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Glutaric acidaemia type I (GA-I) is a cerebral organic disorder characterized by the accumulation of glutaric acid (GA) and seizures. As seizures are precipitated in children with GA-I and the mechanisms underlying this disorder are not well established, we decided to investigate the role of nitric oxide (NO) in GA-induced convulsive behaviour in pup rats. Pup male Wistar rats (18-day-old) were anesthetized and placed in stereotaxic apparatus for cannula insertion into the striatum for injection of GA. The experiments were performed 3 days after surgery (pup rats 21-day-old). An inhibitor of NO synthesis (N-G-nitro-l-arginine methyl ester-L-NAME, 40 mg/kg) or saline (vehicle) was administered intraperitoneally 30 min before the intrastriatal injection of GA (1 µl, 1.3 µmol/striatum) or saline. Immediately after the intrastriatal injections, the latency and duration of seizures were recorded for 20 min. The administration of L-NAME significantly increased the latency to the first seizure episode and reduced the duration of seizures induced by GA in pup rats. The administration of the NO precursor l-arginine (L-ARG; 80 mg/kg) prevented the effects of L-NAME. Besides, GA significantly increased nitrate and nitrite (NOx) levels in the striatum of pup rats and the preadministration of L-NAME prevented this alteration. L-ARG blocked the reduction of striatal NOx provoked by L-NAME. These results are experimental evidence that NO plays a role in the seizures induced by GA in pup rats, being valuable in understanding the physiopathology of neurological signs observed in children with this organic acidaemia and to develop new therapeutic strategies.

Some brain diseases are associated with oxidative stress and altered monoamine oxidase (MAO) activity. The objective of this study was to evaluate the antioxidant and neuroprotective actions through MAO inhibition of 3-(pyridin-2-yl)-2-(pyridine-2-ylimino) thiazolidin-4-one (PPIT, a synthetic molecule containing a thiazolidinone nucleus), as well as its effects on toxicity parameters in Swiss female mice. Five in vitro assays were carried out to verify the PPIT antioxidant capacity: protein carbonylation (PC), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picryl-hydrazil (DPPH), ferric ion (Fe3+ ) reducing antioxidant power (FRAP), and superoxide dismutase (SOD)-like activity. The results showed that PPIT reduced the level of PC in the homogenate of the brain. This compound did not demonstrate SOD mimetic activity, but it acted as a free radical scavenger (ABTS and DPPH) and exhibited reducing activity in the FRAP assay. In addition, the effects of PPIT on cerebral MAO activity (MAO-A and B isoforms) were investigated in vitro. Our data revealed inhibition of the MAO-B activity by PPIT with no effects on MAO-A. Lastly, an acute oral toxicity test was conducted in mice. No changes in food intake, body weight, and biochemical markers of kidney and liver damage were detected in mice treated with a high dose of PPIT (300 mg/kg). In conclusion, the present study demonstrated that PPIT exhibits antioxidant activity and selectively inhibits the MAO-B isoform without causing apparent toxicity. These findings suggest PPIT as a potential therapeutic candidate to be tested in preclinical models of brain diseases involving perturbations of MAO-B activity and redox status.

The present study investigated the protective role of antioxidant (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD), an organoselenium compound, against the renal injury induced by cisplatin in rats. Canola oil or BPD (50mgkg 1 ) was administered orally by gavage once a day for 6days to rats. The first dose of BPD was given 24h before a single intraperitoneal injection of saline or cisplatin (7mgkg 1 ). At day 7, animals were killed and parameters related to renal injury were determined. The histological analysis showed that cisplatin caused renal injury in rats, which was accompanied by an increase in urea and creatinine levels in plasma. The increase of plasma creatinine levels negatively correlated with renal antioxidant defenses including ascorbic acid (AA) and reduced glutathione (GSH) content as well as glutathione S-transferase (GST), glutathione peroxidase (GPx) and catalase (CAT) activities. As revealed by histological analysis, BPD ameliorated tubular injury in rat kidney and reduced plasma markers altered by cisplatin. The administration of BPD to rats attenuated the reduction of renal AA and GSH content in animals exposed to cisplatin. The decrease of GST activity, but not GPx and CAT activities, in rats exposed to cisplatin was totally reversed by BPD administration. BPD was also effective in attenuating the inhibition of a sulfhydryl enzyme sensitive to oxidative stress, d-aminolevulinic dehydratase, in kidneys of rats exposed to cisplatin. The present study demonstrated that BPD reduced renal injury induced by cisplatin in rats and this effect seems to be related to antioxidant mechanisms. Copyright © 2012 John Wiley &S ons, Ltd.

