Pietro M. Chagas

2,2′-dithienyl diselenide, an organoselenium compound, elicits antioxidant action and inhibits monoamine oxidase activity in vitro

Context: Organoselenium compounds have been described as antioxidant and neuroprotective agents. Objective: To evaluate the antioxidant action of 2,2′-dithienyl diselenide (DTDS) and its effects in brain monoamine oxidase (MAO) activity in vitro. Materials and methods: Assays for reactive species (RS), lipid peroxidation, protein oxidation, MAO A and B activities in rat brain homogenate as well as mimetic dehydroascorbate reductase and glutathione S-transferase activities were performed using DTDS (μM range). Results: DTDS was effective in decreasing the levels of RS as well as lipid peroxidation induced by malonate, sodium nitroprusside or FeCl2/EDTA and protein carbonyl in the rat brain homogenate. DTDS elicited dehydroascorbate reductase-like and glutathione S-transferase-like activities. DTDS was effective in inhibiting both MAO-A and MAO-B activities. Discussion: The results demonstrated that DTDS is an antioxidant agent with non-selective inhibitory effect on MAO activity. Conclusion: DTDS is a promising molecule to be evaluated in experimental models of neurological diseases.

Evaluation of the pharmacological properties of salicylic acid-derivative organoselenium: 2-Hydroxy-5-selenocyanatobenzoic acid as an anti-inflammatory and antinociceptive compound☆☆☆

The present study evaluated the antinociceptive and anti-inflammatory effects of per oral (p.o.) administration of salicylic acid-derivative organoselenium compounds in chemical models of nociception in mice. The compounds (50 mg/kg; p.o.) were administered 30 and 60 min before the nociceptive behavior and compared to the positive-control, acetylsalicylic acid (ASA; 200 mg/kg; p.o.). In addition, a dose-response curve (25-100 mg/kg) for compounds was carried out in the formalin test. When assessed in the chemical models, acetic acid-induced writhing behavior, formalin and glutamate tests, the compounds showed the following antinociceptive profile 1B>2B>1A>2A, suggesting a chemical structure-dependent relationship. Then, the anti-inflammatory properties and toxicological potential of compound 1B were investigated. Compound 1B, similar to the positive-control, ASA, diminished the edema formation and decreased the myeloperoxidase activity induced by croton oil (2.5%) in the ear tissue. The results also indicate that a single oral administration of 1B caused neither signs of acute toxicity nor those of gastrointestinal injury. The administration of 1B did not alter the water and food intakes, plasma alanine and aspartate aminotransferase activities or urea levels and cerebral or hepatic δ-aminolevulinate dehydratase activity. Salicylic acid-derivative organoseleniums, mainly compound 1B, have been found to be novel compounds with antinociceptive/anti-inflammatory properties; nevertheless, more studies are required to examine their therapeutic potential for pain treatment.

Bis(phenylimidazoselenazolyl) diselenide: a compound with antinociceptive properties in mice.

The present study examined the effect of peroral administration of bis(phenylimidazoselenazolyl) diselenide (BPIS) in thermal and chemical models of pain in mice. The involvement of the opioid system in the BPIS antinociceptive effect was also examined, as well as potential nonspecific disturbances in locomotor activity or signs of acute toxicity. BPIS (25–100 mg/kg) induced an increase in tail-immersion response latency and this effect was significant at pretreatment times of 15 min to 4 h, but not at 8 h. The hot-plate response latency was also increased by the administration of BPIS (25–100 mg/kg). BPIS, at doses of 25 and 50 mg/kg, inhibited writhing behaviour caused by an intraperitoneal acetic acid injection. Both early and late phases of nociception caused by the intraperitoneal formalin injection were inhibited by BPIS (10–50 mg/kg). BPIS, administered at doses equal to or greater than 10 and 25 mg/kg, reduced nociception produced by an intraperitoneal injection of capsaicin and glutamate, respectively. The antinociceptive effect of BPIS, when assessed in the tail-immersion test, was not abolished by naloxone. BPIS (10–50 mg/kg) did not alter alanine transaminase and aspartate transaminase activities (parameters of hepatic function) or urea and creatinine levels (parameters of renal function), and did not affect motor activity in the open-field test. The results indicate that BPIS produced an antinociceptive action without causing motor disturbances or toxicity. Moreover, opioidergic mechanisms seem not to be involved in the antinociceptive action of BPIS. Here, BPIS has been found to be a novel organoselenium compound with antinociceptive properties; however, more studies are required to examine its therapeutic potential for pain treatment.

