The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.

IntroductionStress-test echocardiography with speckle tracking modality (STM) is sensitive to detect myocardial ischemia. Data on trimetazidine (TMZ) therapy’s effectiveness on myocardial ischemia and contractile function using STM is limited. This study aimed to assess the anti-ischemic effectiveness of trimetazidine 80 mg once daily (TMZ OD) in patients with symptomatic stable coronary artery disease (CAD) with a history of myocardial infarction (MI), in real-world practice.MethodsThe METHOD study (NCT05210465) was a 6-month observational study evaluating TMZ OD’s anti-ischemic and antianginal effectiveness in CAD patients with MI history using stress echocardiography with dobutamine and STM. Adult outpatients starting TMZ OD alongside standard antianginal therapy were included. The primary outcome was the mean change in left ventricular global longitudinal strain (LV GLS) after 6 months. Secondary outcomes were changes in regional peak systolic deformation (RPSD) and global post-systolic index, along with traditional antianginal effectiveness indicators and quality of life (QoL) using the EQ-5D-5L questionnaire.ResultsThirty-six patients were included. TMZ OD significantly improved LV GLS by 2% (95% CI – 2.6 to – 1.5, p < 0.001). RPSD significant improvements were observed in 12/17 LV segments, ranging from – 2.6% to – 0.5%. Angina frequency and short-acting nitrate use decreased from 1.0 (1.4) to 0.1 (0.4) attacks per week and from 0.5 (1.0) to 0.1 (0.3) times per week, respectively (both p < 0.05). QoL improved significantly in mobility (1.8 [0.9] vs. 1.4 [0.7]), pain (2.0 [0.4] vs. 1.3 [0.5]) and anxiety domains (1.5 [0.7] vs. 1.2 [0.5]), (all p < 0.05). TMZ OD was well tolerated with no reported adverse events.ConclusionsThis real-world study supports TMZ OD role as a valuable adjunct to standard antianginal therapy in outpatients with stable CAD and a history of MI.Trial registration: ClinicalTrialsGov: The METHOD (NCT05210465).

Diabetes mellitus (DM) is a common metabolic disorder. Type 1 diabetes (T1D) can cause hepatopathies as the liver is the primary organ of glucose metabolism. This study sought to investigate the possible protective effects of trimetazidine (TMZ) on T1D liver disease and the mechanism underlying these effects through alleviation of endoplasmic reticulum stress-mediated NLRP3 inflammasome activation. Twenty-four Sprague-Dawley rats were equally divided into four groups: control, TMZ, T1D, and T1D + TMZ groups. After killing, blood samples were collected to assess glucose, insulin, ALT, AST, and IL-1β. Livers were harvested and divided into left and right lobes. The left lobe was further divided into part preserved for IRE1, CHOP, and NLRP3 mRNA expression and the other part homogenized for colorimetric measurement of malondialdehyde (MDA). The right lobe was preserved for histopathological assessment and immunohistochemical assessments of NLRP3 and caspase-1. Trimetazidine ameliorated T1D-induced liver damage. TMZ significantly reduced MDA levels and the ER stress markers inositol requiring enzyme (IRE1) and C/EBP homologous protein (CHOP), leading to suppression of NLRP3 inflammasome activation, IL-1β, and caspase-1 dependent pyroptosis. Additionally, TMZ improved hepatic histological architecture. These results demonstrate a hepatoprotective role for TMZ in T1D-induced liver injury, potentially mediated through suppression of ER stress, inflammation, and caspase-1-dependent pyroptosis.

Trimetazidine modulates angiogenesis, inflammation, and metabolism-related gene expression to promote diabetic foot ulcer healing: a transcriptomic analysis.

Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis.

