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This study aimed to investigate the feasibility of preparing a hydrogel based on (OMePhSe) 2 -loaded poly(Ɛ-caprolactone) nanocapsules using carrageenan gum as a gel-forming agent. Furthermore, the anti-inflammatory action of hydrogel was assessed in an animal model of skin lesion induced by ultraviolet B (UVB) radiation in mice. Nanocapsules were prepared using the interfacial deposition of preformed polymer technique. The hydrogels were obtained by the direct addition of nanocapsules suspension in carrageenan gum (3%). Formulations with free compound, vehicle, and blank nanocapsules were also produced. The hydrogels were characterized by pH, compound content, diameter, spreadability, rheological behavior, and permeation profile. The pharmacological performance was assessed in an animal model of skin injury induced by UVB-radiation in male Swiss mice. All hydrogels had pH around 7.0, compound content close to the theoretical value (2.5 mg/g), an average diameter in nanometric range (around 350 nm), non-Newtonian flow with pseudoplastic behavior, and suitable spreadability factor. The nano-based hydrogel increased the compound content in the epidermis and dermis layers in comparison to the formulation prepared with non-encapsulated (OMePhSe) 2 . Stability studies revealed that the hydrogels of nanoencapsulated compound had superior physicochemical stability in comparison to the formulation of free (OMePhSe) 2. Moreover, topical treatment with the hydrogel containing (OMePhSe) 2 loaded-nanocapsules was more effective in reducing ear thickness and the inflammatory process induced by UVB radiation in mice. Herein, a polysaccharide was applied as a gel-forming agent using a simple and low-cost method. Besides, a superior permeation profile and improved pharmacological action were achieved by the compound encapsulation., Competing Interests: Declaration of Competing Interests The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Given the few antifungal classes available to treat aspergillosis, this study aimed to evaluate the in vitro antifungal activity of diphenyl diselenide (PhSe)2 alone and in combination with classical antifungals against Aspergillus spp., and its in vivo activity in a systemic experimental aspergillosis model. We performed in vitro broth microdilution assay of (PhSe)2 against 32 Aspergillus isolates; and a checkboard assay to test the interaction of this compound with itraconazole (ITC), voriconazole (VRC), amphotericin B (AMB), and caspofungin (CAS), against nine Aspergillus isolates. An experimental model of invasive aspergillosis in mice was studied, and survival curves were compared between an untreated group and groups treated with 100 mg/kg ITC, or (PhSe)2 in different dosages (10 mg/kg, 50 mg/kg and 100 mg/kg). All Aspergillus non-fumigatus and 50% of A. fumigatus were inhibited by (PhSe)2 in concentrations ≤ 64 µg/ml, with significant differences in MICs between the sections. Synergism or additive effect in the in vitro (PhSe)2 interaction with VRC and CAS was observed against the majority of isolates, and with ITC against the non-fumigatus strains. In addition to the inhibitory interaction, (PhSe)2 was able to add a fungicidal effect to CAS. Survival curves from the systemic experimental aspergillosis model demonstrated that the inoculum caused an acute and lethal infection in mice, and no treatment applied significantly prolonged survival over that of the control group. The results highlight the promising activity of (PhSe)2 against Aspergillus species, but more in vivo studies are needed to determine its potential applicability in aspergillosis treatment., Lay Summary: The activity of diphenyl diselenide (PhSe)2 alone and in combination with itraconazole, voriconazole, and caspofungin, is described against three of the most pathogenic Aspergillus sections. (PhSe)2 may prove useful in therapy of infection in future; further study is required., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Interferon tau (IFNT) is the cytokine responsible for the maternal recognition of pregnancy in ruminants and plays a role modulating embryo-maternal communication in the oviduct inducing a local response from immune cells. We aimed to investigate IFNT production, reactive oxygen species, and oxidative stress under the influence of heat stress (HS) during different stages of bovine in vitro embryo production. HS was established when the temperature was gradually raised from 38.5°C to 40.5°C in laboratory incubator, sustained for 6 hr, and decreased back to 38.5°C. To address the HS effects on IFNT production, reactive oxygen species, and oxidative stress, ovaries from a slaughterhouse were used according to treatments: control group (38.5°C); oocytes matured under HS; oocytes fertilized under HS; zygotes cultured in the first day under HS; and cells submitted to HS at oocyte maturation, fertilization, and the first day of zygote culture. The HS negatively affected cleavage and blastocyst rates, in all HS groups. On Day 7, all HS-treated embryos showed decrease IFNT gene and protein expressions, whereas reactive oxygen species were increased in comparison to the control. In conclusion, the compromised early embryo development due to higher temperatures during in vitro oocyte maturation, fertilization, and/or zygote stage have diminished IFNT expression and increased reactive oxygen species in bovine., (© 2020 Wiley Periodicals LLC.)

Humans are ubiquitously exposed to bisphenol A (BPA), one of the most used synthetic monomers for manufacturing polycarbonate plastics. BPA exposure leads to abnormal nociceptive perception and neuroinflammation in rodents. This study investigated whether diphenyl diselenide (PhSe) 2 , a pleiotropic selenium-containing molecule, would be effective against the hypernociceptive behavior induced by the early-life BPA exposure to mice. Three-week-old male and female Swiss mice received intragastrically BPA (5 mg/kg) from 21 st to 60 th postnatal day. After, the mice received by the intragastric route (PhSe) 2 (1 mg/kg) once a day for seven days. After the last day of treatment, the mice performed the hot plate and tail immersion tests. The cerebral cortex samples were used to determine the levels of proteins related to apoptosis and inflammation. The results demonstrated that females were more susceptible than male mice to thermal hypernociception induced by early-life exposure to BPA. (PhSe) 2 was effective against the reduction in the latency to paw and tail withdrawal induced by BPA exposure in female mice. Furthermore, (PhSe) 2 restored the impairment in the levels of inflammatory proteins (COX-2, IL-1β, and p-JNK/JNK) but not those of apoptosis in the cerebral cortex of female mice exposed to BPA. Collectively, these data showed that females were more susceptible to thermal hypernociceptive behavior induced by early-life exposure to BPA than male mice. The administration of (PhSe) 2 reduced thermal hypernociceptive behavior, a sex independent effect, in BPA-exposed mice. (PhSe) 2 modulated inflammatory protein levels in the cerebral cortex of female mice exposed to BPA., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The mechanisms underlying the neuroprotective effects of hesperidin in a murine model of PD are not fully elucidated. The current study was carried out to investigate the ability of hesperidin in modulating proinflammatory cytokines, neurotrophic factors, and neuronal recovery in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic neuronal loss. Adult male C57BL/6 mice were randomly assigned into four groups: (I) sham/vehicle, (II) sham/hesperidin, (III) 6-OHDA/vehicle, and (IV) 6-OHDA/hesperidin. Mice received a unilateral intrastriatal injection of 6-OHDA and treated with hesperidin (50 mg/kg; per oral) for 28 days. After hesperidin treatment, mice were submitted to behavioral tests and had the striatum removed for neurochemical assays. Our results demonstrated that oral treatment with hesperidin ameliorated the anxiety-related and depressive-like behaviors in 6-OHDA-lesioned mice (p < 0.05). It also attenuated the striatal levels of proinflammatory cytokines tumor necrosis factor-α, interferon-gamma, interleukin-1β, interleukin-2, and interleukin-6 and increased the levels of neurotrophic factors, including neurotrophin-3, brain-derived neurotrophic factor, and nerve growth factor in the striatum of 6-OHDA mice (p < 0.05). Hesperidin treatment was also capable to increase striatal levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid and protects against the impairment of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (p < 0.05). In conclusion, this study indicated that hesperidin exerts anxiolytic-like and antidepressant-like effect against 6-OHDA-induced neurotoxicity through the modulation of cytokine production, neurotrophic factors levels, and dopaminergic innervation in the striatum.

