Resistance Training Modulates Hippocampal Neuroinflammation and Protects Anxiety-Depression-like Dyad Induced by an Emotional Single Prolonged Stress Model.

Stress is a triggering factor for anxious and depressive phenotypes. Exercise is known for its action on the central nervous system. This study aimed to evaluate the role of resistance exercise in an anxiety-depression-like dyad in a model of stress. Male Swiss mice (35-day-old) were exercised, three times a week for 4 weeks on nonconsecutive days. The resistance exercise consisted of climbing a 1-m-high ladder 15 times. After mice were subjected to an emotional single prolonged stress (Esps) protocol. Seven days later, they were subjected to anxiety and depression predictive behavioral tests. The results showed that exercised mice gain less weight than sedentary from weeks 3 to 5. Resistance exercise was effective against an increase in immobility time in the forced swim test and tail suspension test and a decrease in grooming time of mice subjected to Esps. Resistance exercise protected against the decrease in the percentage of open arms time and open arm entries, and the increase in the anxiety index in Esps mice. Four-week resistance exercise did not elicit an antidepressant/anxiolytic phenotype in non-stressed mice. Esps did not alter plasma corticosterone levels but increased the hippocampal glucocorticoid receptor content in mice. Resistance exercise protected against the decrease in hippocampal levels of tropomyosin kinase B (TRκB), the p-Akt/Akt, and the p-mTOR/mTOR ratios of Esps mice. Resistance exercise proved to be effective in decreasing hippocampal neuroinflammation in Esps mice. Resistance exercise protected against the increase in the hippocampal Akt/mTOR pathway and neuroinflammation, and anxiety/depression-like dyad in Esps exposed mice.

Memory impairment and depressive-like phenotype are accompanied by downregulation of hippocampal insulin and BDNF signaling pathways in prediabetic mice.

Prediabetes is the stage before diabetes in which not all the symptoms or signs required to diagnose diabetes are present, but blood glucose is abnormally high. This study investigates if memory impairment and depressive-like phenotype are accompanied by the hippocampal insulin and BDNF signaling in prediabetic mice. Male adult Swiss mice received streptozotocin (STZ, 200 mg/kg, ip) to induce prediabetes. Control mice were treated with citrate buffer (5 ml/kg, ip). To characterize prediabetes status, metabolic parameters were determined in mice. The behavioral test battery to assess memory consisted of object recognition (ORT), object location (OLT), and Morris water maze (MWM) tests. The mouse depressive-like phenotype was investigated using the forced swimming (FST) and tail suspension (TST) tests. The pIRS-1/Akt/GLUT4 and BDNF/TrkB/CREB protein contents were determined in the hippocampus of mice. Prediabetic mice showed mild hyperglycemia, reduced body weight gain, and an increase in glucose and insulin tolerance tests (AUCs). Prediabetic mice had smaller recognition and location indexes, in the ORT and OLT, than the control group. Prediabetic mice showed hippocampus-dependent spatial memory impairment, in the MWM test, and an increase in immobility time, in the TST and FST, compared to the control group. The molecular findings indicate the downregulation of hippocampal insulin and BDNF signaling in prediabetic mice. In conclusion, memory impairment and depressive-like phenotype were potentially linked to the downregulation of hippocampal pIRS-1/Akt/GLUT4 and BDNF/CREB signaling in prediabetic mice.

p-Chloro-diphenyl diselenide attenuates plasma lipid profile changes and hepatotoxicity induced by nonionic surfactant tyloxapol in rats.