Hyperthermic seizures enhance responsiveness to pentylenetetrazole and induce cognitive dysfunction: Protective effect of 3-alkynyl selenophene

AIMS In this study we investigated the effect of pre-treatment with 3-alkynyl selenophene (3-ASP) against the increase in responsiveness to pentylenetetrazole [PTZ seizure threshold] and cognitive dysfunction induced by experimental febrile seizures (FS). The effects of 3-ASP were compared to those of diazepam (DZP). MAIN METHODS Young rats, at postnatal day 21, developed seizures after exposure to a stream of heated air to approximately 41°C. A non-spatial long-term memory and PTZ seizure threshold were determined 30 days after FS. The behavioural seizures were stereotyped followed by facial automatisms, often followed by body flexion. Young rats were pre-treated with 3-ASP (50 and 100mg/kg; per oral route), DZP (1 and 5mg/kg; intraperitoneally) or vehicle. KEY FINDINGS 3-ASP and DZP pre-treatments were not effective in protecting against seizures induced by FS. 3-ASP pre-treatment protected against the increase in responsiveness to PTZ and cognitive dysfunction induced by FS. DZP pre-treatment was effective in protecting against the increase in responsiveness to PTZ, but not, against the impaired memory induced by FS. SIGNIFICANCE 3-ASP pre-treatment protected against impairment of memory performance in the step-down passive avoidance task and the increase in the susceptibility to seizures caused by FS early in life of rats.

Bis(phenylimidazoselenazolyl) diselenide as an antioxidant compound: An in vitro and in vivo study.

The organoselenium compounds have been reported for many biological properties, especially as potent antioxidants. The compound bis(phenylimidazoselenazolyl) diselenide (BPIS) is a novel diaryl diselenide derivative, which shows antinociceptive and anti-inflammatory properties in mice, but whose antioxidant activity has not been studied. The present study aimed to investigate the antioxidant and toxicological potential of BPIS in brain of rats in vitro, and the effect of BPIS against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain. BPIS, at low molecular range, reduced lipid peroxidation (LP) and protein carbonyl (PC) content in rat brain homogenates (IC50 values of 1.35 and 0.74 μM, respectively). BPIS also presented dehydroascorbate reductase-like and glutathione-S-transferase-like, as well as DPPH and NO-scavenging activities. Related to togicological assays, BPIS inhibited δ-ALA-D and Na(+), K(+)-ATPase activities in rat brain homogenates and [(3)H]glutamate uptake in synaptosomes in vitro, but these effects were observed at higher concentrations than it had antioxidant effect (IC50 values of 16.41, 26.44 and 3.29 μM, respectively). In vivo, brains of mice treated with SNP (0.335 μmol per site; i.c.v.) showed an increase in LP and PC and a reduction in non protein thiol content, however, it was not observed significant alterations in antioxidant enzyme activities. BPIS (10 mg/kg; p.o.) protected against these alterations caused by SNP. In conclusion, the results demonstrated the antioxidant action of BPIS in in vitro assays. Furthermore, BPIS protected against oxidative damage caused by SNP in mouse brain, strengthening the potential antioxidant effect of this compound.

Increased xanthine oxidase-related ROS production and TRPV1 synthesis preceding DOMS post-eccentric exercise in rats

AIMS It is well-known that unaccustomed exercise, especially eccentric exercise, is associated to delayed onset muscle soreness (DOMS). Whether DOMS is associated with reactive oxygen species (ROS) and the transient receptor potential vanilloid 1 (TRPV1) is still an open question. Thus, the aim of this study was to investigate the association between TRPV1 and xanthine oxidase-related ROS production in muscle and DOMS after a bout of eccentric exercise. MAIN METHODS Male Wistar rats performed a downhill running exercise on a treadmill at a -16° tilt and a constant speed for 90min (5min/bout separated by 2min of rest). Mechanical allodynia and grip force tests were performed before and 1, 3, 6, 9, 12, 24, 48 and 72h after the downhill running. Biochemical assays probing oxidative stress, purine degradation, xanthine oxidase activity, Ca(2+) ATPase activity and TRPV1 protein content were performed in gastrocnemius muscle at 12, 24, and 48h after the downhill running. KEY FINDINGS Our statistical analysis showed an increase in mechanical allodynia and a loss of strength after the downhill running. Similarly, an increase in carbonyl, xanthine oxidase activity, uric acid levels and TRPV1 immunoreactivity were found 12h post-exercise. On the other hand, Ca(2+) ATPase activity decreased in all analyzed times. SIGNIFICANCE Our results suggest that a possible relationship between xanthine oxidase-related ROS and TRPV1 may exist during the events preceding eccentric exercise-related DOMS.