Background: Cisplatin (CIS) is widely used in the chemotreatment of pediatric tumors. However, the CIS use is limited because of its high incidence of toxicity, mainly nephrotoxicity. Although there are many studies about CIS-related nephrotoxicity in animal models, only a few studies focus on juvenile animals. Because redox disturbances have been associated with kidney damage induced by CIS, this study aimed to compare the effectiveness of Ebselen and diphenyl diselenide (PhSe) 2 against nephrotoxicity induced by CIS in juvenile rats., Methods: Juvenile Wistar rats were randomly divided into six groups: rats from groups I to III received an intraperitoneal (i.p.) injection with saline solution. The other groups received CIS (i.p., 6 mg/kg) on the first day. One hour before CIS injection and on the next four days, animals of groups III and V were intragastrically treated with Ebselen (11 mg/kg) whereas those from groups IV and VI received (PhSe) 2 (12 mg/kg). After 24 h of the last treatment, blood and kidney were collected, and the parameters of renal function and oxidative stress were determined., Results: Kidney damage induced by CIS was confirmed by the increase of creatinine, urea and uric acid levels in the blood of juvenile rats. The renal oxidative disturbance was characterized by an increase in the levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl, and nitrogen oxides (Nox), as well as the decrease in non-protein thiol content (NPSH), glutathione-S-transferase (GST), catalase (CAT) and superoxide dismutase (SOD) activities. CIS inhibited the activities of δ-aminolevulinic acid dehydratase (δ-ALA-D) and Na + , K + -ATPase and down-regulated the Nrf2/Keap-1/HO-1 pathway in the kidney of juvenile rats., Conclusion: Both Ebselen and (PhSe) 2 modulated back to the normal levels all parameters altered by the CIS administration in the kidney of juvenile rats. Thus, this study shows that (PhSe) 2 was as effective as Ebselen in protecting the kidney against oxidative damage caused by CIS in rats., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

The aim of this study was to further evaluate the antitumoral effect of (PhSe) 2 -loaded polymeric nanocapsules (NC (PhSe) 2 ) against a resistant melanoma cell line (SK-Mel-103) and develop a xanthan gum-based hydrogel intending the NC (PhSe) 2 cutaneous application. For the in vitro evaluation, cells were incubated with free (PhSe) 2 or NC (PhSe) 2 (0.7-200 μM) and after 48 h the MTT assay, propidium iodide uptake (necrosis marker) and nitrite levels were assessed. The hydrogels were developed by thickening of the NC (PhSe) 2 suspension or (PhSe) 2 solution with xanthan gum and characterized in terms of average diameter, polydispersity index, pH, drug content, spreadability, rheological profiles and in vitro permeation in human skin. The results showed that NC (PhSe) 2 provided a superior antitumoral effect in comparison to free (PhSe) 2 (IC 50 value of 47.43 μM and 65.05 μM, respectively) and increased the nitrite content. Both compound forms induced propidium iodide uptake, suggesting a necrosis-related pathway could be involved in the cytotoxic action of (PhSe) 2 . All hydrogels showed pH values around 7, drug content close to the theoretical values (5 mg/g) and mean diameter in the nanometric range. Besides, formulations were classified as non-Newtonian flow with pseudoplastic behavior and suitable spreadability factor. Skin permeation studies revealed that the compound content was higher for the nano-based hydrogel in the dermis layer, demonstrating its superior permeation, achieved by the compound encapsulation. It is the first report on an adequate formulation development for cutaneous application of NC (PhSe) 2 that could be used as an adjuvant treatment in melanoma therapy.

Depression is a serious disorder characterized by imbalance of mood and emotions, which is accompanied by the reduction in the monoaminergic signaling. The monoamine oxidase inhibition could lead to an increase in monoaminergic neurotransmitter levels in the brain. According to our previous study, 3-phenyl-4-(phenylseleno) isoquinoline (PSI) is a selective and reversible MAO-B inhibitor in vitro. The present study investigated the putative ex vivo inhibitory effect of a single PSI dose on the cerebral MAO activity and its antidepressant-like action in the mouse forced swimming test (FST). Additionally, the dopaminergic system contribution to the antidepressant-like effect of PSI was also evaluated. For this, PSI was dissolved in canola oil to determine time-course (0.5-24 h) and dose-response (25-100 mg/kg, 10 ml/kg, intragastrically) curves of MAO activity inhibition using adult C57Bl/6 male mice. A single PSI dose of 100 mg/kg inhibited the MAO-B activity in the whole brain 8 h after administration to mice, while it did not alter the MAO-A activity. The FST was carried out 0.5, 8, and 24 h after the PSI administration (100 mg/kg) or vehicle, but its antidepressant-like effect was demonstrated only at 0.5 and 8 h after treatment. Lastly, the contribution of dopaminergic system in the PSI antidepressant-like effect was demonstrated by using dopamine receptors antagonists, SCH23390, haloperidol and sulpiride. Thus, a single PSI dose of 100 mg/kg had an antidepressant-like effect in mice subjected to the FST 0.5 and 8 h after its administration. Moreover, the inhibition of cerebral MAO-B activity and modulation of dopamine receptors contributed to the antidepressant-like effect of PSI in mice., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The opioid withdrawal syndrome is defined as a complex phenomenon involving multiple cellular adaptations, which leads to the emergence of aversive physical and affective signs. The m-trifluoromethyl-diphenyl diselenide (m-CF 3 -PhSe) 2 elicits an antidepressant-like effect by modulating the opioid system in different animal models of mood disorders. Notably, repeated exposure to (m-CF 3 -PhSe) 2 developed neither tolerance nor withdrawal signs in mice. The aim of the present study was to investigate whether (m-CF 3 -PhSe) 2 attenuates the physical signs and the depressive-like phenotype during morphine withdrawal through its neuroprotective effects on oxidative stress, the NMDA receptor and the proBDNF/mBDNF signaling in the hippocampus of mice. Adult Swiss mice received saline solution or escalating doses (20-100 mg/kg, sc) of morphine for six days. For the next three days, the animals were treated with canola oil, (m-CF 3 -PhSe) 2 (5 and 10 mg/kg, ig) or methadone (5 mg/kg, sc) whereas morphine injections were discontinued. On day 9, physical withdrawal signs and depressive-like behavior were assessed 30 min after the last administration of (m-CF 3 -PhSe) 2. Although short-term treatment with (m-CF 3 -PhSe) 2 at both doses suppressed the aversive physical and affective signs in morphine withdrawn-mice, the highest dose of (m-CF 3 -PhSe) 2 per se increased the teeth chattering manifestation. The intrinsic antioxidant property of (m-CF 3 -PhSe) 2 modulated oxidative stress, it also restored the NMDA receptor levels in the hippocampus of morphine withdrawn-mice. Besides, (m-CF 3 -PhSe) 2 downregulated the proBDNF/p-75 NTR /JNK pro-apoptotic pathway without affecting the mBDNF/TrkB/ERK/CREB pro-survival signaling in the hippocampus of morphine withdrawn-mice. The results show that (m-CF 3 -PhSe) 2 treatment modulated the hippocampal neurotoxic adaptations and abolished the depressive-like phenotype following morphine withdrawal in mice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Intracerebroventricular streptozotocin injection (icv STZ) is a well established sporadic Alzheimer's disease (AD) model in rodents. AD is characterized by neuronal degeneration accompanied by central oxidative stress. Studies also indicate peripheral oxidative damage in AD, but if the icv STZ model of sporadic AD mimics this feature is an open question. This study aimed to investigate if icv STZ administration induces peripheral oxidative stress and the antioxidant action of Ebselen, compared to the reference drug (donepezil), in this sporadic AD model. Male adult Swiss mice received icv STZ (days 1 and 3). Mice received Ebselen (10 mg/kg, i.p) or Donepezil (5 mg/kg, i.p) for 14 days. Mice were killed and the kidney and liver were excised to determine parameters of oxidative stress and toxicity markers. The mice icv STZ-injected showed peripheral oxidative stress. Ebselen reversed renal lipid peroxidation in the icv STZ administered mice by modulating NPSH levels, SOD and CAT activities, whereas Donepezil, modulated only NPSH levels. Ebselen and Donepezil counteracted hepatic lipid peroxidation in STZ-injected mice by modulating NPSH levels and CAT activity. The δ-ALA-D activity was inhibited in the kidney, but not in the liver, whereas the icv STZ-injected mice had an increase in the GST activity in both tissues. Ebselen reversed the increase in the hepatic GST activity of the STZ-injected mice. Donepezil increased renal GST activity in the control mice. In conclusion, this study demonstrates that the icv STZ administration induced peripheral oxidative stress. Ebselen, similar to Donepezil, was effective against peripheral oxidative stress in a mouse model of sporadic AD.

