Effect of Thiazolidin-4-one Against Lipopolysaccharide-Induced Oxidative Damage, and Alterations in Adenine Nucleotide Hydrolysis and Acetylcholinesterase Activity in Cultured Astrocytes.

Astrocytes play multiple important roles in brain physiology. However, depending on the stimuli, astrocytes may exacerbate inflammatory reactions, contributing to the development and progression of neurological diseases. Therefore, therapies targeting astrocytes represent a promising area for the development of new brain drugs. Thiazolidinones are heterocyclic compounds that have a sulfur and nitrogen atom and a carbonyl group in the ring and represent a class of compounds of great scientific interest due to their pharmacological properties. The aim of this study was to investigate the effect of 3-(3-(diethylamino)propyl)-2-(4-(methylthio)phenyl)thiazolidin-4-one (DS27) on cell proliferation and morphology, oxidative stress parameters, activity of the enzymes ectonucleotidases and acetylcholinesterase (AChE) and interleukin 6 (IL-6) levels in primary astrocyte cultures treated with lipopolysaccharide (LPS), to model neuroinflammation. The astrocyte culture was exposed to LPS (10 µg/ml) for 3 h and subsequently treated with compound DS27 for 24 and 48 h (concentrations ranging to 10-100 µM). LPS induced an increase in astrocyte proliferation, AChE activity, IL-6 levels, oxidative damage, ATP and ADP and a reduction in AMP hydrolysis in rat primary astrocyte cultures. DS27 treatment was effective in reversing these alterations induced by LPS. Our findings demonstrated that DS27 is able to modulate cholinergic and purinergic signaling, redox status, and the levels of pro-inflammatory cytokines in LPS-induced astrocyte damage. These glioprotective effects of DS27 may be very important for improving neuroinflammation, which is associated with many brain diseases.

Tannic Acid Attenuates Peripheral and Brain Changes in a Preclinical Rat Model of Glioblastoma by Modulating Oxidative Stress and Purinergic Signaling.

Glioblastoma (GB) is a highly aggressive and invasive brain tumor; its treatment remains palliative. Tannic acid (TA) is a polyphenol widely found in foods and possesses antitumor and neuroprotective activities. This study aimed to investigate the effect of TA on oxidative stress parameters and the activity of ectonucleotidases in the serum, platelets, and lymphocytes and/or in the brain of rats with preclinical GB. Rats with GB were treated intragastrically with TA (50 mg/kg/day) for 15 days or with a vehicle. In the platelets of the animals with glioma, the adenosine triphosphate (ATP) and adenosine monophosphate (AMP) hydrolysis and the catalase (CAT) activity decreased. Besides, the adenosine diphosphate (ADP) hydrolysis, adenosine (Ado) deamination, and the reactive oxygen species (ROS) and nitrite levels were increased in glioma animals; however, TA reversed ROS and nitrite levels and AMP hydrolysis alterations. In lymphocytes from animals with glioma, the ATP and ADP hydrolysis, as well as Ado deamination were increased; TA treatment countered this increase. In the brain of the animals with glioma, the ROS, nitrite, and thiobarbituric acid reactive substance (TBARS) levels increased and the thiol (SH) levels and CAT and superoxide dismutase (SOD) activities were decreased; TA treatment decreased the ROS and TBARS levels and restored the SOD activity. In the serum of the animals with glioma, the ATP hydrolysis decreased; TA treatment restored this parameter. Additionally, the ROS levels increased and the SH and SOD activity decreased by glioma implant; TA treatment enhanced nitrite levels and reversed SOD activity. Altogether, our results suggest that TA is an important target in the treatment of GB, as it modulates purinergic and redox systems.

Protective Effects of Inosine on Memory Consolidation in a Rat Model of Scopolamine-Induced Cognitive Impairment: Involvement of Cholinergic Signaling, Redox Status, and Ion Pump Activities.