Type 1 Diabetes Mellitus (T1D) is an organ-specific autoimmune disease characterized by persistent hyperglycemia due to immune-mediated destruction of pancreatic islet β-cells. Targeting immune cell metabolism has emerged as a promising therapeutic strategy. We investigated whether the fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ), one of only three approved drugs directly targeting cellular metabolism, can restrain autoreactive immunity and delay T1D in non-obese diabetic mice (NOD). TMZ enhanced mitochondrial membrane potential, suppressed FAO, and curtailed activation and proliferation of human CD8+ T cells. In dysglycemic NOD mice, a clinically approved dose of TMZ delayed progression to T1D, reduced mean glycemia, and decreased islet CD4⁺/CD8⁺ infiltration. Single-cell RNA sequencing revealed depletion of FAO-high, stress-responsive cells and mitochondrially active stromal cells, indicating improved pancreatic health. Prolonged exposure induced compensatory upregulation of carnitine-palmitoyl-transferase-1A (CPT1A) in CD8⁺ subsets, counterbalancing early benefits. In summary, TMZ transiently restrains CD8⁺ T cell activity, reduces islet infiltration, and improves pancreatic health. The adaptive upregulation of CPT1A demonstrates a novel evasion mechanism to FAO inhibition and underscores the central role of FAO in sustaining pathogenic T cells. Our work highlights metabolic adaptation as a key determinant of autoimmune progression, validating FAO as a therapeutic target in T1D.

Chronic relapsing colonic inflammation, specifically ulcerative colitis (UC), causes persistent mucosal injury and disrupts the gut-brain axis. This disruption leads to basal ganglia neuroinflammation and ultimately extrapyramidal motor dysfunction. Dysregulation of the Dectin 1/leucine-rich repeat kinase 2 (LRRK2)/α-synuclein (αSyn) signaling exacerbates inflammation. This study investigated whether modulation of this pathway affects UC progression and is associated with motor deficits using trimetazidine (TMZ) treatment in a Bagg albino c (BALB/c) mice model. Furthermore, we examined the role of this pathway through molecular docking followed by molecular dynamics simulations to evaluate the plausibility of TMZ interactions with Dectin-1, LRRK2, and α-syn proteins. Our results indicate that TMZ improved behavioral changes and also significantly reduced serum interferone-γ (IFN-γ) and NF-kB levels, along with decreased Dectin-1, LRRK2, and αSyn expression. TMZ also mitigated colonic inflammation, as shown by reducing fecal calprotectin and fecal occult blood, supported by histological examinations. Furthermore, TMZ restored autophagic flux by reducing P62 accumulation and enhancing LAMP2 expression. Molecular docking and dynamics confirmed TMZ binding to Dectin-1, LRRK2, and αSyn, through hydrophobic and hydrophilic interactions. These findings suggest a potential molecular basis for the observed associations between the Dectin-1/LRRK2/α-synuclein axis and UC-related motor dysfunction, warranting further experimental validation, establishing TMZ's therapeutic potential for managing colonic inflammation and associated neurological manifestations.

PurposeContrast-associated acute kidney injury (CA-AKI) is a significant concern following percutaneous coronary intervention (PCI). This study assessed whether adding trimetazidine (TMZ) or TMZ/allopurinol to standard hydration reduces CA-AKI among elective PCI patients.Methods129 patients undergoing elective PCI were randomized into three groups: Group 1 received (IV isotonic saline + TMZ + allopurinol), Group 2 received (IV isotonic saline + TMZ), and Group 3 (control) received (IV isotonic saline only). The primary outcome was the incidence of CA-AKI at 24- and 48-hour post-PCI. Risk was stratified using the Mehran and the Age, Creatinine, and Ejection Fraction (ACEF) scores.ResultsGroup 1 demonstrated a non-significant reduction in CA-AKI incidence compared with Groups 2 and 3 (24 h: 4.65%, 4.55%, and 9.52%; 48 h: 16.28%, 20.45%, and 28.57%; p > 0.05). All patients were classified as low–moderate risk by ACEF and Mehran scores, neither of which predicted CA-AKI. At 48 h, SGLT2 inhibitors users demonstrated a smaller rise in creatinine compared with non-users (–0.04 ± 0.158 mg/dL vs. 0.096 ± 0.237 mg/dL, p < 0.05), as did DPP-4 inhibitor users (–0.05 ± 0.217 mg/dL vs. +0.098 ± 0.237 mg/dL, p < 0.05). Diuretics were associated with greater increases (p < 0.05).ConclusionThe TMZ–allopurinol combination showed a favorable but non-significant trend toward reducing CA-AKI, while ACEF and Mehran scores demonstrated limited predictive value. Improved risk-stratification tools and larger studies in higher-risk patients are needed. SGLT2 and DPP-4 inhibitors showed smaller creatinine increases, suggesting possible nephroprotection, but this remains exploratory.

