neurodegeneration can result from I/R, but the mechanisms are still challenging. We studied the implications of bilateral renal I/R on brain and potential involvement of the oxidative stress (OS) driven extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase (ERK1/2, JNK) and Galectin-3 (Gal-3)/nuclear factor Kappa B (NF-қB)/tumor necrosis factor-alpha (TNF-α), high mobility group box-1 (HMGB-1), and caspase-3 paths upregulation. We tested the impact of Nano-trimetazidine (Nano-TMZ) on these pathways being a target of its neuroprotective effects. METHODS: Study groups; Sham, I/R, TMZ+I/R, and Nano-TMZ+I/R. Kidney functions, cognition, hippocampal OS markers, Gal-3, NF-қB, p65 and HMGB-1 gene expression, TNF-α level, t-JNK/p-JNK and t-ERK/p-ERK proteins, caspase-3, glial fibrillary acidic protein (GFAP) and ionized calcium binding protein-1 (Iba-1) were assessed. RESULTS: Nano-TMZ averted renal I/R-induced hippocampal impairment by virtue of its anti: oxidative, inflammatory, and apoptotic properties. CONCLUSION: Nano-TMZ is more than anti-ischemic.

PARAMETERS OF LEFT VENTRICULAR DIASTOLIC DYSFUNCTION IN PATIENTS WITH HYPERTENSION DISEASE WITH CONCOMITANT TYPE 2 DIABETES.

OBJECTIVE: The aim: To study the parameters of the left ventricular (LV) diastolic function in patients with HT with concomitant T2DM and without it before and after complex treatment with the inclusion of Eplerenone 50 mg per day and Trimetazidine 80 mg per day during 3 months. PATIENTS AND METHODS: Materials and methods: The study included 50 patients, aged 45-54 years (mean age 51.3«1.5 years), women - 24 and men 26 with HT stage II. All patients were divided into 2 groups: 1 group (n=25) - patients with HT stage II (HbA1c level of 5.01«0.13%) and 2 group (n=25) - patients with HT stage II and concomitant T2DM (HbA1c level of 7.6«0.34%). The control group consisted of 20 healthy individuals (HbA1c level of 4.68«0.49%). RESULTS: Results: When analyzing the findings on left atrial volume index (LAVI), the highest indicators were observed in patients with HT with T2DM, but slightly lower in HT, and even lower in the control group, but the differences at this stage were not significant. This suggests that functional changes in cardiomyocyte kinetics, which develop in patients with comorbid pathology and are caused by metabolic and hemodynamic disorders, can progress steadily. CONCLUSION: Conclusions: After a three-month course of treatment with Eplerenone and Trimetazidine, the rate of myocardial relaxation in diastole likely increased in both groups of those examined. The prescribed treatment with Eplerenone and Trimetazidine has led to a decrease in the rate of progression of heart failure and a reduction in cardiovascular risks.

Trimetazidine in heart failure with preserved ejection fraction: a randomized controlled cross-over trial.

AIMS: Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF. METHODS AND RESULTS: The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2 ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters. CONCLUSIONS: Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.

Antitumor effect of trimetazidine in a model of solid Ehrlich carcinoma is mediated by inhibition of glycolytic pathway and AKT signaling.

Disturbance in glucose metabolism was proposed to be a pathogenetic mechanism of breast cancer. Trimetazidine (TMZ) inhibits ß-oxidation of fatty acids through blocking the activity of 3-ketoacylCoA thiolase enzyme, leading to enhancement of glucose oxidation and metabolic respiration. The present study aimed to examine the cytotoxic effect of TMZ in both in vivo and in vitro models of breast cancer, focusing on its impact on the expression of some glycolytic enzymes and AKT signaling. The cytotoxic effect of TMZ was screened against breast (MCF-7) cancer cell line at different concentrations [0.01-100 µM]. In vivo, graded doses (10, 20, 30 mg/kg) of TMZ were tested against solid Ehrlich carcinoma (SEC) in mice. Tumor tissues were isolated for assessment of the expression of glucose transporter-1 (GLUT-1) and glycolytic enzymes by quantitative PCR. The protein expression of AKT and cellular myelocytomatosis (c-Myc) was determined by western blotting, while p53 expression was evaluated by immunohistochemistry. Molecular docking study of TMZ effect on AKT and c-Myc was performed using Auto-Dock Vina docking program. TMZ showed a cytotoxic action against MCF-7 cells, having IC50 value of 2.95 µM. In vivo, TMZ reduced tumor weight, downregulated the expression of glycolytic enzymes, suppressed AKT signaling, but increased p53 expression. Molecular docking and in silico studies proposed that TMZ is an AKT and c-Myc selective inhibitor. In conclusion, TMZ demonstrated a viable approach to suppress tumor proliferation in biological models of breast cancer.

