Trimetazidine is a well-known anti-anginal drug that exerts its effect by converting the
cell's metabolism from fatty acid oxidation to glucose oxidation. This is contrary to
what occurs during a stroke event, in which the cell's metabolism is shifted to fatty
acid metabolism. It also improves the activity of pyruvate dehydrogenase, the enzyme that
allows the entry of pyruvate from the cytosol into the mitochondria for subsequent
oxidation in the Krebs cycle. Therefore, attenuating lactic acid production, controlling
intracellular acidosis and calcium ion overload, thus conserving valuable ATP stores to
meet energy requirements and preventing the occurrence of further ischemia. Clinical
reports indicate that trimetazidine restores energy homeostasis and attenuates free
radical generation to exhibit benefits in ischemia and angina pectoris.
An increasing number of studies have focused on the effect of Trimetazidine on myocardial
I/R injury, and some studies have proposed possible hypotheses. Trimetazidine protects
against myocardial I/R injury and is presumed to be related to autophagy, apoptosis, and
oxidative stress, which are all pathways in stroke.
An in vitro study proving the role of Trimetazidine in apoptosis found that trimetazidine
protected muscle cells against starvation or inflammation-induced atrophy by inhibiting
protein degradation and inducing autophagy. It has recently been shown to ameliorate
lipopolysaccharide (LPS)-induced cardiomyocyte pyroptosis: which plays an important role
in the development of muscle atrophy by promoting neutrophil migration to cardiac tissue.
It was shown that Trimetazidine mitigated the mRNA expression of pyroptosis-related
molecules, including NLRP3, Caspase-1, and GSDMD.25 In another in vitro study, it was
found that TMZ reduced the myocardial infarct size and decreased the expression of TLR4,
MyD88, phospho-NF-κB p65, and the NLRP3 inflammasome.
Furthermore, a study assessing the effect of TMZ on cerebral I/R injury proved that it
reduced infarct volume compared with the vehicle-treated reperfused animals and
significantly decreased the percentage of brain swelling in the TMZ-treated groups.
Trimetazidine in a clinical study added to the standard of care with or without
interventional and/or surgical reperfusion reduced oxidative stress, endothelial
dysfunction, inflammation, and major acute cardiovascular events, whereas, in patients
with chronic coronary syndrome, TMZ decreased oxidative stress and readmission for ACS
and heart failure.
Moreover, there is a recent clinical trial that has proven that Trimetazidine
significantly reduced the serum levels of interleukin - 18 in patients with acute viral
myocarditis compared to the control group.
This makes it possible to detect the severity of the stroke event by measuring the serum
levels of interleukin - 18. It is a pro-inflammatory cytokine, that is encoded by the
IL-18 gene in humans. It is likely to be the first line of immune defense for the brain,
primarily secreted by macrophage cells and mononuclear cells in humans. It is initially
expressed as the inactive precursor pro-IL-18. It is then converted into an active form
by proteolytic cleavage, mainly by the cysteine protease caspase-1, which is also known
as IL-1B converting enzyme (ICE).
Some researchers have proposed the hypothesis that a pro-inflammatory profile induced by
increased IL-18 levels creates a prothrombotic and pro-atherosclerotic environment, which
may eventually contribute to stroke in older people. These results are consistent with
the results of a meta-analysis study which proved that there is a significant association
between IL-18 level and NIHSS scores that makes it a strong tool for reflecting the
severity of stroke and for predicting the prognosis.