Trimetazidine (TMZ) has anti-ischemic effects by increasing glutathione peroxidase and membrane damage caused by reactive oxygen species (ROS) and also production of trimethylamine N-Oxide (TMAO) which causes cytoprotection and provides the renoprotective effect. This preclinical trial was conducted in Animal rat house of Pharmacology Department at BSMMU, Dhaka, Bangladesh from 1st March to 31st 2017 for 30 days, this experimental study sixty-six (66) rats were divided into eight groups. Group I and II received no medication. Three groups (IIIa, IVa and Va) of rats were induced diabetic nephropathy by streptozotocin (STZ). Parallel to these groups, three combined treatment groups (IIIb, IVb and Vb) treated by trimetazidine concomitant with STZ. IIIa and IIIb were sacrificed on 22nd day to detect incidence of nephropathy, groups IVa and IVb were sacrificed on 43rd day to detect onset of nephropathy and groups Va and Vb were sacrificed on 57th day to detect progression of nephropathy. Biochemical indices like the status of oxidative stress were assessed by serum creatinine levels. In streptozotocin treated groups, serum creatinine was significantly (p<0.01) higher when compared to control. In TMZ treated group, whereas serum creatinine was significantly (p<0.01) lower when compared with STZ induced nephropathy groups of rats. It may be assumed from the present study that trimetazidine has cytoprotective as well as prevent renal damaged because of its special antioxidant effects, which can delay the onset, severity and progression of nephropathy induced by STZ in rats by reducing serum creatinine level.

Heart failure (HF) remains a prevalent complication following myocardial infarction (MI), characterized by mitochondrial dysfunction and cardiomyocyte ferroptosis, which jointly contribute to myocardial remodeling and impaired cardiac function. The present study aims to evaluate the cardioprotective efficacy and underlying mechanisms of trimetazidine (TMZ), a clinically established anti-anginal agent, in alleviating post-MI HF regulation of mitochondrial quality control and ferroptosis inhibition. Utilizing an in vivo mouse model established by left coronary artery ligation, TMZ administration significantly improved cardiac function, delayed ventricular remodeling, and reduced myocardial infarct size. Concurrently, TMZ treatment significantly reduced myocardial oxidative stress, evidenced by elevated antioxidant enzyme levels (GSH and SOD), decreased malondialdehyde (MDA), and lower intracellular Fe2+ accumulation, along with upregulation of key anti-ferroptotic markers GPX4 and SLC7A11. Complementary in vitro experiments on oxygen-glucose deprivation (OGD)-injured HL-1 cardiomyocytes confirmed that TMZ preserved cellular viability in a dose-dependent manner by inhibiting ferroptosis. Furthermore, TMZ effectively restored mitochondrial membrane potential, improved mitochondrial morphology, promoted mitophagy by increasing PINK1/Parkin pathway activation, and corrected mitochondrial dynamics through upregulation of MFN1 and downregulation of DRP1. Notably, when the mitophagy inhibitor Mdivi-1 or PINK1 siRNA was used, the protective effect of TMZ was reversed by inhibition of mitophagy. This suggests that mitophagy activated through PINK1/Parkin signaling is essential for TMZ-mediated myocardial protection and ferroptosis suppression. Molecular docking further validated TMZ's potential direct interaction with PINK1. In conclusion, these findings demonstrate that TMZ ameliorates post-MI heart failure by orchestrating mitochondrial quality control through promotion of mitophagy and suppression of GPX4-dependent ferroptosis, offering novel mechanistic insight into its therapeutic potential in the management of ischemic heart disease.