This study investigated the effects of inosine on memory acquisition and consolidation, cholinesterases activities, redox status and Na+, K+-ATPase activity in a rat model of scopolamine-induced cognitive impairment. Adult male rats were divided into four groups: control (saline), scopolamine (1 mg/kg), scopolamine plus inosine (50 mg/kg), and scopolamine plus inosine (100 mg/kg). Inosine was pre-administered for 7 days, intraperitoneally. On day 8, scopolamine was administered pre (memory acquisition protocol) or post training (memory consolidation protocol) on inhibitory avoidance tasks. The animals were subjected to the step-down inhibitory avoidance task 24 hours after the training. Scopolamine induced impairment in the acquisition and consolidation phases; however, inosine was able to prevent only the impairment in memory consolidation. Also, scopolamine increased the activity of acetylcholinesterase and reduced the activity of Na+, K+-ATPase and the treatment with inosine protected against these alterations in consolidation protocol. In the animals treated with scopolamine, inosine improved the redox status by reducing the levels of reactive oxygen species and thiobarbituric acid reactive substances and restoring the activity of the antioxidant enzymes, superoxide dismutase and catalase. Our findings suggest that inosine may offer protection against scopolamine-induced memory consolidation impairment by modulating brain redox status, cholinergic signaling and ion pump activity. This compound may provide an interesting approach in pharmacotherapy and as a prophylactic against neurodegenerative mechanisms involved in Alzheimer's disease.

Blueberry extract as a potential pharmacological tool for preventing depressive-like behavior and neurochemical dysfunctions in mice exposed to lipopolysaccharide.

OBJECTIVE: Major depressive disorder is a debilitating and recurrent psychiatric disorder. Blueberries have several biological properties, including neuroprotective effects, through antioxidant and anti-inflammatory actions. The aim of this study was to evaluate the effect of blueberry extract on depressive-like behavior and lipopolysaccharide (LPS)-induced neurochemical changes. METHODS: Mice were pretreated with vehicle, fluoxetine (20 mg/kg) or blueberry extract (100 or 200 mg/kg) intragastrically for seven days before intraperitoneal LPS (0.83 mg/kg) injection. Twenty-four hours after LPS administration, mice were submitted to behavioral tests. Oxidative stress and neuroinflammatory parameters were evaluated in the cerebral cortex, hippocampus, and striatum. RESULTS: Our data showed that blueberry extract or fluoxetine treatment protected against LPS-induced depressive-like behavior in tail suspension and splash tests (P < 0.05), without changes in locomotor activity (P > 0.05). LPS induced an increase in the levels of reactive oxygen species (P < 0.001), nitrite (P < 0.05) and thiobarbituric acid reactive substances (P < 0.01), as well as a reduction in total sulfhydryl content (P < 0.05) and catalase activity (P < 0.05) in brain structures; blueberry extract restored these alterations (P < 0.05). In addition, blueberry extract attenuated the increase in tumor necrosis factor-alpha (TNF-α) levels induced by LPS administration (P < 0.05). CONCLUSION: This study showed that blueberry extract exerted antidepressant-like effects, protected the brain against oxidative damage, and modulated TNF-α levels induced by LPS.

Effect of blueberry extract on energetic metabolism, levels of brain-derived neurotrophic factor, and Ca2+-ATPase activity in the hippocampus and cerebral cortex of rats submitted to ketamine-induced mania-like behavior.

Bipolar disorder (BD) is a psychiatric disease characterized by mood episodes. Blueberry is rich in bioactive compounds and shows excellent therapeutic potential against chronic diseases. The aim of this study was to evaluate the effects of blueberry extract on behavior, energetic metabolism, Ca2+-ATPase activity, and levels of brain-derived neurotrophic factor (BDNF) in the cerebral cortex and hippocampus of rats submitted to an animal model of mania induced by ketamine. Vehicle, lithium (45 mg/kg, twice a day), or blueberry extract (200 mg/kg), was orally administered to Wistar rats for 14 days. Ketamine (25 mg/kg) or vehicle was administered intraperitoneally, once a day, between the 8th and 14th day. On the 15th day, animals received ketamine or vehicle and were subjected to the open field test. Our results demonstrated that the administration of lithium and blueberry extract prevented ketamine-induced hyperlocomotion (P < 0.01). Blueberry extract attenuated the ketamine-induced reduction in the activity of complex I in the cerebral cortex (P < 0.05). Additionally, the administration of ketamine reduced the activities of complexes I and IV (P < 0.05) and citrate synthase in the hippocampus (P < 0.01). However, blueberry extract attenuated the inhibition in the activity of complex IV (P < 0.01). Furthermore, ketamine reduced the Ca2+-ATPase activity in the cerebral cortex and hippocampus (P < 0.05); however, blueberry extract prevented the change in the cerebral cortex (P < 0.05). There were no significant alterations in the levels of BDNF (P > 0.05). In conclusion, this suggested that the blueberry extract can serve as a potential therapeutic strategy for studies searching for novel therapeutic alternatives for BD patients.

