The effect of the nitroxide pirolin on oxidative stress induced by doxorubicin and taxanes in the rat brain.

The anticancer drugs doxorubicin (DOX), paclitaxel (PTX) and docetaxel (DTX) have been proven to induce oxidative stress (OS)-dependent side-effects in non-targeted tissues. In normal conditions, the blood-brain barrier (BBB) prevents these drugs from penetrating into the brain. However, some studies have demonstrated that small amounts of DOX can penetrate the brain via an oxidatively impaired BBB and cause damage, which suggests that including antioxidants in chemotherapy could possibly protect the brain against the toxicity of anticancer drugs. We investigated whether DOX, DTX and PTX can induce oxidative damage in rat brains in vivo and whether inclusion of the nitroxyl antioxidant Pirolin (PL) to DOX/taxane chemotherapy can protect the brain from the OS toxicity of these drugs. Wistar rats received i.p. a single dose (10 mg/kg b.w.) of DOX, DTX, PTX or PL alone or a combination of a drug + PL. After four days, the rats were anesthetized, the brains were excised, homogenized and used for the measurements of lipid peroxidation (LPO), thiol groups, activities of antioxidant enzymes, DNA damage and tumor necrosis factor-α (TNF-α), neuronal nitric oxide synthase (nNOS) and poly (ADP-ribose) polymerase-1 (PARP-1) expression. The results were analyzed using the Kruskal-Wallis and Conover-Inman tests or ANOVA and the Tukey-Kramer test. Doxorubicin, PTX and DTX induced OS, DNA damage and changes in expression of TNF-α, nNOS and PARP-1 in the rat brain. Pirolin alone increased LPO, manganese superoxide dismutase (MnSOD) and catalase (CAT) activities and the expression of PARP-1 but decreased TNF-α expression. PL, in combination with anticancer drugs, partially protected the rat brain against the toxic effects of DOX and taxanes. The best protective effects of PL were obtained with PTX. Pirolin partially attenuated brain damage caused by DOX/taxanes, highlighting its potential application in protecting the brain against DOX-, DTX- and PTX-evoked OS.