The isoquinoline 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been studied due to its multitarget properties, such as modulation of GABAergic and glutamatergic systems, antioxidant, and anti-inflammatory. This study investigated the contribution of oxidative stress, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO-1) signaling, and the cholinergic system to the anti-amnesic action of FDPI in mice. Adult male Swiss mice received FDPI for 5 days (5-25 mg/kg, i.g.); the animals received scopolamine (1 mg/kg, i.p) from day 3-5. The vehicle-control group was carried out. Afterward, mice performed object recognition tests (ORTs). Scopolamine induced amnesia and cholinergic dysfunction by increasing the acetylcholinesterase (AChE) activity and content, decreasing the muscarinic M1 receptor levels in the prefrontal cortex and hippocampus of mice. This study reveals that scopolamine altered oxidative stress parameters differently in the prefrontal cortex and hippocampus of mice. Whereas the prefrontal cortex was susceptible to oxidative stress, none of the parameters evaluated was altered in the hippocampus of scopolamine-treated mice. FDPI at doses of 10 and 25 mg/kg had an anti-amnesic effect in the ORT tests. FDPI 10 mg/kg reversed the increase in the AChE activity and content, oxidative stress parameters, and modulated Nrf2/HO-1 signaling in the prefrontal cortex of scopolamine-exposed mice. Pearson's correlation analyses reinforced the contribution of the prefrontal cortical cholinergic system, oxidative stress as well as Nrf2/HO-1 signaling in the anti-amnesic effect of FDPI. Considering FDPI effects on the hippocampus, it was effective against the cholinergic dysfunction, AChE activity and content, and M1 receptor levels, which collectively could contribute to its anti-amnesic effect., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale: The association between depression and diabetes has been recognized for many years, but the nature of this relationship remains uncertain., Objectives: This study investigated the antidepressant-like effect of (p-ClPhSe) 2 on mice made diabetic by streptozotocin (STZ) and the contribution of cerebral cortical Keap1/Nrf2/HO-1 signaling pathway for this effect., Methods: Male adult Swiss mice received streptozotocin (STZ, 200 mg/kg, i.p.) to induce diabetes (glycemia ≥ 200 mg/dl) or citrate buffer (5 ml/kg, control group). The mice were treated with (p-ClPhSe) 2 at the dose of 5 mg/kg, i.g., for 7 days. Mice performed behavior tests, tail suspension (TST), and forced swimming tests (FST), to evaluate depressive-like phenotype., Results: Diabetic mice showed an increase in immobility time in the TST and FST when compared to the control group. The protein contents of Keap1/Nrf2/HO-1 pathway were decreased in the cerebral cortex of diabetic mice. Diabetic mice had an increase in the relative adrenal weight and a decrease in the protein content of glucocorticoid receptor. The levels of TBARS and RS and SOD activity were found altered in the cerebral cortex of diabetic mice. The number of FJC-positive cells was increased in the cerebral cortex of diabetic mice. Treatment with (p-ClPhSe) 2 was effective against depressive-like phenotype, oxidative stress, and FJC-positive cells of diabetic mice. (p-ClPhSe) 2 did not reverse the parameters of HPA axis evaluated in this study. (p-ClPhSe) 2 modulated the cerebral cortical Keap1/Nrf2/HO-1 pathway in diabetic mice., Conclusions: This study demonstrates the contribution of cerebral cortical Keap1/Nrf2/HO-1 pathway in the (p-ClPhSe) 2 antidepressant-like action in diabetic mice.

Rationale and Objectives: Stress-induced alterations in oxidative and inflammatory parameters have been implicated in the pathophysiology of mood disorders. Based on the antioxidant and anti-inflammatory properties of the selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI), we assessed its ability to reverse depression-like behavioral alterations, neuroinflammation, and oxidative imbalance induced by acute restraint stress., Methods: Mice submitted to restraint for 240 min received CMI (1 or 10 mg/kg, orally) 10 min after the end of the stress induction. Behavioral and biochemical tests were carried out after further 30 min., Results: Restraint-induced depression-like behavior in the tail suspension test (TST), splash test, and new object exploration test was reversed by CMI. None of the treatments evoked locomotor alteration. In addition, CMI abrogated restraint-induced increases in plasma levels of corticosterone and in markers of oxidative stress and impaired superoxide dismutase and catalase activity in the prefrontal cortex (PFC) and hippocampus (HC). CMI also blocked stress-induced downregulation of mRNA levels of glucocorticoid receptor and brain-derived neurotrophic factor and upregulation of nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis alpha, indoelamine-2,3-dioxygenase, and glycogen synthase kinase 3 beta in PFC and HC., Conclusions: These preclinical results indicate that administration of selenium-containing compounds might help to treat depression associated with inflammation and oxidative stress. Graphical abstract ᅟ.