Trimetazidine protects against doxorubicin-induced chemobrain in rats: Insights into energy imbalance and neuroinflammation.

Frequent convulsions are a hallmark of the neurological disorder "epilepsy," which calls for long-term anticonvulsant medication treatment. Traditional antiseizure medications primarily modulate neurotransmitter systems or ion channels but do not address the underlying neuroinflammation and metabolic dysfunctions that contribute to epileptogenesis. Trimetazidine (TMZ), a cytoprotective agent, has shown potential in reducing seizures at higher doses, but its bioavailability and therapeutic efficacy can be enhanced through intranasal nanoliposomal delivery. This study investigates the formulation, optimization, and evaluation of TMZ-loaded Liposomal Nanocarriers (NTMZ) for enhanced anticonvulsant, antioxidant, and anti-inflammatory effects. NTMZ was designed and optimized using a Box-Behnken design to evaluate the effects of phospholipid concentration, surfactant percentage, and sonication time on particle size, polydispersity index (PDI), and encapsulation efficiency (EE%). The formulations were characterized by dynamic light scattering, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) spectroscopy. In vitro release, ex vivo permeation studies, and antioxidant activity assays were conducted. Pharmacological efficacy was evaluated through pentylenetetrazol (PTZ)-induced kindling and increasing current electroshock seizure (ICES) models in Swiss Albino mice. Biochemical analysis of inflammatory markers (IL-1β, IL-6, TNF-α), neurotransmitter levels (GABA, glutamate), and neuroinflammatory signaling (NF-κB, HMGB1-TLR4) was also performed. NTMZ displayed a particle size of 241.9nm, a PDI of 0.465, and an entrapment efficiency of 87%. In vitro release showed an initial burst release of 62% in 8h, followed by sustained release over 24h. TEM analysis confirmed uniform spherical morphology, and stability tests indicated robust formulations. In vivo studies revealed that 5mg NTMZ significantly outperformed standard TMZ in PTZ and ICES models, reducing seizure severity and cognitive deficits. NTMZ also suppressed neuroinflammatory markers (IL-1β, IL-6, TNF-α, HMGB1, TLR4, and NF-κB), enhanced GABAergic neurotransmission, and lowered glutamate levels. These findings demonstrate the potential of intranasal delivery of NTMZ as a novel formulation for managing epilepsy through its improved bioavailability, reduced dose, sustained release, and potent neuroprotective properties. Simultaneously, pharmacological modulation of neuroinflammation and neurotransmitters were observed.

Combination therapy rapidly improves symptoms and quality of life in recently diagnosed angina patients: the COMBINE Angina study

Ophthalmic antioxidant activity of a model antianginal drug using corneal hydrogel formulation: Effect of carboxymethyl starch on physicomechanical behaviour and release/permeation kinetics.

