Therapeutic potential of N-acetylcysteine as an antiplatelet agent in patients with type-2 diabetes

Abstract

BackgroundPlatelet hyperaggregability is a pro-thrombotic feature of type-2 diabetes, associated with low levels of the antioxidant glutathione (GSH). Clinical delivery of N-acetylcysteine (NAC), a biosynthetic precursor of GSH, may help redress a GSH shortfall in platelets, thereby reducing thrombotic risk in type-2 diabetes patients. We investigated the effect of NAC in vitro, at concentrations attainable with tolerable oral dosing, on platelet GSH concentrations and aggregation propensity in blood from patients with type-2 diabetes.MethodsBlood samples (n = 13) were incubated (2 h, 37°C) with NAC (10-100 micromolar) in vitro. Platelet aggregation in response to thrombin and ADP (whole blood aggregometry) was assessed, together with platelet GSH concentration (reduced and oxidized), antioxidant status, reactive oxygen species (ROS) generation, and plasma NOx (a surrogate measure of platelet-derived nitric oxide; NO).ResultsAt therapeutically relevant concentrations (10-100 micromolar), NAC increased intraplatelet GSH levels, enhanced the antioxidant effects of platelets, and reduced ROS generation in blood from type-2 diabetes patients. Critically, NAC inhibited thrombin- and ADP-induced platelet aggregation in vitro. Plasma NOx was enhanced by 30 micromolar NAC.ConclusionsOur results suggest that NAC reduces thrombotic propensity in type-2 diabetes patients by increasing platelet antioxidant status as a result of elevated GSH synthesis, thereby lowering platelet-derived ROS. This may increase bioavailability of protective NO in a narrow therapeutic range. Therefore, NAC might represent an alternative or additional therapy to aspirin that could reduce thrombotic risk in type-2 diabetes.

ROS scavenger, N‐acetyl‐l‐cysteine and NOX specific inhibitor, VAS2870 reduce platelets apoptosis while enhancing their viability during storage

“…15 Several lines of evidence have shown that NAC significantly reduces systemic platelet activation and thrombosis in diabetes, and it can inhibit thrombin-and adenosine diphosphate (ADP)-induced platelet aggregation as well as agonist-induced ectodomain shedding of glycoprotein Ibα (GPIbα) in vitro. 16,17 Given that NAC can act as a safe ROS scavenger, this study examined its effects on the platelet survival and apoptosis during storage of platelet concentrates. Considering NAC as a general scavenger of ROS generated by different sources, to specifically determine the effect of NOX-generated ROS on platelets, we also applied VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) as a specific inhibitor of these enzymes (mainly NOX1 and NOX2).…”

Thioredoxins, Glutaredoxins, and Peroxiredoxins—Molecular Mechanisms and Health Significance: from Cofactors to Antioxidants to Redox Signaling

“…In diabetes patients, the GSH synthesis itself did not seem to be impaired; however, a lack of the GSH precursors cysteine and glycine was detected. Dietary supplementation of these amino acids or N-acetylcysteine restored GSH synthesis in platelets of diabetic patients and decreased ROS levels and, accordingly, oxidative modifications (228,692). The expression of GR is especially high in islets and inhibition of the enzyme sensitizes b-cells to streptozotocin-induced diabetes (533).…”

ROS Promote Ox-LDL-Induced Platelet Activation by Up-Regulating Autophagy Through the Inhibition of the PI3K/AKT/mTOR Pathway

“…Cellular Physiology and Biochemistry hyperaggregability in patients with type-2 diabetes [22]. Meanwhile, 3-methyladenine (3-MA), a classic autophagy inhibitor, blocks autophagosome formation by inhibiting type III phosphatidylinositol 3-kinases in platelets [23], and the specific mTOR inhibitor, rapamycin, the most frequently used trigger of autophagy, has been used to inhibit mammalian target of rapamycin (mTOR) function in platelets [24].…”