Background: Gliomas are the most aggressive malignant tumors of the central nervous system. The diphenyl diselenide [(PhSe) 2 ] is an organoselenium compound that has multiple pharmacological properties. Previous reports showed that (PhSe) 2 nanoencapsulation potentiates its in vitro antitumoral action and reduces its toxicity., Objective: In this sense, the current study was designed to further evaluate the (PhSe) 2 antitumoral effect by a set of in vitro techniques using a glioma cell line as well as by an animal model of gliobastoma., Methods: For the in vitro tests, the cell viability, propidium iodide uptake and nitrite levels of rat glioma C6 cells were determined after incubation with free (PhSe) 2 or (PhSe) 2 -loaded nanocapsules (NC). The glioblastoma model was induced by implantation of C6 glioma cells in the right striatum of rats. Following, animals were submitted to a repeated intragastric administration treatment with (PhSe) 2 or NC (PhSe) 2 (1 mg/kg/day for 15 days) to assess the possible antitumor effect., Main Findings: Both compound forms decreased the C6 glioma cells viability without causing any effect in astrocytes cells (healthy control). Importantly, the NC (PhSe) 2 had superior cytotoxic effect than its free form and increased the nitrite content. Independent of the (PhSe) 2 forms, the intragastric treatment reduced brain tumor size and caused neither alteration in the plasma renal and hepatic markers of function nor in the parameters of oxidative balance in brain, liver and kidneys., Principal Conclusions: The (PhSe) 2 nanoencapsulation improved its cytotoxic effect against C6 glioma cells and both compound forms attenuated the tumor development., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Dexamethasone (DEX) is a synthetic agonist of glucocorticoid receptors that has been associated with neurotoxicity and neuropsychiatric diseases. (p-ClPhSe) 2 is an organoselenium compound reported to have antioxidant, antidepressant-like, and neuroprotective actions. This study investigated whether antioxidant activity and modulation of the glutamatergic system contribute to the antidepressant-like effect of (p-ClPhSe) 2 in mice subchronically exposed to DEX. Swiss mice received intraperitoneal injections of DEX (2 mg/kg) or saline (vehicle) once a day for 21 days. After, the mice received (p-ClPhSe) 2 (1-10 mg/kg) or mineral oil (vehicle) by the intragastric route (i.g.) for 7 days. The mice exposed to DEX were treated with fluoxetine (20 mg/kg, i.g.) once a day for 7 days. 24 h after the last treatment, the animals performed the locomotor activity (LMA), tail suspension, and forced swimming tests. Ex vivo assays were performed in samples of prefrontal cortex (PFC). The results show that (p-ClPhSe) 2 reversed depressive-like behavioral phenotype induced by DEX without affecting LMA. Further, (p-ClPhSe) 2  at all doses reduced ROS levels and increased CAT activity in the PFC of DEX-exposed mice. The highest dose of (p-ClPhSe) 2 was effective against the decrease of SOD activity in the PFC of mice exposed to DEX. (p-ClPhSe) 2 increased the [ 3 H] glutamate uptake/release and decreased the Na + /K + -ATPase activity as well as the EAAT1 and NMDA R2A protein contents in the PFC of DEX-exposed mice. Regarding the NMDA R2B levels, there was no difference among experimental groups. In conclusion, this study reveals the effectiveness of (p-ClPhSe) 2 in reversing the depressive-like phenotype of DEX-exposed mice. In addition, (p-ClPhSe) 2 modulated oxidative stress and glutamate neurotransmission in the PFC of mice subchronically exposed to DEX., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study aimed to characterize the physicochemical properties of 3,3'-diindolylmethane (DIM)-loaded nanocapsules (NCs) as well as the antinociceptive effect using distinct animal models (hot plate test, formalin-induced nociception and complete Freud's adjuvant induced paw inflammation). The DIM-loaded NCs (composed by primula oil and ethylcellulose) were characterized using differential scanning calorimetry, thermogravimetric analysis, Fourier-transformed infrared spectroscopy, X-ray diffractometry and scanning electron microscopy. The physicochemical characterization demonstrated that DIM could be molecularly dispersed into the NCs, whose size was nanometric with a spherical shape. An improvement in DIM thermal stability was achieved by its encapsulation and there were no interactions among the formula components. For the nociceptive evaluation, male adult Swiss mice were pretreated with the NCs or free DIM by the intragastric route at the dose of 10 mg/Kg (time-response curve), 5 or 2.5 mg/Kg (dose-response curve). The behavioral tests were performed over an experimental period of 0.5-8 h. Both free and nanoencapsulated DIM reduced the mechanical hypernociception induced by CFA, mitigated nociceptive behavior of formalin-induced neurogenic and inflammatory pain and increased paw withdrawal latency assessed by the hot-plate test. Importantly, the DIM nanoencapsulation promoted a rapid initiation and prolonged the bioactive antinociceptive action (up to 8 h) as well as reduced the effective dose in comparison to its free form. In summary, this study reported that the NCs had adequate nanometric size, increased DIM stability and its antinociceptive action in different animal models, suggesting that the formulation may be a possible therapeutic alternative to the management of pain and inflammatory-related pathologies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Diabetes is a metabolic disease characterized by hyperglycemia because of insulin resistance and/or insufficient insulin release. The most common diabetic brain complications include cognitive decline and depression. The present study investigated whether the 4-4'-dichlorodiphenyl diselenide (p-ClPhSe) 2 is effective against memory impairment induced by diabetes in mice and the role of hippocampal BDNF/TrkB signaling in this effect. Male adult Swiss mice received an injection of streptozotocin (STZ) (200 mg/kg, i.p.) to induce diabetes. The results revealed that STZ injection in mice resulted in resilience (glycemia <200 mg/dl) or diabetes (glycemia ≥200 mg/dl). The vehicle-control group received citrate buffer (5 ml/kg). The animals were subchronically treated with (p-ClPhSe) 2 (1 or 5 mg/kg, i.g.) for 7 days. Mice performed a battery of well-validated behavior tests designated to evaluate memory, object recognition (ORT), object location (OLT), and Morris water maze (MWM). The hippocampal protein contents of the BDNF/TrkB pathway were determined in the samples of experimental groups. Fluoro Jade C (FJC) was used for staining degenerating neurons. The STZ administration resulted in memory impairment that was demonstrated in the mouse ORT, OLT, and MWM tests. The molecular findings indicate an increase in hippocampal protein levels of proBDNF and TrKB but a decrease in those of mBDNF and pCREB in diabetic mice. The number of FJC-positive cells was increased in the hippocampus of diabetic mice. (p-ClPhSe) 2 at the dose of 5 mg/kg modulated the hippocampal BDNF/TrkB pathway, reduced FJC-positive cells and reversed memory impairment induced by STZ in mice. These findings demonstrate the effectiveness of (p-ClPhSe) 2 against memory impairment caused by diabetes in mice. (p-ClPhSe) 2 modulated the hippocampal BDNF/TrkB signaling pathway in diabetic mice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The current study evaluated whether fructose supplementation affects oxidative stress and metabolic parameters in the liver and gastrocnemius muscle of rats subjected to swimming exercise. Male adult Wistar rats received a fructose solution (10%) or water during 1 h before exercise and during the rest interval by the intragastric route. The swimming protocol consisted of 6 days: each day, rats underwent 3 sessions of 17 min each, with a load of 5% of body mass, and rest intervals of 3 min. Fructose supplementation changed metabolic and oxidative parameters in the liver and gastrocnemius muscle of sedentary rats. Swimming exercise counteracted the increase of triglyceride levels in plasma and liver induced by fructose supplementation. It also reduced thiobarbituric acid reactive species levels in the liver, and catalase and superoxide dismutase activities in the gastrocnemius muscle of supplemented rats. However, fructose supplementation worsened metabolic (hepatic triglyceride levels) and oxidative parameters (thiobarbituric acid reactive species levels) in the liver and gastrocnemius of exercised rats. This study demonstrates that oxidative stress and metabolic parameters were differently affected by fructose supplementation when rats were kept sedentary or underwent swimming exercise. The present results indicate the need of a new insight of the role of fructose supplementation during physical exercise.

Despite resistance exercises being associated with health outcomes, numerous issues are still unresolved and further research is required before the exercise can faithfully be prescribed as medicine. The goal of this study was to investigate whether there are sex differences in resistance training effects on metabolic alterations induced by monosodium glutamate (MSG), a model of obesity, in male and female rats. Male and female Wistar rats received MSG (4 g/kg body weight/day, s.c.) from postnatal day 1 to 10. After 10 days from MSG administration, the rats were separated into two groups: MSG-sedentary and MSG-exercised. At postnatal day 60, the animals started a resistance training protocol in an 80 degrees inclined vertical ladder apparatus and performed it for 7 weeks. Control rats received saline solution and were divided in saline-sedentary and saline-exercised. Resistance training restored all plasma biochemical parameters (glucose, cholesterol, triglycerides, aspartate aminotransferase, and alanine aminotransferase) increased in male and female rats treated with MSG. The MSG administration induced hyperglycemia associated with a decrease in the skeletal muscle glucose transporter 4 (GLUT4) levels and accompanied by deregulation in proteins, G-6Pase, and tyrosine aminotransferase, involved in hepatic glucose metabolism of male and female rats. MSG induced dyslipidemia and lipotoxicity in the liver and skeletal muscle of male rats. Regarding female rats, lipotoxicity was found only in the skeletal muscle. The resistance training had beneficial effects against metabolic alterations induced by MSG in male and female rats, through regulation of proteins (GLUT2, protein kinase B, and GLUT4) involved in glucose and lipid pathways in the liver and skeletal muscle., (© 2019 Wiley Periodicals, Inc.)

Traumatic brain injury (TBI) is a leading cause of disability worldwide, triggering chronic neurodegeneration underlying cognitive and mood disorder still without therapeutic prospects. Based on our previous observations that guanosine (GUO) attenuates short-term neurochemical alterations caused by TBI, this study investigated the effects of chronical GUO treatment in behavioral, molecular, and morphological disturbances 21 days after trauma. Rats subject to TBI displayed mood (anxiety-like) and memory dysfunction. This was accompanied by a decreased expression of both synaptic (synaptophysin) and plasticity proteins (BDNF and CREB), a loss of cresyl violet-stained neurons, and increased astrogliosis and microgliosis in the hippocampus. Notably, chronic GUO treatment (7.5 mg/kg i.p. daily starting 1 h after TBI) prevented all these TBI-induced long-term behavioral, neurochemical, and morphological modifications. This neuroprotective effect of GUO was abrogated in the presence of the adenosine A 1 receptor antagonist DPCPX (1 mg/kg) but unaltered by the adenosine A 2A receptor antagonist SCH58261 (0.05 mg/kg). These findings show that a chronic GUO treatment prevents the long-term mood and memory dysfunction triggered by TBI, which involves adenosinergic receptors.

