Neurosci Lett. 2001 Apr 20;302(2-3):121-4.
Nitro-aspirin (NCX4016) reduces brain damage induced by focal cerebral ischemia in the rat.
Fredduzzi S, Mariucci G, Tantucci M, Del Soldato P, Ambrosini MV. Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione di Biologia Sperimentale, Via del Giochetto, 06124, Perugia, Italy.
The potential neuroprotective effects of the novel nitro-derivate of aspirin (NCX4016) on permanent focal cerebral ischemia in spontaneously hypertensive rats (SHRs) was investigated. Reference compounds were acetylsalicilic acid (ASA) and FK506 (tacrolimus). Ten minutes after surgery, SHRs were randomly divided into four groups of ten, pharmacologically treated and sacrificed 24 h after treatment. Brains were removed and processed to measure infarct volume, 70 kDa heat shock protein (hsp70), glial fibrillary acidic protein (GFAP) and vimentin (Vim) immunoreactivity (IR), and apoptosis using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end-labeling (TUNEL) assay. NCX-4016 significantly reduced total infarct volume compared to ASA (-20%, P < 0.05), FK506 (-18%, P < 0.05) and vehicle treatment (-20%, P < 0.05). Experimental groups did not differ in hsp70-IR and GFAP-IR. Conversely, hyperplastic astrocytes, measured by Vim-IR, were significantly lower in NCX-4016 than in the vehicle group (-36%, P<0.01). TUNEL assay indicated a significantly lower degree of apoptosis in NCX-4016 group than vehicle in both the homolateral (-27%, P < 0.01) and contralateral hemisphere (-29%, P < 0.05). These findings indicate that NO release associated with aspirin confers neuroprotective effects against ischemic injury.
J Pharmacol Exp Ther. 2001 Apr;297(1):380-7.
The nitroderivative of aspirin, NCX 4016, reduces infarct size caused by myocardial ischemia-reperfusion in the anesthetized rat.
Rossoni G, Manfredi B, Colonna VD, Bernareggi M, Berti F. Department of Pharmacological Sciences, Chemotherapy and Medical Toxicology, University of Milan, Via Vanelli 32, 20129 Milan, Italy.
NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic ventricular dysfunction and to reduce myocardial infarct size in the rabbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) and aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Drugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachycardia and fibrillation; they were reduced dose dependently and correlated with survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardiac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arrhythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by L-NAME. The beneficial effects of NCX 4016 appear to derive in large part from the NO moiety, which modulates a number of cellular events leading to inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis.