Comparative Efficacy of Different Drugs for the Treatment of Dilated Cardiomyopathy: A Systematic Review and Network Meta-analysis.

BACKGROUND AND OBJECTIVE: At present, the therapies of dilated cardiomyopathy concentrated on the symptoms of heart failure and related complications. The study is to evaluate the clinical efficacy of a combination of various conventional and adjuvant drugs in treating dilated cardiomyopathy via network meta-analysis. METHODS: The study was reported according to the PRISMA 2020 statement. From inception through 27 June 2022, the PubMed, Embase, Cochrane library, and Web of Science databases were searched for randomized controlled trials on medicines for treating dilated cardiomyopathy. The quality of the included studies was evaluated according to the Cochrane risk of bias assessment. R4.1.3 and Revman5.3 software were used for analysis. RESULTS: There were 52 randomized controlled trials in this study, with a total of 25 medications and a sample size of 3048 cases. The network meta-analysis found that carvedilol, verapamil, and trimetazidine were the top three medicines for improving left ventricular ejection fraction (LVEF). Ivabradine, bucindolol, and verapamil were the top 3 drugs for improving left ventricular end-diastolic dimension (LVEDD). Ivabradine, L-thyroxine, and atorvastatin were the top 3 drugs for improving left ventricular end-systolic dimension (LVESD). Trimetazidine, pentoxifylline, and bucindolol were the top 3 drugs for improving the New York Heart Association classification (NYHA) cardiac function score. Ivabradine, carvedilol, and bucindolol were the top 3 drugs for reducing heart rate (HR). CONCLUSION: A combination of different medications and conventional therapy may increase the clinical effectiveness of treating dilated cardiomyopathy. Beta-blockers, especially carvedilol, can improve ventricular remodeling, cardiac function, and clinical efficacy in patients with dilated cardiomyopathy (DCM). Hence, they can be used if patients tolerate them. If LVEF and HR do not meet the standard, ivabradine can also be used in combination with other treatments. However, since the quality and number of studies in our research were limited, large sample size, multi-center, and high-quality randomized controlled trials are required to corroborate our findings.

Impact of Trimetazidine on the Incident Heart Failure After Coronary Artery Revascularization.

ABSTRACT: Abnormal myocardial metabolism is a common pathophysiological process underlying ischemic heart disease and heart failure (HF). Trimetazidine is an antianginal agent with a unique mechanism of action that regulates myocardial energy metabolism and might have a beneficial effect in preventing HF in patients undergoing myocardial revascularization. We aimed to evaluate the potential benefit of trimetazidine in preventing incident hospitalization for HF after myocardial revascularization. Using the common data model, we identified patients without prior HF undergoing myocardial revascularization from 8 hospital databases in Korea. To compare clinical outcomes using trimetazidine, database-level hazard ratios (HRs) were estimated using large-scale propensity score matching for each database and pooled using a random-effects model. The primary outcome was incident hospitalization for HF. The secondary outcome of interest was major adverse cardiac events (MACEs). After propensity score matching, 6724 and 11,211 patients were allocated to trimetazidine new-users and nonusers, respectively. There was no significant difference in the incidence of hospitalization for HF between the 2 groups (HR: 1.08, 95% confidence interval [CI], 0.88-1.31; P = 0.46). The risk of MACE also did not differ between the 2 groups (HR: 1.07, 95% CI, 0.98-1.16; P = 0.15). In conclusion, the use of trimetazidine did not reduce the risk of hospitalization for HF or MACE in patients undergoing myocardial revascularization. Therefore, the role of trimetazidine in contemporary clinical practice cannot be expanded beyond its current role as an add-on treatment for symptomatic angina.

The application of trimetazidine in healthy individuals: a systematic review.