High doses of 2,2'-dithienyl diselenide cause systemic toxicity in rats: an in vitro and in vivo study.

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

Bis(phenylimidazoselenazolyl) diselenide elicits antinociceptive effect by modulating myeloperoxidase activity, NOx and NFkB levels in the collagen-induced arthritis mouse model

Bis(phenylimidazoselenazolyl) diselenide (BPIS) is an organoselenium with acute antinociceptive and antioxidant properties.

(p-ClPhSe)2 Reduces Hepatotoxicity Induced by Monosodium Glutamate by Improving Mitochondrial Function in Rats†

It is has been demonstrated that mitochondrial dysfunction, oxidative stress, and chronic inflammatory process are associated with progress of morbid obesity in human patients. For this reason, the searching for safe and effective antiobesity drugs has been the subject of intense research. In this context, the organic selenium compounds have attracted much attention due to their pharmacological properties, such as antihyperglycemic, antioxidant, and anti‐inflammatory. The aim of this study was to evaluate the hepatoprotective action of p‐chloro‐diphenyl diselenide (p‐ClPhSe)2, an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats. Wistar rats were treated during the first ten postnatal days with MSG (4 g/kg by subcutaneous injections) and received (p‐ClPhSe)2 (10 mg/kg, intragastrically) from 90th to 97th postnatal day. Mitochondrial function, purine content and the levels of proteins involved in apoptotic (poly [ADP‐ribose] polymerase [PARP]) and inflammatory processes (inducible nitric oxide synthases [iNOS] and p38) were determined in the liver of rats. The present study, demonstrated that postnatal administration of MSG to male rats induced a mitochondrial dysfunction, accompanied by oxidative stress and an increase in the ADP levels, without altering the efficiency of phosphorylation in the liver of adult rats. Furthermore, the MSG administration also induces hepatotoxicity, through an increase in PARP, iNOS, and p38 levels. (p‐ClPhSe)2 treatment had beneficial effects against mitochondrial dysfunction, oxidative stress, and modulated protein markers of apoptosis and inflammation in the liver of MSG‐treated rats. J. Cell. Biochem. 118: 2877–2886, 2017.

Monosodium glutamate induced nociception and oxidative stress dependent on time of administration, age of rats and susceptibility of spinal cord and brain regions

ABSTRACT Monosodium glutamate (MSG), a food flavor enhancer used worldwide, has been studied because it may cause neurotoxicity, which is associated with oxidative stress. The aim of this study was to investigate whether spinal cord and brain regions are affected by oxidative stress and the temporal profile of nociceptive responses induced by MSG in newborn and adult rats. The newborn (post natal day, PND 1) Wistar rats received ten subcutaneous injections of MSG (4.0g/kg) or saline solution. At PND 3, 11 or 90, the rats performed nociceptive tests and parameters of oxidative stress were evaluated in samples of spinal cord and brain regions. Adult rats (PND 90) were injected with MSG (4.0g/kg, 10 injections) or saline solution, but MSG did not induce nociception or oxidative stress. The neonatal administration of MSG increased nociceptive behavior in the tail immersion, hot plate and formalin tests and decreased the SOD activity in spinal cord of PND 3 rats. In rats at PND 11 and 90, the neonatal administration of MSG increased mechanical allodynia and nociceptive behavior in the hot plate and formalin tests. The neonatal administration of MSG induced oxidative stress in the hippocampus of rats at PND 11 and in the cerebral cortex at PND 90. These findings demonstrate that nociception and oxidative stress was induced in rats dependent on the time of MSG administration, susceptibility of spinal cord and brain regions and the age of rats. HIGHLIGHTSMSG neonatal administration induced nociception from PND 3 to adulthood.MSG‐induced oxidative stress affected differently brain regions.MSG‐induced oxidative stress was dependent on the time of injection and rat age.MSG administration in adult rats did not induce nociception and oxidative stress.