RESUMO
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.
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Insuficiência Cardíaca , Trimetazidina , Vasodilatadores , Feminino , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Volume Sistólico/fisiologia , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Trimetazidina/uso terapêutico , Trimetazidina/farmacologia , Vasodilatadores/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
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.
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Cardiomiopatias Diabéticas , Miocárdio , Trimetazidina , Animais , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Camundongos , Masculino , Miocárdio/patologia , Miocárdio/metabolismo , Camundongos Endogâmicos C57BL , Apoptose/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Vasodilatadores/farmacologia , Modelos Animais de Doenças , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismoRESUMO
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.
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Esclerose Lateral Amiotrófica , Doenças Mitocondriais , Trimetazidina , Camundongos , Animais , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Superóxido Dismutase-1/metabolismo , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Camundongos Transgênicos , Leucócitos Mononucleares/metabolismo , Superóxido Dismutase/metabolismo , Autofagia , Modelos Animais de DoençasRESUMO
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.
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Trimetazidina , Humanos , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Vasodilatadores/farmacologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , AtletasRESUMO
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-ÒB)/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-ÒB, 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.
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Nefropatias , Traumatismo por Reperfusão , Trimetazidina , Humanos , Trimetazidina/farmacologia , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Galectina 3/metabolismo , Caspase 3/metabolismo , Sistema de Sinalização das MAP Quinases , Isquemia , Traumatismo por Reperfusão/metabolismo , Reperfusão , Proteínas HMGB/metabolismoRESUMO
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.
Assuntos
Carcinoma , Trimetazidina , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Simulação de Acoplamento Molecular , Proteína Supressora de Tumor p53RESUMO
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.
Assuntos
Insuficiência Cardíaca , Trimetazidina , Humanos , Masculino , Feminino , Idoso , Trimetazidina/uso terapêutico , Trimetazidina/farmacologia , Fosfocreatina/farmacologia , Fosfocreatina/uso terapêutico , Estudos Cross-Over , Volume Sistólico , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/uso terapêuticoRESUMO
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.
Assuntos
Esportes , Trimetazidina , Humanos , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Nível de SaúdeRESUMO
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.
Assuntos
Diabetes Mellitus Experimental , Neuropatias Diabéticas , Proteína HMGB1 , Trimetazidina , Ratos , Animais , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Ratos Sprague-Dawley , Neuropatias Diabéticas/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológicoRESUMO
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.
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Albumina Sérica Humana , Trimetazidina , Humanos , Trimetazidina/farmacologia , Sítios de Ligação , Ligação Proteica , Dicroísmo Circular , Simulação de Acoplamento MolecularRESUMO
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.
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Neoplasias da Mama , Carcinoma , Trimetazidina , Humanos , Animais , Camundongos , Feminino , Trimetazidina/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Apoptose , Carcinoma/tratamento farmacológico , Resultado do Tratamento , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular TumoralRESUMO
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.
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Transtorno Bipolar , Trimetazidina , Humanos , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Angina Pectoris/tratamento farmacológico , AntioxidantesRESUMO
Islet transplantation offers improved glycemic control in individuals with type 1 diabetes mellitus. However, in vitro islet culture is associated with islet apoptosis and eventually will lose their functionality prior to transplantation. In this study, we examined the effects of mesenchymal stem cells (MSCs) secretome preconditioned with diazoxide (DZ) and trimetazidine (TMZ) on rat islet cells during pre-transplant culture. With and without preconditioned hAD-MSCs' concentrated conditioned media (CCM) were added to the culture medium containing rat islets every 12 h for 24 and 48 h, after testing for selected cytokine concentrations (interleukin (IL)-4, IL-6, IL-13). Insulin content, glucose-stimulated insulin secretion, islet cell apoptosis, and mRNA expression of pro-apoptotic (BAX, BAK-1, and PUMA) and anti-apoptotic factors (BCL-2, BCL-xL, and XIAP) in rat islets were assessed after 24 and 48 h of culture. The protein level of IL-6 and IL-4 was significantly higher in TMZ-MSC-CM compared to MSC-non-CM. In rat isolated islets, normalized secreted insulin in the presence of 16.7 mM glucose was significantly higher in treated islet groups compared to control islets at both 24 and 48 h cultivation. Also, the percentage of apoptotic islet cells TMZ-MSC-CCM-treated islets was significantly lower compared to MSC-CM and MSC-CCM-treated islets in both 24 and 48 h cultivation. Consistent with the number of apoptotic cells, after 24 h culture, the expression of BCL-2 and BCL-xL genes in the control islets was lower than all treatment islet groups and in 48 h was lower than only TMZ-MSC-CM-treated islets. Also, the expression of the XIAP gene in control islets was significantly lower compared to the TMZ-MSC-CCM-treated islets at both at 24 and 48 h. In addition, mRNA level of the BAX gene in TMZ-MSC-CCM-treated islets was significantly lower compared to other groups at 48 h. Our findings revealed that TMZ proved to be more effective than DZ and could enhance the potential of hAD-MSCs-CM to improve the function and viability of islets prior to transplantation.