OBJECTIVE: Currently, there is no evidence to support trimetazidine (TMZ) administration aimed at enhancing physical performance or post-exercise recovery in healthy individuals or athletes from the general and athletic populations, respectively. Considering the lack of empirical data, from a scientific and practical perspective, it would be interesting to review research with high methodological quality that examines the effects of TMZ on healthy individuals and athletes from various age groups. MATERIALS AND METHODS: Data sources included English articles that were initially searched by keywords utilizing PubMed, Scopus databases, and the Cochrane Library and published prior to November 2022. Thus, a systematic review of the scientific literature was performed with a traditional PRISMA methodology. An initial keyword search found 2,673 publications, and further screening selected 66 articles, of which only two articles met the inclusion criteria. RESULTS: Two trials examining the effect of TMZ on healthy members of the general population that were published in 2017 and 2019 were analyzed. Publications examining athletes were not recruited for this analysis. CONCLUSIONS: Currently, there are no data reporting a positive effect of TMZ on physical performance, post-exercise recovery, or other health parameters in members of the general population, while its administration is associated with the development of relatively common adverse effects.

Probing the potential toxicity of trimetazidine by characterizing its interaction with human serum albumin.

The small molecular drugs pharmacodynamics and pharmacokinetics could be affected by human serum albumin (HSA) transport, so we studied the interaction between HSA and the widely used anti-ischemic agent, trimetazidine (TMZ), using different approaches. As shown by synchronous fluorescence spectroscopy, the interaction affects the microenvironment confirmation around tyrosine residues. The site-competitive experiments showed that TMZ had an affinity toward subdomain III A (site II) of HSA. The enthalpy and entropy changes (ΔH and ΔS), which were 37.75 and 0.197 K J mol-1, respectively, showed that the predominant intermolecular interactions are hydrophobic forces. According to FTIR research, the interaction between HSA and TMZ caused polypeptide carbonyl-hydrogen bonds to rearrange. The HSA esterase enzyme activity was decreased with TMZ. Docking analysis confirmed the site-competitive experiments and thermodynamic results. This study demonstrated that TMZ interacted with HSA, and the structure and function of HSA were influenced by TMZ. This study could aid in understanding the pharmacokinetics of TMZ and provide basic data for safe use.

Trimetazidine provides protection against diabetic polyneuropathy in rats via modulation of soluble HMGB1.

OBJECTIVE: The aim of this study was to evaluate the neuroprotective efficacy of trimetazidine (TMZ) in a diabetic neuropathy model of the sciatic nerve. MATERIALS AND METHODS: We performed intraperitoneal (IP) single-dose streptozotocin (STZ) injection for a diabetes mellitus neuropathy model in 24 rats; 8 rats were in the control group, and no chemical administration was performed. 24 diabetic rats were randomly divided into 3 groups: Group 1 rats (n = 8; diabetes and saline groups) were given 1 ml/kg saline treatment. Diabetes and trimetazidine (TMZ)-treated rats (n = 8) were given TMZ 10 mg/kg/day i.p. in Group 2. Group 3 rats were given TMZ 20 mg/kg/day by i.p. for 4 weeks. At the end of the study, EMG and inclined plane testing were used, and blood samples were taken. RESULTS: Amplitudes of CMAP increased significantly in the TMZ treatment group when compared with the group that had been given saline treatment. The latency of CMAP was significantly shortened in the TMZ treatment group as compared to the saline treatment group. When compared to the saline treatment group, 10 mg/kg and 20 mg/kg TMZ treatment significantly reduced HMGB1, Pentraxin-3, TGF-beta, and MDA levels. CONCLUSIONS: We demonstrated the neuroprotective effect of TMZ on diabetic polyneuropathy in rats via modulation of soluble HMGB1.

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

Insights into the therapeutic outcomes of trimetazidine/doxorubicin combination in Ehrlich solid-phase carcinoma mouse tumor model.

