ABSTRACT
PURPOSE: The aim of this study was to create and assess biological activity of a new compound based on carnosine and acetylsalicylic acid (ASA) that will comprise antioxidant effect with antiplatelet activity, while simultaneously preventing side effects on the gastrointestinal tract. METHODS: Salicyl-carnosine (SC) was synthesized by condensation of ASA and carnosine. Antioxidant activity was determined by spectrophotometric and chemiluminescence methods. Antiplatelet activity was carried out by the light transmission-aggregometry method using the inductor ADP. Chronic gastric ulcer in rats was modeled using glacial acetic acid. RESULTS: Using SOD-like activity, iron-induced chemiluminescence, BaSO4-activated respiratory burst, and evaluation of red blood cell structure stabilization during oxidative damage induced by sodium hypochlorite, it was shown that SC possesses antioxidant activity analogous, or better, than that of carnosine. Antiplatelet activity of SC was evaluated in the blood of healthy individuals, and was also shown to be comparable to, or exceeding that of ASA. Also SC demonstrates high resistance to hydrolysis by tissue and serum carnosinases. Most importantly, it was shown that SC has protected the gastric mucosa against the formation of stomach ulcerative lesions and promoted their epithelization, therefore overcoming the undesirable inherent side effects of ASA. CONCLUSIONS: SC preserves pharmacologically significant properties of ASA and carnosine while retaining an anti-ulcer activity and resistance to the carnosinase hydrolysis at the same time. These properties are particularly promising for the potential development of new anti-inflammatory and antithrombotic drugs. Graphical abstract .
Subject(s)
Anti-Ulcer Agents , Antioxidants , Aspirin , Carnosine , Platelet Aggregation Inhibitors , Acetic Acid , Animals , Anti-Ulcer Agents/chemistry , Anti-Ulcer Agents/pharmacology , Anti-Ulcer Agents/therapeutic use , Antioxidants/chemistry , Antioxidants/pharmacology , Antioxidants/therapeutic use , Aspirin/analogs & derivatives , Aspirin/chemistry , Aspirin/pharmacology , Aspirin/therapeutic use , Carnosine/analogs & derivatives , Carnosine/chemistry , Carnosine/pharmacology , Carnosine/therapeutic use , Erythrocytes/drug effects , Hemolysis/drug effects , Humans , Hydrolysis , Leukocytes/drug effects , Male , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Rats, Wistar , Respiratory Burst/drug effects , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapy , Superoxides/chemistryABSTRACT
An antidiabetic drug of the thiazolidinedione class, rosiglitazone (RG) demonstrates anti-inflammatory properties in various brain pathologies. The mechanism of RG action in brain cells is not fully known. To unravel mechanisms of RG modulation of toll-like receptor (TLR) signaling pathways, we compare primary rat neuron and astrocyte cultures stimulated with the TLR4 agonist lipopolysaccharide (LPS) and the TLR3 agonist poly I:C (PIC). Both TLR agonists induced tumor necrosis factor (TNFα) release in astrocytes, but not in neurons. Neurons and astrocytes released interleukin-10 (IL-10) and prostaglandin E2 (PGE2) in response to LPS and PIC. RG decreased TLR-stimulated TNFα release in astrocytes as well as potentiated IL-10 and PGE2 release in both astrocytes and neurons. RG induced phosphorylation of p38 and JNK MAPK (mitogen-activated protein kinase) in neurons. The results reveal new role of RG as a modulator of resolution of neuroinflammation.