Thiazolidine-2,4-dione derivative exhibits antitumoral effect and reverts behavioral and metabolic changes in a model of glioblastoma.

The aim of the present study was to evaluate the anti-glioma activity of 3-(4-fluorobenzyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (AV23) in a preclinical model of glioblastoma, as well as behavioral parameters and toxicological profile. The implantation of C6 cells in the left striatum of male Wistar rats was performed by stereotaxic surgery. After recovery, animals were treated with vehicle (canola oil) or AV23 (10 mg/kg/day) intragastrically for 15 days. It was found that AV23 reduced tumor volume by 90%. Serum biochemical parameters such as triglycerides, cholesterol, HDL-cholesterol, LDL-cholesterol, albumin, aspartate aminotransferase, urea, creatinine and total proteins were not changed; however, there was a slight increase in alanine aminotransferase. The compound AV23 reverted the hypoglycemia and the reduction in body weight caused by glioblastoma. Additionally, AV23 was able to revert the reduction of locomotion caused by the tumor implantation. Therefore, the compound AV23 can be considered a promising candidate in the treatment of glioblastoma.

Selective in vitro anticancer effect of blueberry extract (Vaccinium virgatum) against C6 rat glioma: exploring their redox status.

The aim of this study was to investigate the anticancer potential of blueberry extract (Vaccinium virgatum) against a C6 rat glioma lineage. Cultures of the C6 cells were exposed to blueberry extract at concentrations of 50 to 600 µg/mL for 12, 24, 48, or 72 h and then evaluated for cell viability, proliferation, migration, colony formation and oxidative stress. We also evaluated the effects of blueberry extract on primary rat cortical astrocytes. Our results show that treatment with blueberry extract did not alter the viability or proliferation of normal primary astrocytes but it did significantly reduce the viability in 21.54 % after 48 h and proliferation in 8.59 % after 24 h of C6 cells at 200 µg/mL. We also observed a reduction in the size of the colonies of 29.99 % at 100 µg/mL when compared to the control cells and cell migration was also reduced at 50 µg/mL. After 72 h, there was a reduction in the reactive oxygen species levels ranging from 46.26 to 34.73 %, in addition to a 380.2 % increase in total thiol content. Superoxide dismutase, catalase, and glutathione S-transferase activities were also enhanced when compared to the control. Taken together this data suggests that blueberry extract exerts some selective anticancer activity in C6 glioma cells.

Multitarget Effect of 2-(4-(Methylthio)phenyl)-3-(3-(piperidin-1-yl)propyl)thiazolidin-4-one in a Scopolamine-Induced Amnesic Rat Model.