Assuntos
Ilhotas Pancreáticas , Células-Tronco Mesenquimais , Trimetazidina , Ratos , Animais , Trimetazidina/farmacologia , Trimetazidina/metabolismo , Interleucina-6/metabolismo , Secretoma , Proteína X Associada a bcl-2/metabolismo , Ilhotas Pancreáticas/metabolismo , Insulina/metabolismo , Diazóxido/metabolismo , Diazóxido/farmacologia , Glucose/metabolismoRESUMO
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.
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Isquemia Miocárdica , Trimetazidina , Ratos , Camundongos , Animais , Masculino , Trimetazidina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Cálcio/metabolismo , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Hipóxia/metabolismo , Isquemia/metabolismoRESUMO
Myocardial ischemia-reperfusion injury (MI/R) leads to the inevitable clinical consequences of myocardial infarction and subsequent heart failure. Trimetazidine (TMZ), an anti-ischemic agent, exerts protective potential in MI/R but had limited efficacy for some patients. Here we sought to investigate the single and combined application of gentiopicroside (GPS) and TMZ in MI/R. Notably, GPS had little cytotoxicity to cardiomyocytes. GPS attenuated hypoxia/reoxygenation (H/R)-induced cell death, reactive oxygen species production, lactate dehydrogenase and malondialdehyde releases, and antioxidant stress enzyme superoxide dismutase activity, indicating the protective efficacy of GPS against H/R-induced oxidative injury. Importantly, GPS enhanced the protective efficacy of TMZ against H/R-mediated cardiomyocyte injury. Additionally, GPS mitigated the transcription and releases of pro-inflammatory cytokine interleukin-6 and tumor necrosis factor-α in H/R-treated cardiomyocytes, which were enhanced after co-treatment with TMZ. Mechanistically, GPS activated the AMP-activated protein kinase (AMPK) signaling to inhibit H/R-induced NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, which was further enhanced after costimulation with TMZ. Importantly, blocking the AMPK signaling reversed the protective roles of GPS and its combination with TMZ in H/R-induced oxidative insult and inflammation. In vivo, both GPS and TMZ alleviated the abnormal cardiac structure, cardiomyocyte apoptosis, and cardiac dysfunction in MI/R rats, which were further enhanced after administration with GPS and TMZ together. Furthermore, GPS intensified TMZ-mediated inhibition of oxidative injury, inflammation, and the AMPK/NLRP3 signaling in MI/R rats. Collectively, GPS enhances the protective efficacy of TMZ against MI/R injury through AMPK activation-mediated inhibition of NLRP3 inflammasome signaling, implying a promising therapeutic agent for the treatment of MI/R.