Previous findings showed that the nanoencapsulation of diphenyl diselenide [(PhSe) 2 ], an organoselenium compound, provided superior biological effects and lower toxicological potential than its free form in vitro. However, few studies reported the behavioral and biochemical effects of this nanocapsules formulation in vivo. Zebrafish (Danio rerio) has emerged as a useful animal model to determine the pharmacological and toxicological effects of nanoparticles. Here, we evaluated the behavioral and brain oxidative effects after zebrafish exposure to (PhSe) 2 -loaded nanocapsules. Formulations were prepared by interfacial deposition of preformed polymer method and later tested at concentrations ranging from 0.1 to 2.0 μM. Both locomotor and exploratory activities were assessed in the novel tank diving test. Moreover, brain oxidative status was determined by measuring thiobarbituric acid-reactive substance levels, glutathione peroxidase, glutathione redutase and glutathione S-transferase activities. (PhSe) 2 -loaded nanocapsules showed no alteration on travelled distance, immobility, and erratic swimming, suggesting the absence of behavioral impairments. Interestingly, the higher concentration tested had anxiolytic-like effects, since animals spent more time in the top area and showed a decreased thigmotaxis behavior. Biochemical analysis demonstrated that the concentrations used in this study did not affect oxidative stress-related parameters in brain samples, reinforcing the low toxicological potential of the formulation. In conclusion, the exposure to (PhSe) 2 -loaded nanocapsules caused no locomotor impairments as well as did not modify the oxidative status of zebrafish brain, indicating that this formulation is probably non-toxic and promising for future pharmacological studies., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

The lipopolysaccharide (LPS) is an endotoxin derived from gram-negative bacteria, which induces inflammation. The aims of this study were to evaluate the possible α-(phenylselanyl) acetophenone (PSAP) activity in reducing comorbid hyperalgesia, depressive-like and anxiogenic-like symptoms induced by LPS in mice. In additional, investigated physical chemical properties of PSAP through in silico analysis by ADMET predictor software. The LPS (100 μg/kg, intraperitoneally) or saline were administered and after 4 h the treatment with PSAP (0.001-10 mg/kg, intragastric route [i.g.]) or FLX (10 mg/kg, i.g.) was performed, and after 30 min, the behavioral tests were carried out. LPS reduced the latency time for the first episode of immobility and increased the immobility time in the FST as well as decreased the grooming time in the splash test. PSAP reversed these alterations demonstrating an antidepressive-like effect. LPS also enhances the anxiogenic behavior in the elevated plus maze test (EPM). PSAP reversed these parameters, showing anxiolytic-like effect. LPS also decreased the latency time (s) on the hot plate and the treatment with PSAP at all doses significantly reversed the hyperalgesic effect of LPS. LPS increased the activation of p38MAPK and p-p65NF-κB pathways as well as the COX-2 levels in the cerebral cortex, which are indicative of an inflammatory response. Besides, it also reduced the levels of mBDNF, involved in neuroplasticity. Treatment with PSAP restored all these neurochemical alterations induced by LPS. The results demonstrated that PSAP presents antidepressive-like, anxiolytic-like and anti-hyperalgesic effects related to reduction in neuroinflammation., (Copyright © 2018. Published by Elsevier Ltd.)

Alzheimer 's disease (AD) is characterized by progressive cognitive decline including memory impairment, cortical dysfunction, and neuropsychiatric disturbances. The drug discovery to treat AD consists to develop compounds able to act in multiple molecular targets involved in the pathogenesis of the disease and the repositioning of old drugs for new application. This way, the intracerebroventricular (icv) injection of streptozotocin (STZ) has been used as a metabolic model of sporadic AD. The aim of the present study was to investigate whether ebselen (1-10 mg/kg), a multifunctional selenoorganic compound, ameliorates memory impairment, hippocampal oxidative stress, apoptosis and cell proliferation in a mouse model of sporadic AD induced by icv STZ (3 mg/kg, 1 μl/min). The administration of ebselen (10 mg/kg, i.p.) reversed memory impairment and hippocampal oxidative stress, by increasing the activities of antioxidant enzymes and the level of a non-enzymatic antioxidant defense, in Swiss mice administered with icv STZ. The anti-apoptotic property of ebselen was demonstrated by its effectiveness against the increase in the ratios of Bax/Bcl-2, cleaved PARP/PARP and the cleaved caspase-3 levels in the hippocampus of icv STZ mice. Although ebselen reversed memory impairment, it was ineffective against the reduction in the number of BrdU positive cells induced by icv STZ. In conclusion, the multifunctional selenoorganic compound ebselen was effective to reverse memory impairment, hippocampal oxidative stress and apoptosis in a mouse model of sporadic AD induced by icv STZ., (Copyright © 2018. Published by Elsevier Ltd.)

The present study aimed to investigate the m-trifluoromethyl-diphenyl diselenide [(m-CF 3 -PhSe) 2 ] effects on prefrontal cortical MOR and KOR protein levels and phenotype induced by repeated forced swim stress (FSS) in mice. Adult Swiss mice were subjected to repeated FSS sessions, and after that, they performed the spontaneous locomotor/exploratory activity, tail suspension, and splash tests. (m-CF 3 -PhSe) 2 (0.1 to 5 mg/kg) was administered to mice 30 min before the first FSS session and 30 min before the subsequent repeated FSS. (m-CF 3 -PhSe) 2 abolished the phenotype induced by repeated FSS in mice. In addition, a single FSS session increased μ but reduced δ-opioid receptor contents, without changing the κ content. Mice subjected to repeated FSS had an increase in the μ content when compared to those of naïve group or subjected to single FSS. Repeated FSS induced an increase of δ-opioid receptor content compared to those mice subjected to single FSS. However, the δ-opioid receptor contents were lower than those found in the naïve group. The mice subjected to repeated FSS showed an increase in the κ-opioid receptor content when compared to that of the naïve mice. (m-CF 3 -PhSe) 2 regulated the protein contents of μ and κ receptors in mice subjected to repeated FSS. These findings demonstrate that (m-CF 3 -PhSe) 2 was effective to abolish the phenotype induced by FSS, which was accompanied by changes in the contents of cortical μ- and κ-opioid receptors.

In this paper, we report a protocol for the preparation of 2-substituted-N-alkynylindoles via metalation of N-alkynylindoles followed by the capture of a 2-indolyl lithium intermediate with different electrophiles. The reactivity of the indoles prepared was also demonstrated through the reaction with CBr4/Ph3P for the preparation of 2-gem-dibromovinyl N-alkynylindoles and the hydrotelluration reaction of N-alkynylindoles, which led to vinylic tellurides. Some compounds prepared showed AChE inhibitory potential in the low micromolar range similar to that obtained with donepezil, a commercially available cholinesterase inhibitor.

Although cisplatin (CIS) has been associated with serious adverse effects, such as hepatotoxicity and nephrotoxicity in adult rats, there is few reports on its use in newborn rats. The aim of this study was to evaluate acute toxic effects of CIS in newborn rats. Adult and newborn Wistar rats received CIS by the i. p. route, at the dose of 5 or 10 mg/kg. After 24 h of treatment, blood, kidney, and liver were excised from the animals and parameters of renal and hepatic functions, oxidative stress markers were determined. Acute administration of CIS caused an increase of AST activity and urea levels, suggesting hepatorenal toxicity in newborn and adult rats. However, the pattern and intensity of damage was different between ages and tissues. Newborn rats showed more pronouncedly oxidative stress damage, characterized by an increase in reactive species and protein carbonyl levels, lower NPSH content and highest inhibition in δ-ALA-D and CAT activities. Besides that, it was observed a faster molecular response in protein levels involved with apoptosis and oxidative stress response; whereas in the beginning the damage was less severe in the kidney than in the liver of adult rats. Thus, the present study shows that there are body response differences between adult and newborn rats to CIS acute exposure being that newborn rats are more susceptible than adults., (Copyright © 2018. Published by Elsevier B.V.)

