Inhibitory effects of trimetazidine dihydrochloride on aggregation, serotonin release and malondialdehyde production in rabbit platelets.

Shirahase, Hiroaki; Suzuki, Yukiko; Osumi, Seimei; Kakeya, Nobuharu; Kurahashi, Kazuyoshi

doi:10.1254/jjp.47.29

Cited by 10 publications

(6 citation statements)

References 9 publications

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“…Finally, since it has been reported in recent years that trimetazidine decreases adhesiveness and aggregation of platelets in humans (28), a study was performed on rabbit platelets to characterize this "antiplatelet" action of trimetazidine (29). The results suggested that trimetazidine might attenuate platelet aggregation and serotonin release by inhibiting thromboxane A2 production from endogenous arachidonic acid.…”

Section: Other Pharmacological Effects Of Trimetazidinementioning

confidence: 96%

Trimetazidine, A Cellular Anti‐ischemic Agent

Harpey

Clauser

Labrid

et al. 1988

Cardiovascular Drug Reviews

109

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Trimetazidine (S 50 16), a molecule developed by the Servier Research Institute, is a cellular anti-ischemic agent. Its chemical name is I -(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride (Fig. I ). Initial pharmacological studies have indicated that trimetazidine prevents cellular changes associated with ischemia or hypoxia, but it has no effect under normoxic conditions ( I ,2).Trimetazidine is freely soluble in water (80%), sparingly soluble in methanol, but insoluble in other organic solvents. Trimetazidine solution is slightly sensitive to light although substantially less than dihydropyridines. The molecular weight of tnmetazidine is, as a dihydrochloride, 339.27 and, in basic form, 266.34. The molecule has two pKa values (4.32 and 8.95) and the pH value of an aqueous solution (5 mg/ml) is 3; this aqueous solution is stable at room temperature. PHARMACOLOGY Effects on the Hypoxic Cell and on the Ischemic TissueIschemia is defined as a deficiency of blood supply in a given tissue, and consequently of oxygen supply to the cells. Ischemia results in a decrease of oxidative metabolism that is responsible for the various functional disorders observed in the cell: reduction in the production of energetic compounds, accumulation of protons, and increase in the generation of oxygen-derived free radicals. The aggression of oxygenderived free radicals towards living tissues is therefore superimposed on the energy disorders and added to the effects of acidosis, which severely alters cellular homeostasis and results in accumulation of calcium within the cell. This considerable excess of intracellular calcium blocks all vital enzymatic functions, leading to necrosis.Despite hypoxia or induced ischemia, trimetazidine maintains homeostasis and cellular functions and inhibits cytolysis. This activity has been evidenced in vivo, by Camilleri and Joseph (3), Fitoussi et al. (4), and Catroux et al. ( 5 ) , using different models of ischemia. After induction of left ventricular infarction in the rat by coro-

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Section: Other Pharmacological Effects Of Trimetazidinementioning

confidence: 96%

Trimetazidine, A Cellular Anti‐ischemic Agent

Harpey

Clauser

Labrid

et al. 1988

Cardiovascular Drug Reviews

109

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“… 35 , 36 Moreover, Shirahase et al found that the antianginal effects of trimetazidine may be related to inhibition of platelet aggregation and inhibition of 5-HT release. 37 Thus, if experimentation with trimetazidine can confer insight into how 5-HT and platelets are dysregulated in CHD and/or depression, and if trimetazidine can be shown to ameliorate these circumstances, then significant headway would be made toward understanding and treating this comorbidity. There has been some investigation into the comorbidity along these lines.…”

Section: Discussionmentioning

confidence: 99%

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

Wei¹,

Stone²,

Zhang³

et al. 2018

NDT

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

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“…But under ischemic conditions it reduces the myocardial intracellular acidosis, and indirectly limits the accumulation of Na + and Ca a+ [10,25]. TMZ significantly reduces free radical production [ 10,16], and decreases adhesiveness and aggregation of platelets [1,22]. This effect may be due to a blockade of the process preceding the cyclooxygenase pathway and related to the free-radical scavenger property of this compound.…”

Section: Discussionmentioning

confidence: 99%