Assuntos
Traumatismo por Reperfusão Miocárdica , Trimetazidina , Ratos , Animais , Trimetazidina/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Miócitos Cardíacos/metabolismo , Inflamação/metabolismoRESUMO
Tramadol (TRA) causes neurotoxicity whereas trimetazidine (TMZ) is neuroprotective. The potential involvement of the PI3K/Akt/mTOR signaling pathway in the neuroprotection of TMZ against TRA-induced neurotoxicity was evaluated. Seventy male Wistar rats were divided into groups. Groups 1 and 2 received saline or TRA (50 mg/kg). Groups 3, 4, and 5 received TRA (50 mg/kg) and TMZ (40, 80, or 160 mg/kg) for 14 days. Group 6 received TMZ (160 mg/kg). Hippocampal neurodegenerative, mitochondrial quadruple complex enzymes, phosphatidylinositol-3-kinases (PI3Ks)/protein kinase B levels, oxidative stress, inflammatory, apoptosis, autophagy, and histopathology were evaluated. TMZ decreased anxiety and depressive-like behavior induced by TRA. TMZ in tramadol-treated animals inhibited lipid peroxidation, GSSG, TNF-α, and IL-1ß while increasing GSH, SOD, GPx, GR, and mitochondrial quadruple complex enzymes in the hippocampus. TRA inhibited Glial fibrillary acidic protein expression and increased pyruvate dehydrogenase levels. TMZ reduced these changes. TRA decreased the level of JNK and increased Beclin-1 and Bax. TMZ decreased phosphorylated Bcl-2 while increasing the unphosphorylated form in tramadol-treated rats. TMZ activated phosphorylated PI3Ks, Akt, and mTOR proteins. TMZ inhibited tramadol-induced neurotoxicity by modulating the PI3K/Akt/mTOR signaling pathways and its downstream inflammatory, apoptosis, and autophagy-related cascades.
Assuntos
Fármacos Neuroprotetores , Síndromes Neurotóxicas , Tramadol , Trimetazidina , Masculino , Ratos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Trimetazidina/farmacologia , Tramadol/toxicidade , Neuroproteção , Ratos Wistar , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/farmacologia , Apoptose , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Autofagia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Bentonite is reported to be used for extending ocular drug delivery safely in a controlled manner. Bentonite combined hydroxypropyl methylcellulose (HPMC)-poloxamer based sol-to-gel formulation has been developed for the prophylactic ocular anti-inflammatory effect of trimetazidine after corneal application. HPMC-poloxamer sol formulation was prepared incorporating trimetazidine to bentonite at 1: 2*10-5 to 1:5*10-6 ratios using cold method, and investigations were carried out in carrageenan-induced rabbit eye model. Pseudoplastic shear thinning behavior without any yield value and high viscosity at low shear rate were the positive attribute of the tolerability of the sol formulation after ocular instillation. Presence of bentonite nanoplatelets revealed more sustained in vitro release (~79-97 %) and corneal permeation (~79-83 %) over a period of 6 h in comparison to its absence. Prominent acute inflammation has been produced in the carrageenan-induced untreated eye, whereas the absence of ocular inflammation has been noticed in the previously sol-treated eye even after carrageenan injection. HPMC-poloxamer-based formulation exhibited stronger binding affinity (5.13 kcal/mol) in the presence of bentonite rather than its absence (3.99 kcal/mol), resulting in a stable and sustained effect. HPMC-poloxamer in-situ gel of trimetazidine containing bentonite could be utilized for sustained ocular delivery and the control of ophthalmic inflammation prophylactically.