Obesity is a chronic and complex medical condition characterized by excessive fat accumulation and its complications include metabolic syndrome, diabetes and chronic inflammation. The aim of this study was to expand the knowledge about p-chloro-diphenyl diselenide (p-ClPhSe) 2 effects on enzymes and proteins involved in the metabolism of lipids and carbohydrates in a model of neuroendocrine obesity induced by MSG. Male Wistar rats were treated during the first ten postnatal days with MSG (4 g/kg, s.c.) and received (p-ClPhSe) 2 (10 mg/kg, i.g.) from 90 th to 97th postnatal day. The hypothalamic function, insulin resistance and other biochemical parameters were determined in the rat blood, liver and skeletal muscle. The MSG administration induced hypothalamic neurotoxicity accompanied by metabolic disorders, including obesity, a transient insulin resistance, and metabolic alterations, demonstrated in the blood, liver and skeletal muscle, and lipotoxicity, characterized in the liver and skeletal muscle. The metabolic disorders in the liver and skeletal muscle were accompanied by the decrease in AMPK phosphorylation and activation of Akt. (p-ClPhSe) 2 restored most of metabolic parameters altered by MSG administration in rats. The hypothalamic neurotoxicity induced by MSG was accompanied by metabolic disorders in rats, which were regulated by (p-ClPhSe) 2 ., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 (4.0 g/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 (4.0 g/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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

There is a well-known relationship between the cholinergic system and learning, memory, and other common cognitive processes. The process for researching and developing new drugs has lead researchers to repurpose older ones. This study investigated the effects of ebselen on the activity of acethylcholinesterase (AChE) isoforms in vitro and in an amnesia model induced by scopolamine in Swiss mice. In vitro, ebselen at concentrations equal or higher than 10 μM inhibited the activity of cortical and hippocampal G4/AChE, but not G1/AChE isoform. Treatment of mice with ebselen (50 mg/kg, i.p.) was effective against impairment of spatial recognition memory in both Y-maze and novel object recognition tests induced by scopolamine (1 mg/kg, i.p.). Ebselen (50 mg/kg) inhibited hippocampal AChE activity in mice. The present study demonstrates that ebselen inhibited the G4/AChE isoform in vitro and elicited an anti-amnesic effect in a mouse model induced by scopolamine. These findings reveal ebselen as a potential compound in terms of opening up valid therapeutic avenues for the treatment of memory impairment diseases., (© 2018 Wiley Periodicals, Inc.)

Bisphenol A (BPA) is a chemical toxicant that has deleterious effects on human. BPA causes oxidative stress in tissues, including the liver. Diphenyl diselenide (PhSe) 2 improves the antioxidant response via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein (keap 1) pathway in macrophage cells. In the present study, we investigated whether (PhSe) 2 counteracts hepatic oxidative stress induced by BPA in male and female Swiss mice. Three-week-old mice received by the intragastric (i.g.) route BPA (5 mg/kg) from 21st to 60th postnatal day (PND). At PND 61, the mice were treated with (PhSe) 2 (1 mg/kg, i.g.) for seven days. Parameters of hepatic damage and oxidative stress were determined in male and female mice. The results show that BPA increased the activity of aspartate aminotransferase in female mice, and in male mice the activity of alanine aminotranseferase was increased. Male and female mice had an increase in fat mass accumulation. Male mice showed an increase in hepatic oxidative damage of proteins and a decrease in non-enzymatic (ascorbic acid and non-protein thiol) and enzymatic (superoxide dismutase) defenses, which are consistent with oxidative stress status. Male mice were more susceptible than female mice to hepatic oxidative stress induced by BPA. BPA decreased Nrf2/Keap1 protein content in male mice. (PhSe) 2 reduced hepatic oxidative stress induced by BPA in male mice. Our results demonstrate that male mice were more susceptible to hepatic oxidative stress induced by BPA than female mice. (PhSe) 2 regulated Nrf2/Keap-1 signaling pathway and countered hepatic oxidative stress induced by BPA in male mice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Appropriate treatment of pain requires analgesics and anti-inflammatory drugs generally associated with undesirable side effects and not fully effective in a significant proportion of patients. Organoselenium compounds elicit a plenty of pharmacological effects in different animal models. Among these compounds, the 2,2`-dipyridyl diselenide (DPD) has a potent antioxidant effect and low toxicity. In this way, the aim of this study was to investigate the possible DPD antinociceptive effect and its mechanism of action, as well as the safety of the compound. Female Swiss mice were treated with vehicle or DPD (0.01-50 mg/kg) intragastrically. Dose-response curve and time-course of the antinociceptive effect of DPD were performed on formalin and tail immersion tests. Morphine (2.5 mg/kg, subcutaneous, 15 min earlier) was used as a positive control in behavioral tests. The results showed that DPD presents a rapid antinociceptive effect in low doses, without changing the spontaneous locomotor activity and parameters of toxicity in mice. The DPD antinociceptive effect was also confirmed in male Swiss mice in both formalin and tail immersion tests. In addition, DPD reduced the paw edema induced by 2.5% formalin and ear edema induced by 2.5% croton oil. l-arginine (600 mg/kg, intraperitoneally) reduced the DPD antinociceptive effect in the first phase of the formalin test. Moreover, DPD attenuated the increase in iNOS, NF-κB and JNK phosphorylation in the spinal cord of mice injected with formalin. These results showed that DPD exerts peripheral and central nociceptive actions associated with anti-inflammatory effect and this organoselenium compound could be an interesting alternative therapy for pain treatment., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

The progressive decline of neurological functions, such as learning and memory, is an unavoidable consequence of aging. Our previous work suggested that the combination of physical exercise and a diet supplemented with diphenyl diselenide improves age-related memory decline in rats. The present study investigated the effects of physical exercise and a diet supplemented with diphenyl diselenide on the levels of proteins involved in the hippocampal neuroprotection to figure out the mechanisms related to the beneficial effects of this intervention in aged rats. Male Wistar rats (27 months old) were fed daily with standard chow supplemented with 1 ppm of diphenyl diselenide and subjected to swimming training with a workload (1% of body weight, 20 min/day) for 4 weeks. The hippocampus was dissected from the brain and used for the western blot and immunohistochemistry analyses. The results of this study demonstrate that the association of diphenyl diselenide-supplemented diet and swimming exercise increased the levels of proteins involved in neuroprotection and decreased the activation of those related to apoptosis and neuroinflammation in the hippocampus of old rats. This study suggests that physical exercise and a diet supplemented with (PhSe) 2 promoted neuroprotection in the hippocampus of aged rats.