One of the key features of cancer is metabolic reprogramming that can be exploited to sensitize cancer cells to chemotherapy. Trimetazidine (TMZ) is a metabolic anti-ischemic drug that blocks the activity of long-chain 3-ketoacyl CoA thiolase leading to the inhibition of fatty acid oxidation. AIMS: The objective of the current investigation was to evaluate the idea that TMZ could synergize the antitumor activity of doxorubicin (DOX). MAIN METHODS: The hypothesis was examined in vitro using the human breast cancer cell lines MCF-7 and MDA-MB231. In addition, the in vivo experiments were conducted using the Ehrlich solid phase carcinoma model. KEY FINDINGS: In vitro cytotoxicity experiments demonstrated that TMZ improved the potency of DOX in MCF-7 cell lines in a synergistic manner. In vivo testing confirmed that DOX/TMZ combination exhibits synergistic effect at both DOX/TMZ 1:10 and 1:5 ratios, where DOX was administered at one tenth and one fifth of its original dose, respectively. The co-treatment (1:5 ratio) significantly reduced tumor Nicotinamide adenine dinucleotide (NAD)+/NADH ratio (6.1-fold) and Adenosine triphosphate (ATP) levels (61 %) with concurrent activation of AMP-activated protein kinase (AMPK) (2.2-fold) and peroxisome proliferator-activated receptor-gamma coactivator (PGC)1-α (5.5-fold) protein expression versus control. The same treatment decreased the nuclear levels of NF-κB (p65) (57.5 %) and induced tumor apoptosis as evidenced by elevated Bax/Bcl-2 ratio (6.8-fold) along with active caspase-3 levels (6.6-fold) against control. SIGNIFICANCE: The current investigation constitutes a proof-of-concept study that provided preclinical evidence for the anticancer activity of DOX/TMZ combination and warrants further investigation for repurposing TMZ in DOX protocols.

Inhibition of ACAA1 Restrains Proliferation and Potentiates the Response to CDK4/6 Inhibitors in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with unfavorable outcomes. Developing therapeutic targets for TNBC remains a challenge. Here, we identified that acetyl-CoA acyltransferase 1 (ACAA1) is highly expressed in the luminal androgen receptor (LAR) subtype of TNBC compared with adjacent normal tissues in our TNBC proteomics dataset. Inhibition of ACAA1 restrained TNBC proliferation and potentiated the response to the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib. Mechanistically, ACAA1 interacted with CDK4, and the inhibition of ACAA1 blocked RB transcriptional corepressor 1 (RB1) phosphorylation, resulting in G1-S cell-cycle arrest. Importantly, trimetazidine, a traditional drug for ischemic heart disease, caused a decrease in ACAA1 protein levels and enhanced the efficacy of abemaciclib in preclinical TNBC models. In conclusion, this study identifies that ACAA1 is a therapeutic target in TNBC and suggests the combination of trimetazidine and abemaciclib could be beneficial for ACAA1-high TNBCs. SIGNIFICANCE: ACAA1 is highly expressed in TNBC, serving as a potential therapeutic target in ACAA1-high tumors and a predictive biomarker of resistance to CDK4/6 inhibitors for RB1-proficient patients.

Trimetazidine Affects Mitochondrial Calcium Uniporter Expression to Restore Ischemic Heart Function via Reactive Oxygen Species/NFκB Pathway Inhibition.

ABSTRACT: Studies have demonstrated the roles of trimetazidine beyond being an antianginal agent in ischemic heart disease (IHD) treatment associated with mechanisms of calcium regulation. Our recent studies revealed that mitochondrial calcium uniporter (MCU, the pore-forming unit responsible for mitochondrial calcium entrance) inhibition provided cardioprotective effects for failing hearts. Because trimetazidine and MCU are associated with calcium homeostasis, we hypothesized that trimetazidine may affect MCU to restore the failing heart function. In the present study, we tested this hypothesis in the context of cardiac ischemia in vivo and in vitro. The IHD model was established in male C57BL/6 mice followed by trimetazidine administration intraperitoneally at 20 mg/kg q.o.d for 8 weeks. In vitro studies were performed in a hypoxia model using primary rat neonate cardiomyocytes. The mice survival outcomes and heart function, pathohistologic, and biological changes were analyzed. The results demonstrated that trimetazidine treatment resulted in longer life spans and heart function improvement accompanied by restoration of mitochondrial calcium levels and increase in ATP production via MCU down-regulation. Studies in vitro further showed that trimetazidine treatment and MCU inhibition decreased reactive oxygen species (ROS) production, inhibited the NFκB pathway, and protected the cardiomyocytes from hypoxic injury, and vice versa. Thus, the present study unveils a unique mechanism in which trimetazidine is involved in ameliorating the ischemic failing heart via MCU down-regulation and the following mitochondrial calcium homeostasis restoration, ROS reduction, and cardiomyocyte protection through NFκB pathway inhibition. This mechanism provides a novel explanation for the treatment effects of trimetazidine on IHD.