Assuntos
Poloxâmero , Trimetazidina , Animais , Coelhos , Derivados da Hipromelose , Trimetazidina/farmacologia , Bentonita , Carragenina , Géis , Sistemas de Liberação de Medicamentos/métodos , Anti-Inflamatórios , Córnea/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , ReologiaRESUMO
Hexavalent chromium salt, like potassium dichromate (PD), is chromium's most precarious valence state in industrial wastes. Recently, there has been increasing interest in ß-sitosterol (BSS), a bioactive phytosterol, as a dietary supplement. BSS is recommended in treating cardiovascular disorders due to its antioxidant effect. Trimetazidine (TMZ) was used traditionally for cardioprotection. Through the administration of BSS and TMZ, the cardiotoxic effects of PD were to be countered in this study, in addition to examining the precise mechanism of PD-induced cardiotoxicity. Thirty male albino rats were divided into five groups; the control group: administered normal saline daily (3 mL/kg); the PD group: administered normal saline daily (3 mL/kg); BSS group: administered BSS daily (20 mg/kg); TMZ group: administered TMZ daily (15 mg/kg); and the BSS + TMZ group: administered both BSS (20 mg/kg) and TMZ (15 mg/kg) daily. All experimental groups, except the control, received on the 19th day a single dose of PD (30 mg/kg/day, S.C.). Normal saline, BSS, and TMZ were received daily for 21 consecutive days p.o. The exposure to PD promoted different oxidative stresses, pro-inflammatory, and cardiotoxicity biomarkers. BSS or TMZ succeeded solely in reducing these deleterious effects; however, their combination notably returned measured biomarkers close to normal values. The histopathological investigations have supported the biochemical findings. The combination of BSS and TMZ protects against PD cardiotoxicity in rats by reducing oxidative stress and apoptotic and inflammatory biomarkers. It may be promising for alleviating and protecting against PD-induced cardiotoxicity in people at an early stage; however, these findings need further clinical studies to be confirmed. HIGHLIGHTS: ⢠Potassium dichromate induces cardiotoxicity in rats through the upregulation of oxidative stress, proinflammatory, and apoptotic pathways biomarkers. ⢠ß-Sitosterol possesses a possible cardioprotective effect by modulating several signaling pathways. ⢠Trimetazidine, the antianginal agent, has a potential cardioprotective impact on PD-intoxicated rat model. ⢠The combination of ß-Sitosterol and trimetazidine was the best in modulating different pathways involved in PD cardiotoxicity in rats via the interplay between NF-κB/AMPK/mTOR/TLR4 and HO-1/NADPH signaling pathways.
Assuntos
Trimetazidina , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/farmacologia , Biomarcadores , Cardiotoxicidade/tratamento farmacológico , NADP/metabolismo , NADP/farmacologia , NF-kappa B/metabolismo , Dicromato de Potássio , Solução Salina/farmacologia , Transdução de Sinais , Receptor 4 Toll-Like , Serina-Treonina Quinases TOR/metabolismo , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Animais , RatosRESUMO
OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.
Assuntos
Transtorno Bipolar , Trimetazidina , Ratos , Humanos , Animais , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Transcriptoma , Reposicionamento de Medicamentos , Leucócitos Mononucleares , Modelos Animais de DoençasRESUMO
Ischemia/reperfusion (I/R) injury is a tissue damage during reperfusion after an ischemic condition. I/R injury is induced by pathological cases including stroke, myocardial infarction, circulatory arrest, sickle cell disease, acute kidney injury, trauma, and sleep apnea. It can lead to increased morbidity and mortality in the context of these processes. Mitochondrial dysfunction is one of the hallmarks of I/R insult, which is induced via reactive oxygen species (ROS) production, apoptosis, and autophagy. MicroRNAs (miRNAs, miRs) are non-coding RNAs that play a main regulatory role in gene expression. Recently, there are evidence, which miRNAs are the major modulators of cardiovascular diseases, especially myocardial I/R injury. Cardiovascular miRNAs, specifically miR-21, and probably miR-24 and miR-126 have protective effects on myocardial I/R injury. Trimetazidine (TMZ) is a new class of metabolic agents with an anti-ischemic activity. It has beneficial effects on chronic stable angina by suppressing mitochondrial permeability transition pore (mPTP) opening. The present review study addressed the different mechanistic effects of TMZ on cardiac I/R injury. Online databases including Scopus, PubMed, Web of Science, and Cochrane library were assessed for published studies between 1986 and 2021. TMZ, an antioxidant and metabolic agent, prevents the cardiac reperfusion injury by regulating AMP-activated protein kinase (AMPK), cystathionine-γ-lyase enzyme (CSE)/hydrogen sulfide (H2S), and miR-21. Therefore, TMZ protects the heart against I/R injury by inducing key regulators such as AMPK, CSE/H2S, and miR-21.