Nucleophilic Selenocyclization Reaction of Benzodiynes Promoted by Sodium Selenide: Synthesis of Isoselenochromenes.

We describe here the synthesis of isoselenochromenes via a nucleophilic selenocyclization reaction of benzodiynes with sodium selenide. The central parameters that affect this cyclization reaction were studied, and the best reaction conditions were applied to different substrates to determine the scope of the method. The results indicated that isoselenochromenes were obtained in higher yields when the reactions were performed by the addition of NaBH4 (3 equiv), at room temperature, under nitrogen atmosphere, to a solution of elemental selenium (2 equiv) in dimethylformamide (2 mL). After 1 h, a benzodiynes (0.25 mmol) solution in EtOH (3 mL) was added at room temperature. The reaction was stirred at 75 °C until the starting material was consumed. The best conditions were applied to benzodiynes having electron-rich, electron poor aromatic rings, and alkyl groups directly bonded to the alkynes. The same reaction condition was extended to isothiochromene derivatives but failed to prepare isotelurochromenes. The isoselenochromenes were easily transformed into three new classes of organoselenium compounds using classical methods available in the literature. We also conducted several control experiments to propose a reaction mechanism.

Strength exercise suppresses STZ-induced spatial memory impairment and modulates BDNF/ERK-CAMKII/CREB signalling pathway in the hippocampus of mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has generated scientific interest because of its prevalence in the population. Studies indicate that physical exercise promotes neuroplasticity and improves cognitive function in animal models and in human beings. The aim of the present study was to investigate the effects of strength exercise on the hippocampal protein contents and memory performance in mice subjected to a model of sporadic AD induced by streptozotocin (STZ). Swiss mice received two injections of STZ (3 mg/kg, intracerebroventricular). After 21 days, they began physical training using a ladde. Mice performed this protocol for 4 weeks. After the last exercise training session, mice performed the Morris Water Maze test. The samples of hippocampus were excised and used to determine protein contents of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase-Ca2+ (ERK), calmodulin-dependent protein kinase (CAMKII) and cAMP-response element-binding protein (CREB) signalling pathway. Strength exercise was effective against the decrease in the time spent and distance travelled in the target quadrant by STZ-injected mice. Strength exercise was also effective against the reduction of mature BDNF, tropomyosin receptor kinase B and neuronal nuclear antigen (NeuN) hippocampal protein levels in STZ mice. The decrease in the hippocampal ratio of pERK/ERK, pCAMKII/CAMKII and pCREB/CREB induced by STZ was reversed by strength exercise. Strength exercise decreased Bax/Bcl2 ratio in the hippocampus of STZ-injected mice. The present study demonstrates that strength exercise modulated the hippocampal BDNF/ERK-CAMKII/CREB signalling pathway and suppressed STZ-induced spatial memory impairment in mice.

In Vitro Effects of 2-{4-[Methylthio(methylsulfonyl)]phenyl}-3-substitutedthiazolidin-4-ones on the Acetylcholinesterase Activity in Rat Brain and Lymphocytes: Isoform Selectivity, Kinetic Analysis, and Molecular Docking.

This work evaluated the in vitro effect of thiazolidin-4-ones on the activity of AChE (total and isoforms) isolated from the cerebral cortex, hippocampus, and lymphocytes. Kinetic parameters were evaluated and molecular docking was performed. Our results showed that thiazolidinones derived from 4-(methylthio)benzaldehyde (1) and from 4-(methylsulfonyl)benzaldehyde (2) were capable of inhibiting the AChE activity in vitro. Three compounds, two with a propylpiperidine (1b and 2b) moiety and one with a 3-(diethylamino)propyl (1c) moiety showed IC50 values of 13.81 µM, and 3.13 µM (1b), 55.36 µM and 44.33 µM (1c) for cerebral cortex and hippocampus, respectively, and 3.11 µM for both (2b). Enzyme kinetics revealed that the type of AChE inhibition was mixed. Compound 1b inhibited the G1 and G4 AChE isoforms, while compounds 1c and 2b selectively inhibited the G4 isoform. Molecular docking showed a possible three-dimensional fit into the enzyme. Our findings showed that these thiazolidin-4-ones, especially those containing the propylpiperidine core, have a potential cholinesterase inhibitory activity and can be considered good candidates for future Alzheimer's therapy.

Diphenyl diselenide modulates gene expression of antioxidant enzymes in the cerebral cortex, hippocampus and striatum of female hypothyroid rats.