Background: Diabetes mellitus and cancer often coexist, increasing the risk of liver injury. Doxorubicin (DOXO) is a widely used antineoplastic drug with known hepatotoxic effects. Dapagliflozin (DAPA) and trimetazidine (TMZ) have been reported to exert hepatoprotective actions, but their combined effects remain unclear. Methods: Forty-eight male Sprague Dawley rats were allocated into six groups: control, streptozotocin (STZ), STZ + DOXO, STZ + DOXO + DAPA, STZ + DOXO + TMZ, and STZ + DOXO + DAPA + TMZ. Liver injury was assessed by histopathology, oxidative stress markers (MDA, GSH), and immunohistochemistry (Tumor Necrosis Factor-alpha (TNF-α), 8-Hydroxy-2′-deoxyguanosine (8-OHdG), Caspase-3, Transforming Growth Factor-beta 1 (TGF-β1), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Nuclear Factor kappa-B/p65 (NF-κB/p65)). Results: STZ and STZ + doxorubicin groups developed marked hepatic injury. Unexpectedly, the STZ + doxorubicin group showed lower alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, along with reduced Malondialdehyde (MDA) and elevated glutathione (GSH), suggesting compensatory antioxidant and apoptotic responses. Dapagliflozin more effectively normalized transaminases and reduced oxidative DNA damage, whereas trimetazidine exerted stronger effects on MDA, GSH, and inflammatory markers. The combination provided additive but not consistently superior benefits. Immunohistochemical analyses confirmed these findings, showing attenuated expression of TNF-α, 8-OHdG, caspase-3, and TGF-β1 and reduced TUNEL-positive hepatocytes and NF-κB/p65 immunoreactivity following treatment, indicating coordinated anti-apoptotic and anti-inflammatory effects. Conclusions: Dapagliflozin and trimetazidine each attenuated diabetes- and doxorubicin-related hepatic injury through partly distinct mechanisms, with the combination providing additive but not consistently superior effects. These findings suggest a potential hepatoprotective role for both agents; however, the clinical implications remain uncertain and require confirmation in further mechanistic and translational studies.

Objectives: This study aims to investigate whether trimetazidine (TMZ) alone has a preventive effect on contrast-induced nephropathy (CIN) in patients with preserved kidney function who underwent angiographic procedures and the variables associated with CIN development. Patients and methods: Between June 2023 and September 2023, a total of 305 patients (199 males, 106 females; mean age: 60±10 years; range, 54 to 67 years) who underwent coronary angiographic procedures with diagnosed or suspected stable coronary artery disease and an estimated glomerular filtration rate (eGFR) of &gt;60 mL/min/1.73 m2 were included. A total of 153 patients received TMZ (TMZ group), while 152 patients were naïve to TMZ (non-TMZ group). Results: Ten patients (6.5%) in the non-TMZ group and nine patients (5.8%) in the TMZ group developed CIN within 48 to 72 h (p=0.801) after the procedures. The mean serum creatinine level increased from 0.84±0.1 mg/dL to 0.89±0.2 mg/dL in the non-TMZ group (p&lt;0.001) and from 0.84±0.1 mg/dL to 0.88±0.2 mg/dL in the TMZ group (p=0.008). Multivariate logistic regression analysis revealed that only age (odds ratio [OR]: 1.10, 95% CI: 1.03-1.18, p=0.003) was an independent predictor of CIN. A cut-off value of 60 years (area under the curve [AUC]=0.785; sensitivity, 100%; specificity, 52%) predicted CIN development in the non-TMZ group, whereas it was 72.5 years (AUC=0.711; sensitivity, 55%; specificity, 90%) for the TMZ group. Conclusion: Our study results suggest that the use of TMZ may be beneficial on CIN in elderly patients undergoing coronary angiographic procedures, even if the eGFR is ≥60 mL/min/1.73 m2.

ABSTRACT Objective This study seeks to unravel the effects of trimetazidine (TMZ) on hypertensive nephropathy (HN) in mice and its underlying mechanisms. Methods Sixty male 129 mice (8−10 weeks old) were randomly categorized into six groups (n = 10 per group): control, model, TMZ, TMZ + small interfering RNA targeting prolyl hydroxylase domain protein 2 (si-PHD2), TMZ + zinc protoporphyrin [ZnPP, a heme oxygenase-1 (HO-1) inhibitor], and TMZ + KC7F2 [a hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor]. All groups except the control group received angiotensin II to induce HN models. TMZ was administered by gavage for 28 days, while the other TMZ-based groups received additional si-PHD2, ZnPP, or KC7F2. Blood pressure, renal function, proinflammatory cytokines, and kidney pathology were measured. Protein/mRNA levels of PHD2, HO-1, HIF-1α, and Collagen I were analyzed via reverse transcription quantitative polymerase chain reaction/Western blot. Results The model group showed increased blood pressure, renal injury, fibrosis, and elevated levels of PHD2, HIF-1α, HO-1, Collagen I, and inflammatory markers compared to the control group (P < 0.05). TMZ treatment alleviated renal damage and downregulated PHD2, while upregulating HIF-1α and HO-1. These effects were further enhanced by PHD2 knockdown (TMZ + si-PHD2), but reversed by the inhibition of HO-1 or HIF-1α (TMZ + ZnPP, TMZ + KC7F2). Conclusion TMZ improves HN in mice by modulating the PHD2/HIF-1α/HO-1 pathway.

