title: Protective effect of triflusal and its main metabolite HTB in an in vitro model of anoxia-reoxygenation in rat brain slices: comparison with acetylsalicylic and salicylic acids.
abstract: Triflusal is a fluorinated derivative of acetylsalicylic acid (ASA) with demonstrated antithrombotic activity. Recently, evidence for a neuroprotective effect has been obtained. The aim of this study was to compare the neuroprotective effects of the main metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid, HTB) and the ASA metabolite salicylic acid (SA) in an in vitro model of anoxia-reoxygenation in rat brain slices. Rat brain slices (n=10 per group) were subjected to a period of anoxia followed by 180 min reoxygenation. We measured oxidative stress parameters (lipid peroxidation, glutathione system), prostaglandins (PGE(2)), nitric oxide pathway activity (NO) (nitrites+nitrates, constitutive and inducible NO synthase activity) and LDH efflux, a biochemical marker of cell death. Various concentrations (10, 100 and 1,000 microM) of triflusal, HTB, ASA or SA were tested. Triflusal at 10, 100 and 1,000 microM decreased LDH efflux in rat brain slices after anoxia/reoxygenation by 24%, 35% and 49% respectively. This effect was proportionately greater than that of ASA (0%, 13% and 32%). The results with HTB were similar to those with triflusal, whereas SA showed a greater protective effect than ASA (13%, 33% and 35%). The antioxidant effects of HTB and SA on the biochemical mechanisms of cell damage studied here were also greater than the effects of triflusal and ASA, a finding attributable mainly to the decrease in lipid peroxidation and to the ability of HTB to also increase glutathione levels. The triflusal metabolite reduced inducible NO synthase activity by 18%, 21% and 30%, whereas SA inhibited this activity by 9%, 17% and 23%. Triflusal and HTB led to greater increases in NO synthase than ASA or AS. In conclusion, the metabolite HTB plays an important role in the neuroprotective effect of triflusal, at least in the experimental model of anoxia-reoxygenation tested here.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Málaga, Campus de Teatinos s/n, 29071 Málaga, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: González-Correa
authors.forename: M M
authors.initials: MM
authors.lastname: Arrebola
authors.forename: I M
authors.initials: IM
authors.lastname: Ureña
authors.forename: D
authors.initials: D
authors.lastname: Ruiz-Villafranca
authors.forename: J
authors.initials: J
authors.lastname: Muñoz-Marín
authors.forename: A
authors.initials: A
authors.lastname: Guerrero
authors.forename: F
authors.initials: F
authors.lastname: Sánchez de la Cuesta
authors.forename: J P
authors.initials: JP
authors.lastname: De La Cruz
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D002534:Hypoxia, Brain / Q000517:prevention & control*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control; D012459:Salicylates / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010975:Platelet Aggregation Inhibitors; D012459:Salicylates; D017392:Thiobarbituric Acid Reactive Substances; C016167:triflusal; C033502:4-trifluoromethylsalicylic acid; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D005978:Glutathione; D015232:Dinoprostone; D001241:Aspirin