Tyloxapol is a nonionic surfactant oligomer inductor of dyslipidemia, which in turn is a risk factor for liver damage. Selenium-based compounds have emerged as promising therapeutic candidates for treating different experimental disorders. This study investigated the effects of p-chloro-diphenyl diselenide (p-ClPhSe)2 on toxicity induced by Tyloxapol in rats. Plasma lipid profile, hepatic functionality and oxidative stress parameters were evaluated in adult male Wistar rats treated with (p-ClPhSe)2 (10 mg/kg; oral administration by gavage) for seven days and exposed to a single Tyloxapol injection (400 mg/kg; intraperitoneal route) 30 min after the last (p-ClPhSe)2 treatment. Tyloxapol exposure increased the plasma levels of total cholesterol, triacylglycerol, non-HDL-cholesterol and the calculated cardiac risk index (CRI). The plasma activities of alanine and aspartate aminotransferase (ALT and AST, liver function markers) were increased in rats exposed to Tyloxapol, which demonstrates a hepatic lipotoxicity. In the liver, reactive oxygen species (ROS) content was enhanced and the non-protein sulfhydryl (NPSH) levels were decreased by Tyloxapol. The data revealed that repeated treatment with (p-ClPhSe)2 reduced plasma lipid alterations and hepatotoxicity induced by Tyloxapol. Although (p-ClPhSe)2 did not reduce ROS levels increased by Tyloxapol, it increased NPSH content in the liver. Pearson's correlation coefficient revealed a positive relationship between the levels of hepatic NPSH and plasma HDL. HDL is known by eliciting antioxidant activity; therefore, the improvement in HDL function could be suggested as a therapeutic target. In conclusion, the results demonstrate the protective effects of (p-ClPhSe)2 on the hepatic lipotoxicity induced by Tyloxapol in rats.

4,4'-Dichlorodiphenyl diselenide reverses a depressive-like phenotype, modulates prefrontal cortical oxidative stress and dysregulated glutamatergic neurotransmission induced by subchronic dexamethasone exposure to mice.

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 [3H] 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.

Enhanced pharmacological actions of p,p'-methoxyl-diphenyl diselenide-loaded polymeric nanocapsules in a mouse model of neuropathic pain: Behavioral and molecular insights.

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-1ß 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 (ERK1,2 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.

p,p'-Methoxyl-diphenyl diselenide-loaded polymeric nanocapsules as a novel approach to inflammatory pain treatment: Behavioral, biochemistry and molecular evidence.

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;ERK1,2; p38) as well as iNOS, COX-2, Nf-κB and IL-1ß 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.

p,p'-Methoxyl-diphenyl diselenide-loaded polymeric nanocapsules are chemically stable and do not induce toxicity in mice.

Organoselenium compounds have been targeted to new therapeutic tools development due to their pharmacological actions. However, some toxicity issues and physicochemical limitations delay the clinical application of these compounds. The incorporation of organoselenium molecules into nanostructured systems arises as a promising alternative to overcome such restrictions. The current study proposed the characterization of the polymeric nanocapsules of p,p'-methoxyl-diphenyl diselenide [(OMePhSe)2] as well as the evaluation of the in vivo toxicity and biodistribution profile. The nanocapsules, which were composed by medium-chain triglycerides as the oil core and poly(ε-caprolactone) as the polymeric wall, showed nanometric size (236±4), low polydispersity (<0.2), negative zeta potential (-5.4±0.06), neutral pH values (7.2±0.08) and a high encapsulation efficiency (98%). Besides, the nanoencapsulation process increased the (OMePhSe)2 stability. The repeated intragastric administration of (OMePhSe)2 nanoencapsulated (25mg/kg/day during 7days) did not cause any alteration in the oxidative status, hematological parameters, and plasma biochemical markers of cellular damage. Moreover, the (OMePhSe)2 incorporation into nanocapsules increased the selenium concentrations in the tissues (kidneys, liver and plasma) suggesting an improvement in its oral bioavailability.

p,p'-Methoxyl-diphenyl diselenide elicits an antidepressant-like effect in mice without discontinuation anxiety phenotype.