Depressive symptoms precipitated by stress are prevalent in population. In experimental models of social stress, endogenous opioids mediate different aspects of defensive and submissive behaviors. The present study investigated the opioid receptors, mitogen-activated protein kinase (MAPKs) and protein kinase B (Akt) contribution to m-trifluoromethyl-diphenyl diselenide [(m-CF 3 -PhSe) 2 ] effects on social avoidance induced by social defeat stress (SDS). Adult Swiss mice were subjected to SDS and treated with (m-CF 3 -PhSe) 2 (5 to 25mg/kg) for 7days. After that, the mice performed locomotor and social avoidance tests. The opioid receptors, MAPKs and Akt protein contents were determined in the prefrontal cortical samples of mice. Firstly, the mice were segregated in susceptible or resilient subpopulation based on their social avoidance induced by stress. (m-CF 3 -PhSe) 2 (25mg/kg) was effective against the stress-induced social avoidance and improved social interaction behavior in mice. SDS increased the μ and κ protein contents but reduced those of δ opioid receptors in susceptible mice. Resilient and (m-CF 3 -PhSe) 2 -treated mice had no alteration in the levels of opioid receptors. Moreover, (m-CF 3 -PhSe) 2 was effective against the increase of c-Jun N-terminal kinase (JNK) and the decrease of Akt phosphorylation protein contents induced by SDS in susceptible mice. The protein content of extracellular signal-regulated kinase (ERK) phosphorylation was reduced in both susceptible and resilient mice, whereas p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation was increased only in resilient mice. (m-CF 3 -PhSe) 2 was partially effective against the pERK decrease and ineffective against the increase in p38 MAPK phosphorylation in mice subjected to SDS. These results suggest that the modulation of protein contents of opioid receptors, JNK and Akt phosphorylation is associated with resilience to SDS promoted by (m-CF 3 -PhSe) 2 in mice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neuropathic pain is a public health problem and its treatment is a global challenge. The organoselenium compound p,p'-methoxyl-diphenyl diselenide [(OMePhSe) 2 ] has a potential antinociceptive action and its incorporation into nanocapsules improves this action. The current study evaluated if (OMePhSe) 2 administration, free or incorporated into nanocapsules, reduces the chronic pain-like behavior induced by the partial sciatic nerve ligation (PSNL) surgery, a neuropathic pain mouse model. It was also investigated the (OMePhSe) 2 restorative effect against the increase in inflammatory and apoptotic protein contents at the central nervous system caused by PSNL to mice. Male Swiss mice were subjected to PSNL during 4 weeks and treated with (OMePhSe) 2 , free or incorporated into nanocapsules, in a single (25mg/kg, i.g.) or repeated administration schedule (25mg/kg, i.g., once a day for seven days). Both treatments reduced mechanical hypernociception induced by PSNL, but the nanoencapsulation increased the (OMePhSe) 2 antinociceptive action two-fold in comparison to its free form. PSNL increased the inflammatory protein contents (iNOS, COX-2, NF-κB, IL-1β and TNF-α) and those of bax and clivated PARP, and reduced bcl-2 content, apoptotic proteins, in the mouse cerebral contral lateral cortex. Furthermore, PSNL induced an activation of MAPK pathway (ERK 1,2 and p38). The free or nanoencapsulated (OMePhSe) 2 repeated administration restored the molecular changes in the protein contents. This study demonstrates the (OMePhSe) 2 nanocapsule effectiveness in an animal model of chronic pain., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Parkinson's disease (PD) is a dopaminergic neurodegenerative disorder, which presents motor and non-motor symptoms. 7-Fluoro-1,3-diphenylisoquinoline (FDPI) is an isoquinoline compound with antioxidant and antidepressant properties. This study investigated whether FDPI reverses motor and non-motor symptoms in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It was also assessed the anti-inflammatory mechanisms in FDPI pharmacological action. C57Bl/6 male adult mice received four MPTP (20mg/kg, intraperitoneal) or saline (vehicle) injections to induce an acute PD model. FDPI (10mg/kg, intragastric) was daily administered to mice from the 2nd to 9th day after the induction and mice performed the behavioral tests on the 8th and 9th days. Striatum samples were collected for biochemical and molecular analyses. The results of the rotarod and challenging beam tests demonstrated that the administration of FDPI attenuated the impairments in balance and coordination of mice induced by MPTP. The FDPI reversed the short-term memory deficit and depressive-like behavior induced by MPTP in mice. FDPI attenuated the reduction in the striatal tyrosine hydroxylase levels, and it reversed the increase in the cyclooxygenase-2 levels and myeloperoxidase activity caused by MPTP in mice. Therefore, FDPI reversed motor and non-motor symptoms induced by an acute PD model and its restorative effects seem to be mediated by an anti-inflammatory action associated with a modulation of the striatal cyclooxygenase-2 levels and myeloperoxidase activity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study aimed the development of nanocapsules (NCs) for oral indole-3-carbinol (I3C) administration and evaluation of antinociceptive potential of this compound in its two forms, free and nanoencapsulated, using acute pain models. NCs showed adequate physicochemical characteristics and protected the I3C against UVC radiation exposure. It was observed no chemical bond between I3C and polymer by FTIR. Besides, X-ray and DSC analysis suggested that I3C was molecularly dispersed in NCs. The dialysis bag technique showed that almost 100% of the compound was released from NCs at 360min. Mathematical modeling demonstrated that this release occurred in two rates, with an initial burst effect followed by a slower release of I3C. Regarding the in vivo analysis, time-response curve showed that both forms of I3C caused an inhibition in inflammatory phase of nociception induced by formalin and increased the latency response in hot plate test. Interestingly, NCs were able to prolong the I3C effect in both tests. Furthermore, in dose-response curve, only I3C in its nanoencapsulated form presented effect on inflammatory phase of the formalin test. In conclusion, NCs to I3C incorporation presented adequate nanometric characteristics and prolonged its antinociceptive action in acute pain models tested., (Copyright © 2017. Published by Elsevier B.V.)

The current study investigated the effect of organoselenium compound p,p'-methoxyl-diphenyl diselenide [(OMePhSe) 2 ], free or incorporated into nanocapsules, on behavioral, biochemical and molecular alterations in an inflammatory pain model induced by complete Freund's adjuvant (CFA). Male Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h later they were treated via the intragastric route with a single (OMePhSe) 2 administration, in its free form (dissolved in canola oil) or (OMePhSe) 2 NC. The anti-hypernociceptive time- and dose-response curves were carried out using the von Frey hair test. Biochemical and histological parameters were determined in samples of injected paws and those of cerebral contralateral cortex were collected to determine immuno content of inflammatory proteins. Both (OMePhSe) 2 forms reduced the hypernociception induced by CFA as well as attenuated the altered parameters of the inflammatory process in the paw (paw edema, myeloperoxidase and histological). However, the (OMePhSe) 2 NC had a more prolonged anti-hypernociceptive action (7h) at a lower dose (10mg/kg) and superior effects on the paw alterations than the free compound form (4h and 25mg/kg). Furthermore, independent of the (OMePhSe) 2 form, its administration decreased the MAPKs pathway activation (JNK;ERK 1,2 ; p38) as well as iNOS, COX-2, Nf-κB and IL-1β protein contents in the cerebral contralateral cortex that were increased by paw CFA injection. Therefore, (OMePhSe) 2 NC had superior anti-inflammatory action, which possibly occurs by the inflammatory protein content modulation and also attenuates paw biochemical and histological inflammatory alterations induced by CFA injection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) is one of the most common types of brain injuries that cause death or persistent neurological disturbances in survivors. Most of the promising experimental drugs were not effective in clinical trials; therefore, the development of TBI drugs represents a huge unmet need. Guanosine, an endogenous neuroprotective nucleoside, has not been evaluated in TBI to the best of our knowledge. Therefore, the present study evaluated the effect of guanosine on TBI-induced neurological damage. Our findings showed that a single dose of guanosine (7.5 mg/kg, intraperitoneally (i.p.) injected 40 min after fluid percussion injury (FPI) in rats protected against locomotor and exploratory impairments 8 h after injury. The treatment also protected against neurochemical damage to the ipsilateral cortex, glutamate uptake, Na + /K + -ATPase, glutamine synthetase activity, and alterations in mitochondrial function. The inflammatory response and brain edema were also reduced by this nucleoside. In addition, guanosine protected against neuronal death and caspase 3 activation. Therefore, this study suggests that guanosine plays a neuroprotective role in TBI and can be exploited as a new pharmacological strategy.

Selenium is an essential trace element for animals and its role in the chemistry of life relies on a unique functional group: the selenol (-SeH) group. The selenol group participates in critical redox reactions. The antioxidant enzymes glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) exemplify important selenoproteins. The selenol group shares several chemical properties with the thiol group (-SH), but it is much more reactive than the sulfur analogue. The substitution of S by Se has been exploited in organic synthesis for a long time, but in the last 4 decades the re-discovery of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) and the demonstration that it has antioxidant and therapeutic properties has renovated interest in the field. The ability of ebselen to mimic the reaction catalyzed by GPx has been viewed as the most important molecular mechanism of action of this class of compound. The term GPx-like or thiol peroxidase-like reaction was previously coined in the field and it is now accepted as the most important chemical attribute of organoselenium compounds. Here, we will critically review the literature on the capacity of organoselenium compounds to mimic selenoproteins (particularly GPx) and discuss some of the bottlenecks in the field. Although the GPx-like activity of organoselenium compounds contributes to their pharmacological effects, the superestimation of the GPx-like activity has to be questioned. The ability of these compounds to oxidize the thiol groups of proteins (the thiol modifier effects of organoselenium compounds) and to spare selenoproteins from inactivation by soft-electrophiles (MeHg + , Hg 2+ , Cd 2+ , etc.) might be more relevant for the explanation of their pharmacological effects than their GPx-like activity. In our view, the exploitation of the thiol modifier properties of organoselenium compounds can be harnessed more rationally than the use of low mass molecular structures to mimic the activity of high mass macromolecules that have been shaped by millions to billions of years of evolution.