Peroxisome proliferator-activated receptor-g (PPAR-g) agonists not only improve metabolic abnormalities ofdiabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimentalmodels. Here, we investigated the effect of PPAR-g agonist pioglitazone against acute renal injury on a cisplatin modelin mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10mgkg –1 ). Pioglitazone wasadministered for six consecutive days in doses of 15 or 30mgkg –1 day –1 , per os (p.o.), starting 3days before cisplatin injection.Cisplatintreatmenttomiceinducedamarkedrenalfailure,characterizedbyasignificantincreaseinserumureaandcreatininelevels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levelsof non-enzymatic antioxidant defenses [glutathione (GSH) and as corbic acid levels] and components of the enzymatic antioxidantdefenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and andglutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against theincrease in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazoneadministration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protectedagainst the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These resultsindicated that pioglitazone has a protective effectagainstcisplatin-inducedrenal damagein mice.The protection ismediatedby preventing the decline of antioxidant status. The results have implications in use of PPAR-g agonists in human applicationfor protecting against drugs-induced nephrotoxicity. Copyright © 2012 John Wiley & Sons, Ltd.Keywords: peroxisome proliferator-activated receptor-g; pioglitazone; cisplatin; nephrotoxicity; mice

Organoselenium compounds have important pharmacological properties. However, these compounds can cause toxicity, typically related to oxidation of endogenous thiols. The aim of this study was to investigate whether 2,2′-dithienyl diselenide (DTDS) has potential toxicity in vitro and in vivo. Therefore, sulfhydryl-containing enzyme activities, δ-aminolevulinic acid dehydratase (δ-ALA-D) and Na+–K+-ATPase were used to predict DTDS toxicity in rat brain homogenate in vitro. In in vivo experiments, a DTDS administration (50 or 100 mg kg−1, p.o.) to rats was performed and toxicological parameters were determined. DTDS inhibited δ-ALA-D (IC50 2 µm) and Na+–K+-ATPase (IC50 17 µm) activities in vitro. The inhibitory effect of DTDS on δ-ALA-D and Na+–K+-ATPase activities was restored by dithiothreitol. DTDS (5–25 µm) elicited a thiol oxidase-like activity. In vivo, DTDS (50 and 100 mg kg−1) caused systemic toxicity, evidenced by a decrease in water and food intakes and body weight gain, as well as the death of rats. DTDS at the dose of 100 mg kg−1 increased plasma alanine and aspartate aminotransferase activities and decreased urea levels. At 50 and 100 mg kg−1, it increased lipid peroxidation levels. At the highest dose, DTDS inhibited δ-ALA-D activity. By contrast, Na+–K+-ATPase activity and antioxidant defense were not altered in the brains of rats exposed to DTDS. In conclusion, interaction with the cisteinyl residues seems to mediate the inhibitory effect of DTDS on sulfhydryl-containing enzymes in vitro. In addition, high oral doses of DTDS induce toxicity in rats. Copyright © 2011 John Wiley & Sons, Ltd.