INTRODUCTION: Cellular antioxidant signaling can be altered either by thyroid disturbances or by selenium status. AIMS: To investigate whether or not dietary diphenyl diselenide can modify the expression of genes of antioxidant enzymes and endpoint markers of oxidative stress under hypothyroid conditions. METHODS: Female rats were rendered hypothyroid by continuous exposure to methimazole (MTZ; 20 mg/100 ml in the drinking water) for 3 months. Concomitantly, MTZ-treated rats were either fed or not with a diet containing diphenyl diselenide (5 ppm). mRNA levels of antioxidant enzymes and antioxidant/oxidant status were determined in the cerebral cortex, hippocampus and striatum. RESULTS: Hypothyroidism caused a marked upregulation in mRNA expression of catalase, superoxide dismutase (SOD-1, SOD-3), glutathione peroxidase (GPx-1, GPx-4) and thioredoxin reductase (TrxR-1) in brain structures. SOD-2 was increased in the cortex and striatum, while TrxR-2 increased in the cerebral cortex. The increase in mRNA expression of antioxidant enzymes was positively correlated with the Nrf-2 transcription in the cortex and hippocampus. Hypothyroidism caused oxidative stress, namely an increase in lipid peroxidation and reactive oxygen species levels in the hippocampus and striatum, and a decrease in nonprotein thiols in the cerebral cortex. Diphenyl diselenide was effective in reducing brain oxidative stress and normalizing most of the changes observed in gene expression of antioxidant enzymes. CONCLUSION: The present work corroborates and extends that hypothyroidism disrupts antioxidant enzyme gene expression and causes oxidative stress in the brain. Furthermore, diphenyl diselenide may be considered a promising molecule to counteract these effects in a hypothyroidism state.

Contribution of dopaminergic and adenosinergic systems in the antinociceptive effect of p-chloro-selenosteroid.

This study investigated the antinociceptive action of p-chloro-selenosteroid (PCS), administered by intragastric route (i.g.) to mice against acute models. The contribution of adenosinergic, dopaminergic, serotonergic, nitric oxide and opioid systems was investigated. It was evaluated if the administration of PCS triggers toxic effect. Treatment with PCS (10mg/kg) reduced writhing induced by acetic acid and its effect lasts up to 48 h after treatment. The compound caused an inhibition in neurogenic and inflammatory phases of nociception and in paw edema induced by formalin. The licking behavior triggered by glutamate was reduced by PCS. In the tail-immersion test, PCS elicited an increase in delta latency response. Pretreatment with caffeine (3mg/kg, intraperitoneally [i.p.]) and SCH58261 (3mg/kg, i.p.), antagonist at adenosinergic receptors, SCH23390 (0.05 mg/kg, i.p.) and sulpiride (5mg/kg, i.p.), antagonist at dopaminergic receptors, caused a reduction in the antinociceptive action of PCS in the glutamate test. By contrast, pretreatment with WAY100635 (0.7 mg/kg, i.p.), ketanserin (0.3mg/kg, i.p.), ondasentron (0.5mg/kg, i.p.), l-arginine (600 mg/kg, i.p.) and naloxone (1mg/kg, subcutaneous [s.c.]) did not abolish the antinociceptive effect caused by PCS (10mg/kg, i.g.) administration. The animals treated with PCS did not show alterations in locomotor and exploratory activities, in biochemical parameters evaluated, food and water consumption, as well as in the body weight. These results clearly showed the antinociceptive action of PCS in different animal models without causing acute toxic effects in mice. Adenosinergic and dopaminergic systems seem to be related to the mechanisms by which PCS elicits antinociception.

Correlations between behavioural and oxidative parameters in a rat quinolinic acid model of Huntington's disease: protective effect of melatonin.

The present study was designed to examine the correlations between behavioural and oxidative parameters in a quinolinic acid model of Huntington's disease in rats. The protective effect of melatonin against the excitotoxicity induced by quinolinic acid was investigated. Rats were pre-treated with melatonin (5 or 20mg/kg) before injection of quinolinic acid (240nmol/site; 1µl) into their right corpora striata. The locomotor and exploratory activities as well as the circling behaviour were recorded. The elevated body swing test was also performed. After behavioural experiments, biochemical determinations were carried out. Melatonin partially protected against the increase of circling behaviour caused by quinolinic acid injection. No alteration was found in the number of crossings and rearings of animals treated with melatonin and/or quinolinic acid. Melatonin decreased the percentage of contralateral biased swings induced by quinolinic acid. Melatonin protected against the increase in reactive species and protein carbonyl levels as well as the inhibition of superoxide dismutase activity resulting from quinolinic acid injection. Melatonin was partially effective against the inhibition of striatal catalase activity and a decrease of non-protein thiol levels induced by quinolinic acid. Melatonin was not effective against the inhibition of Na(+), K(+) ATPase activity caused by quinolinic acid injection. There were significant correlations between circling behaviour and oxidative parameters. The antioxidant property of melatonin is involved, at least in part, in its neuroprotective effect. The results reinforce the idea that melatonin could be useful in overwhelming neurotoxicity caused by quinolinic acid, a rat model of Huntington's disease.