The injection of complete Freund's adjuvant (CFA) in the hindpaw of rodents induces tissue inflammation and nociceptive hypersensitivity. In addition, it has been reported that organoselenium compounds have antinociceptive properties in animal models. The purpose of this study was to investigate the potential antinociceptive effect of bis(phenylimidazoselenazolyl) diselenide (BPIS) in the inflammatory nociception model in mice and its possible mechanism of action. C57BL/6 mice received CFA intraplantar in right hindpaw and the inflammatory response was verified 24h after injection as well as the antinociceptive effect of BPIS. The CFA-induced mechanical allodynia was reversed by BPIS treatment (1mg/kg, p.o.) observed through the von Frey hair test. Additionally, L-arginine (600mg/kg; i.p.), administered before BPIS treatment, blocked its antinociceptive effect. Regarding myeloperoxidase activity, NOx and 3-nitrotyrosine levels, BPIS administration did not reverse alterations observed in the paw of animals injected with CFA. BPIS reversed the increase in spinal NOx content induced by CFA. In the spinal cord, it was also found that CFA induced an increase in malondialdehyde content and a decrease in glutamate uptake, and these alterations were reversed by BPIS. Moreover, BPIS treatment induced an increase in non-protein thiol levels in spinal cord of animals that received CFA injection. No alterations were found in glutathione peroxidase, reductase and S-transferase activities of experimental groups. The obtained data reinforce the relevance of BPIS as an antinociceptive agent as well as highlight the importance of the nitric oxide pathway in the spinal cord and its antioxidant potential for its mechanism of action., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Behavioral studies have suggested that (p-ClPhSe) 2 elicits an anorectic-like action in rats by inducing multiple effects such as satiety-enhancing effect, malaise and specific flavor; however, the molecular mechanisms underlying its anorexigenic action remain unclarified. Here, male Sprague-Dawley rats received acute and sub-chronic intraperitoneal treatments with (p-ClPhSe) 2 ; thereafter, in vivo and ex vivo analyses were carried out. The present study reveals that the reduction of food intake resulting from a single treatment with (p-ClPhSe) 2 (1mg/kg, i.p.) was associated with decreased hypothalamic levels of pro-melanin-concentrating hormone (pro-MCH) and orexin precursor. In addition, repeated administrations of (p-ClPhSe) 2 (10mg/kg; i.p.) for 7 days induced sustained food intake suppression, body weight loss and white fat reduction. Measurements of brown adipose tissue content and temperature as well as data obtained from a pair-fed group indicated that the effects of (p-ClPhSe) 2 on the body weight are closely related to its anorexigenic actions, ruling out the possibility of increased thermogenesis. Furthermore, (p-ClPhSe) 2 reduced the hypothalamic orexin precursor levels when repeatedly administered to rats. Sub-chronic treatment with (p-ClPhSe) 2 caused a decrease of serum triglyceride levels and down-regulation of hepatic cholesterol content. Therefore, the current study characterized the anorectic and reducing body weight actions of (p-ClPhSe) 2 in Sprague-Dawley rats. Besides, the set of results suggests that food intake suppressant effects triggered after (p-ClPhSe) 2 administration to rats are mainly related with the lower orexin levels in hypothalamus after acute and sub-chronic treatments., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Certain stressful life events have been associated with the onset of depression. This study aims to investigate if 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) is effective against social avoidance induced by social defeat stress model in mice. Furthermore, it was investigated the effects of FDPI in the mouse prefrontal cortical plasticity-related proteins and some parameters of toxicity. Adult Swiss mice were subjected to social defeat stress for 10 days. Two protocols with FDPI were carried out: 1- FDPI (25 mg/kg, intragastric) was administered to mice 24 h after the last social defeat stress episode; 2- FDPI (1-25 mg/kg, intragastric) was administered to mice once a day for 10 days concomitant with the social defeat stress. The mice performed social avoidance and locomotor tests. The prefrontal cortical protein contents of kinase B (Akt), extracellular signal-regulated kinase (ERK), cAMP-response element binding protein (CREB), pro-brain-derived neurotrophic factor (proBDNF), p75 NTR , neuronal nuclear protein (NeuN) and nuclear factor-κB (NF-κB) were determined in mice. A single administration of FDPI (25 mg/kg) partially protected against social avoidance induced by stress in mice. Repeated administration of FDPI (25 mg/kg) protected against social avoidance induced by stress in mice. Social defeat stress decreased the protein contents of p75 NTR , NeuN and the pERK/ERK ratio but increased those of proBDNF and the pCREB/CREB ratio, without changing that of NF-κB. Repeated administration of FDPI modulated signaling pathways altered by social defeat stress in mice. The present findings demonstrate that FDPI promoted resilience to stress in mice., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Animal and clinical researches indicate that the opioid system exerts a crucial role in the etiology of mood disorders and is a target for intervention in depression treatment. This study investigated the contribution of the opioid system to the antidepressant-like action of acute or repeated m-trifluoromethyl-diphenyl diselenide administration to Swiss mice. m-Trifluoromethyl-diphenyl diselenide (50 mg/kg, intragastric) produced an antidepressant-like action in the forced swimming test from 30 min to 24 h after treatment. This effect was blocked by the µ and δ-opioid receptor antagonists, naloxonazine (10 mg/kg, intraperitoneally) and naltrindole (3 mg/kg, intraperitoneally), and it was potentiated by a κ-opioid receptor antagonist, norbinaltrophimine (1 mg/kg, subcutaneously ). Combined treatment with subeffective doses of m-trifluoromethyl-diphenyl diselenide (10 mg/kg, intragastric) and morphine (1 mg/kg, subcutaneously) resulted in a synergistic antidepressant-like effect. The opioid system contribution to the m-trifluoromethyl-diphenyl diselenide antidepressant-like action was also demonstrated in the modified tail suspension test, decreasing mouse immobility and swinging time and increasing curling time, results similar to those observed using morphine, a positive control. Treatment with m-trifluoromethyl-diphenyl diselenide induced neither tolerance to the antidepressant-like action nor physical signs of withdrawal, which could be associated with the fact that m-trifluoromethyl-diphenyl diselenide did not change the mouse cortical and hippocampal glutamate uptake and release. m-Trifluoromethyl-diphenyl diselenide treatments altered neither locomotor nor toxicological parameters in mice. These findings demonstrate that m-trifluoromethyl-diphenyl diselenide elicited an antidepressant-like action by direct or indirect μ and δ-opioid receptor activation and the κ-opioid receptor blockade, without inducing tolerance, physical signs of withdrawal and toxicity.

The modern life leads to excess consumption of food rich in fructose; however, the long-term changes in carbohydrate and lipid metabolism could lead to metabolic dysfunction in humans. The present study evaluated the in vitro insulin-mimetic action of p-chloro-diphenyl diselenide (p-ClPhSe) 2 . The second aim of this study was to investigate if (p-ClPhSe) 2 reverses metabolic dysfunction induced by fructose load in Wistar rats. The insulin-mimetic action of (p-ClPhSe) 2  at concentrations of 50 and 100 μM was determined in slices of rat skeletal muscle. (p-ClPhSe) 2  at a concentration of 50 μM stimulated the glucose uptake by 40% in skeletal muscle. A dose-response curve revealed that (p-ClPhSe) 2  at a dose of 25 mg/kg reduced (∼20%) glycemia in rats treated with fructose (5 g/kg, i.g.). The administration of fructose impaired the liver homeostasis and (p-ClPhSe) 2 (25 mg/kg) protected against the increase (∼25%) in the G-6-Pase and isocitrate dehydrogenase activities and reduced the triglyceride content (∼25%) in the liver. (p-ClPhSe) 2 regulated the liver homeostasis by stimulating hexokinase activity (∼27%), regulating the TCA cycle activity (increased the ATP and citrate synthase activity (∼15%)) and increasing the glycogen levels (∼67%). In conclusion, (p-ClPhSe) 2 stimulated carbohydrate metabolism and reversed metabolic dysfunction in rats fed with fructose., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Organoselenium compounds and indoles have gained attention due to their wide range of pharmacological properties. Depression is a recurrent and disabling psychiatric illness and current evidences support that oxidative stress and neuroinflammation are mechanisms underlying the pathophysiology of this psychiatric condition. Here, we evaluated the effect of 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI) in lipopolysaccharide (LPS)-induced depressive-like behaviour, neuroinflammation and oxidative stress in male mice. CMI pre-treatment (20 and 50 mg/kg, intragastrically) significantly attenuated LPS (0.83 mg/kg, intraperitoneally)-induced depressive-like behaviour in mice by reducing the immobility time in the tail suspension test (TST) and forced swimming test (FST). CMI pre-treatment ameliorated LPS-induced neuroinflammation by reducing the levels of interleukin (IL)-1β, IL-4 and IL-6 in the hippocampus and prefrontal cortex, as well as markers of oxidative damage. Additionally, we investigated the toxicological effects of CMI (200 mg/kg, i.g.) in the liver, kidney and brain through determination of the activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), δ-aminolevulinate dehydratase (δ-ALA-D) and creatinine levels. These biomarkers were not modified, indicating the possible absence of neuro-, hepato- and nephrotoxic effects. Our results suggest that CMI could be a therapeutic approach for the treatment of depression and other neuropsychiatric disorders associated with inflammation and oxidative stress.

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. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)