The aim of this study was to investigate the effect of SCH 58261, a selective adenosine A(2A) receptor (A(2A)R) antagonist, on kainic acid (KA)-induced seizures in 21-day-old rats. Rats were pretreated with SCH 58261 (1 or 3 mg/kg) by intraperitoneal (i.p.) route 30 min before KA (10 mg/kg, i.p.) administration. The appearance of clonic seizures, the latency for the onset of the first clonic seizure episode, and the number of deaths induced by KA were evaluated. To test the hypothesis of the oxidative imbalance induced by KA exposure, reactive species (RS) levels, catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) activities in the brains of rats were measured. Both doses of SCH 58261 prolonged the latency for the onset of the first clonic seizure episode. SCH 58261, at the highest dose, decreased the appearance of clonic seizures as well as the mortality rate induced by KA administration. SCH 58261, at the dose of 3 mg/kg, was also effective in protecting against alterations in oxidative stress parameters (RS levels, CAT, GPx, and GST activities) in the brains of young rats exposed to KA. Our data reveal that SCH 58261 was protective against the neurotoxicity induced by KA. Therefore, the blockade of A(2A)R might represent a novel approach for the treatment of seizures.

The in vitro effect of (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) was evaluated through iron/EDTA-induced thiobarbituric acid reactive species (TBARS) and reactive species (RS) determinations as well as of the scavenging 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical quantification. BPD at the concentrations of 10 and 50 μΜ decreased RS and TBARS levels, respectively. The antioxidant activity was not related to the scavenging DPPH radical mechanism. A second objective of this study was to investigate the hepatoprotective action of BPD, administered by oral route, against oxidative damage induced by 2-nitropropane (2-NP) (100 mg/kg of body weight) in liver of rats. At the dose of 50 mg/kg, BPD protected against the increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities induced by 2-NP. BPD (10 and 50 mg/kg) protected against the increase in TBARS levels and alkaline phosphatase (ALP) activity. Sections of liver from 2-NP-exposed rats presented intense infiltration of inflammatory cells and loss of cellular architecture. BPD (10 and 50 mg/kg) attenuated 2-NP-induced hepatic histological alterations. The inhibition of δ-aminolevulinic dehydratase (δ-ALA-D), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) activities and the decreased GSH levels caused by 2-NP were protected by BPD (50 mg/kg). Catalase activity and ascorbic acid levels were not altered by 2-NP. These results demonstrated the antioxidant and hepatoprotective effects of BPD in liver of rats.

This study was designed to investigate the influence of 2-methyl-6-phenylethynyl pyridine hydrochloride (MPEP), an antagonist of metabotropic glutamate receptor subtype 5, in lipopolysaccharide (LPS) and d-galactosamine (d-GalN)-induced fulminant hepatic failure in mice. Mice were given an intraperitoneal injection of 50 µg kg−1 LPS and 500 mg kg−1d-GalN. MPEP (1, 5 and 25 mg kg−1) was administered intraperitoneally 1 h before LPS/d-GalN injection. Twenty-four hours after administration of LPS/d-GalN, plasma was collected and used for biochemical assays. Mice were euthanized and histological analysis and toxicological parameters were carried out in the liver. MPEP, at all doses tested, protected against the increase in aspartate and alanine aminotransferase activities induced by LPS/d-GalN exposure. Ascorbic acid levels were not altered in all experimental groups. Glutathione S-transferase activity was increased by administration of LPS/d-GalN and MPEP did not modify the enzyme activity in mice. MPEP, at the doses of 5 and 25 mg kg−1, was effective in protecting against the decrease in catalase activity caused by LPS/d-GalN administration in mice. The histological data showed that sections of liver from LPS/d-GalN-exposed mice presented extensive injuries. MPEP, at all doses tested, reduced the scores of liver damage and markedly ameliorated the degree of liver damage. The hepatoprotective effect of MPEP on fulminant hepatic failure induced by LPS and d-GalN in mice was demonstrated. Copyright © 2009 John Wiley & Sons, Ltd.

The presented synthesis of the title compounds (IV) and (VII) via Sonogashira cross-coupling reaction proceeds cleanly under mild conditions.