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  • Title: Time-course correlation of early toxic events in three models of striatal damage: modulation by proteases inhibition.
    Author: Pérez-De La Cruz V, Elinos-Calderón D, Carrillo-Mora P, Silva-Adaya D, Konigsberg M, Morán J, Ali SF, Chánez-Cárdenas ME, Pérez-De La Cruz G, Santamaría A.
    Journal: Neurochem Int; 2010; 56(6-7):834-42. PubMed ID: 20332007.
    Abstract:
    Metabolic alterations in the nervous system can be produced at early stages of toxicity and are linked with oxidative stress, energy depletion and death signaling. Proteases activation is responsible for triggering deadly cascades during cell damage in toxic models. In this study we evaluated the early time-course of toxic events (oxidative damage to lipids, mitochondrial dysfunction and LDH leakage, all at 1, 3 and 6h) in rat striatal slices exposed to quinolinic acid (QUIN, 100 microM) as an excitotoxic/pro-oxidant model, 3-nitropropionic acid (3-NP, 1mM) as an inhibitor of mitochondrial succinate dehydrogenase, and a combined model produced by the co-administration of these two toxins at subtoxic concentrations (21 and 166 microM for QUIN and 3-NP, respectively). In order to further characterize a possible causality of caspases or calpains on the toxic mechanisms produced in these models, the broad calpain inhibitor IC1 (50 microM), and the pan-caspase inhibitor Z-VAD (100 microM) were tested. Lipid peroxidation (LP) was increased at all times and in all models evaluated. Both IC1 and Z-VAD exerted significant protection against LP in all models and at all times evaluated. Mitochondrial dysfunction (MD) was consistently affected by all toxic models at 3 and 6h, but was mostly affected by 3-NP and QUIN at 1h. IC1 differentially protected the slices against 3-NP and QUIN at 1h and against QUIN at 3h, while Z-VAD exhibited positive actions against QUIN and 3-NP at all times tested, and against their combination at 3 and 6h. LDH leakage was enhanced at 1 and 3h in all toxic models, but this effect was evident only for 3-NP + QUIN and 3-NP at 6h. IC1 protected against LDH leakage at 1h in 3-NP + QUIN and 3-NP models, at 3h in all toxic models, and at 6h in 3-NP + QUIN and 3-NP models. In turn, Z-VAD protected at 1 and 6h in all models tested, and at 3h in the combined and QUIN models. Our results suggest differential chronologic and mechanistic patterns, depending on the toxic insult. Although LP, MD and membrane cell rupture are shared by the three models, the occurrence of each event seems to obey to a selective recruitment of damaging signals, including a differential activation of proteases in time. Proteases activation is likely to be an up-stream event influencing oxidative stress and mitochondrial dysfunction in these toxic models.
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