Trimetazidine increase glutathione peroxidase and limits membrane damage caused by reactive oxygen species (ROS). It also has cytoprotective effect and limits the production of trimethylamine N-Oxide (TMAO) and provides the renoprotective effect. This study was designed to evaluate the renoprotective effect of trimetazidine (TMZ) in an experimental model of streptozotocin (STZ induced diabetic nephropathy in rats. For this experimental study sixty-six rats (66) were divided into eight groups. Group I (C1) and group II (C2) were normal healthy rat groups and sacrificed on 22nd day. Three groups of rats were induced diabetic nephropathy by streptozotocin (STZ) single intraperitonial administration at a dose of 50mg/kg body weight. Biochemical indices like serum blood sugar and the status of oxidative stress was assessed by renal cortical glutathione (GSH) levels. In streptozotocin treated groups, renal glutathione was significantly (p<0.01) lower when compared to control. In TMZ treated group, whereas renal glutathione was significantly (p<0.01) higher when compared with STZ induced nephropathy groups of rats. It may be assumed from this study that trimetazidine has nephroprotective effects because of its special antioxidant effects, which can delay the onset, severity and progression of nephropathy induced by streptozotocin in rats. Therefore, trimetazidine may be extensively studied in human with diabetic nephropathy for confirmation of its nephro-protective effects.

Metabolic dysregulation in the heart plays a critical role in the pathogenesis of atrial fibrillation (AF), yet the underlying molecular mechanisms remain unclear. Loss-of-function variants in the zinc finger homeobox 3 gene (ZFHX3) increase AF risk by promoting structural and electrical remodeling. However, the role of ZFHX3 knockdown (KD) in cardiac metabolism has not been fully elucidated. This study investigated the impact of ZFHX3 KD on energy metabolism in atrial myocytes and assessed the therapeutic potential of trimetazidine (TMZ). Seahorse XFe24 extracellular flux analysis, bioluminescent assays, microplate enzyme activity assays, and Western blotting were used to study energy substrate (glucose and fatty acid) oxidation stress, intracellular lactate content, glucose uptake, pyruvate dehydrogenase (PDH) activity, and regulatory protein expression in control and ZFHX3 KD HL-1 cells with or without TMZ (10 μM) treatment. ZFHX3 KD cells exhibited a higher acute response in oxygen consumption after Etomoxir injection, upregulated CD36 and phosphorylated ACC expression, increased glucose uptake and lactate production, reduced PDH activity, and higher levels of PDK4 and LDHA. Furthermore, ZFHX3 KD cells showed mitochondrial Ca2+ overload and increased phosphorylated PDH and oxidized CaMKII proteins, all of which were significantly attenuated by TMZ. Additionally, TMZ improved mitochondrial dysfunction in ZFHX3 KD cells by decreasing basal and maximal respiration, spare capacity, and proton leak. These findings suggest that ZFHX3 downregulation shifts substrate preference toward fatty acid utilization at the expense of glucose oxidation, contributing to metabolic and mitochondrial calcium dysregulation. TMZ mitigates these effects, highlighting its therapeutic potential in AF associated with ZFHX3 deficiency.

Yangxinshi tablet protects against myocardial injury and increases skeletal muscle exercise capacity by regulating mitochondrial bioenergetics.