Major depressive disorder is the most severe and debilitating disease among psychiatric illnesses. The abrupt interruption of antidepressant treatment may lead to a complex physiological and neuropsychiatric syndrome. The organoselenium compound (MeOPhSe)2 has been reported to have neuroprotective properties in animal models. The study aimed to investigate the effects of single or repeated administration of (MeOPhSe)2 on depressive-like behavior and if the compound administration, and its discontinuation, may affect the anxiolytic-like phenotype in Swiss mice. The results showed that repeated intragastric administration of (MeOPhSe)2 (dose range: 0.1-5mg/kg), different from a single administration, reduced the immobility time in the mouse tail suspension test. A single administration of (MeOPhSe)2 at a dose of 5mg/kg decreased the immobility time, increased the swimming time and did not alter the climbing behavior in the modified forced swimming test (mFST). Repeated administration of (MeOPhSe)2 decreased the immobility time, did not alter the swimming time and increased the climbing behavior in the mouse mFST. Repeated administration of (MeOPhSe)2 at a dose of 5mg/kg elicited a mouse anxiolytic-like phenotype in the elevated plus maze and light-dark tests. Markers of hepatic and renal function tests were not altered by repeated administration of (MeOPhSe)2 to mice. The findings indicate that a single or repeated administration of (MeOPhSe)2 elicited an antidepressant-like action in mice. Moreover, repeated treatment with (MeOPhSe)2 produced an anxiolytic-like action in mice and its profile remained stable after discontinuation.

Pomegranate seed oil nanoemulsions improve the photostability and in vivo antinociceptive effect of a non-steroidal anti-inflammatory drug.

The combination of pomegranate seed oil and ketoprofen in nanoemulsions aiming to improve the antinociceptive effect was evaluated according to the writhing test and Complete Freud's Adjuvant induced paw inflammation in mice. The formulations showed adequate characteristics and improved ketoprofen's photostability against UVC radiation exposure. The dialysis bag technique showed that 100% of the drug was released from the nanoemulsions after 3h and the oil amount had no influence on the releasing. Furthermore, time- and dose-response curves were obtained to determine the antinociceptive effect of the formulations. In the post-test, the nanoemulsion containing ketoprofen significantly reduced abdominal constrictions in time-response curve, showing effect up to 12h while the free ketoprofen showed effect up to 3h. In addition, the blank nanoemulsion presented a reduction of abdominal constriction up to 1h of pre-treatment. Regarding the dose-response curve, the free ketoprofen presents effect at 0.5mg/Kg dose and nanoemulsion at 1.0mg/Kg dose. Time- and dose-response curves were performed to determine the antinociceptive effect in inflammatory pain. After the evaluation of mechanical allodynia testing at the Von Frey Hair, the free ketoprofen showed effect up to 6h while nanoemulsions presented effect up to 10h. Moreover, acute toxicity was performed with ALT and AST activity evaluations and urea levels. After 7 days of treatment, no toxic effects for nanoemulsions were found. In conclusion, ketoprofen-loaded pomegranate seed oil nanoemulsions presented adequate characteristics and a high antinociceptive activity in the animal models tested.

Depression-related behavior and mechanical allodynia are blocked by 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene in a mouse model of neuropathic pain induced by partial sciatic nerve ligation.

Clinically, it is suggested that chronic pain might induce mood disorders like depression and anxiety. Based on this antidepressant drugs have emerged as a new therapy for pain. In this study, the effect of acute and subchronic treatments with 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene (F-DPS) on behavioral changes induced by partial sciatic nerve ligation (PSNL) was evaluated. At the 4th week after surgery, PSNL caused a significant depression-like behavior in mice evaluated in the forced swimming test (FST) and the tail suspension test (TST), which was accompanied by increased pain sensitivity. The anxiety-like behavior assessed in the light-dark test (LDT) was not modified by PSNL. Acute treatment with F-DPS, at a dose of 1 mg/kg, intragastrically (i.g.) administered 30 min before the FST, produced a significant anti-immobility effect in PSNL mice. The antidepressant drug paroxetine showed acute antidepressant-like action at a dose 10 times higher than F-DPS. Subchronic treatment with F-DPS (0.1 mg/kg, i.g.) reversed depression-like behavior of sciatic nerve-ligated mice in the TST and FST and produced a significant anxiolytic-like action in both sham-operated and PSNL animals. Although the acute F-DPS treatment did not produce anti-allodynic effect, F-DPS subchronic treatment significantly reduced pain sensitivity in PSNL mice. These findings demonstrated that F-DPS blocked behavioral changes induced by neuropathic pain, suggesting that it might be attractive in the pharmacological approach of pain-emotion diseases.