Cholinergic system dysfunction, oxidative damage, and alterations in ion pump activity have been associated with memory loss and cognitive deficits in Alzheimer's disease. 1,3-thiazolidin-4-ones have emerged as a class of compounds with potential therapeutic effects due to their potent anticholinesterase activity. Accordingly, this study investigated the effect of the 2-(4-(methylthio)phenyl)-3-(3-(piperidin-1-yl)propyl)thiazolidin-4-one (DS12) compound on memory, cholinergic and oxidative stress parameters, ion pump activity, and serum biochemical markers in a scopolamine-induced memory deficit model. Male Wistar rats were divided into four groups: I-Control; II-Scopolamine; III-DS12 (5 mg/kg) + scopolamine; and IV-DS12 (10 mg/kg) + scopolamine. The animals from groups III and IV received DS12 diluted in canola oil and administered for 7 days by gavage. On the last day of treatment, scopolamine (1 mg/kg) was administered intraperitoneally (i.p.) 30 min after training in an inhibitory avoidance apparatus. Twenty-four hours after scopolamine administration, the animals were subjected to an inhibitory avoidance test and were thereafter euthanized. Scopolamine induced memory deficits, increased acetylcholinesterase activity and oxidative damage, and decreased Na+/K+-ATPase activity in cerebral cortex and hippocampus. Pretreatment with DS12 prevented these brain alterations. Scopolamine also induced an increase in acetylcholinesterase activity in lymphocytes and whereas butyrylcholinesterase in serum and treatment with DS12 prevented these changes. In animals treated with DS12, no changes were observed in renal and hepatic parameters when compared to the control group. In conclusion, DS12 emerged as an important multitarget compound capable of preventing neurochemical changes associated with memory deficits.

The Protective Action of Rubus sp. Fruit Extract Against Oxidative Damage in Mice Exposed to Lipopolysaccharide.

Neuroinflammation is an event that occurs in several pathologies of brain. Rubus sp. (blackberry) is a powerful antioxidant fruit, and its extract has neuroprotective activity. The aim of this study was to investigate the blackberry extract properties on lipopolysaccharide (LPS)-induced neuroinflammation, in relation to oxidative parameters and acetylcholinesterase activity in the brain structures of mice. We also investigated interleukin-10 levels in serum. Mice were submitted to Rubus sp. extract treatment once daily for 14 days. On the fifteenth day, LPS was injected in a single dose. LPS induced oxidative brain damage and the blackberry extract demonstrated preventive effects in LPS-challenged mice. LPS administration increased reactive oxygen species levels in the cerebral cortex and striatum, as well as lipid peroxidation in the cerebral cortex. However, the blackberry extract prevented all these parameters. Furthermore, LPS decreased thiol content in the striatum and hippocampus, while a neuroprotective effect of blackberry extract treatment was observed in relation to this parameter. The blackberry extract also prevented a decrease in catalase activity in all the brain structures and of superoxide dismutase in the striatum. An increase in acetylcholinesterase activity was detected in the cerebral cortex in the LPS group, but this activity was decreased in the Rubus sp. extract group. Serum IL-10 levels were reduced by LPS, and the extract was not able to prevent this change. Finally, we observed an antioxidant effect of blackberry extract in LPS-challenged mice suggesting that this anthocyanin-rich extract could be considered as a potential nutritional therapeutic agent for preventive damage associated with neuroinflammation.

Therapeutic approaches employing natural compounds and derivatives for treating bipolar disorder: emphasis on experimental models of the manic phase.

Bipolar disorder (BD) is a complex psychiatric disease characterized by mood swings that include episodes of mania and depression. Given its cyclical nature, BD is especially hard to model; however, the standard practice has been to mimic manic episodes in animal models. Despite scientific advances, the pathophysiology of BD is not fully understood, and treatment remains limited. In the last years, natural products have emerged as potential neuroprotective agents for the treatment of psychiatric diseases. Thus, the aim of this review was to explore the therapeutic potential of natural compounds and derivatives against BD, taking into account preclinical and clinical studies. Reliable articles indexed in databases such as PubMed, Web of Science and Science Direct were used. In clinical studies, treatment with herbal plants extracts, omega-3, inositol, n-acetylcysteine and vitamin D has been associated with a clinical improvement in symptoms of mania and depression in BD patients. In animal models, it has been shown that red fruits extracts, curcumin, quercetin, gallic acid, alpha-lipoic acid and carvone can modulate many neurochemical pathways involved in the pathophysiology of manic episodes. Thus, this review appointed the advances in the consumption of natural compounds and derivatives as an important therapeutic strategy to mitigate the symptoms of BD.

Ameliorative effect of tannic acid on hypermethioninemia-induced oxidative and nitrosative damage in rats: biochemical-based evidences in liver, kidney, brain, and serum.

We investigated the ability of tannic acid (TA) to prevent oxidative and nitrosative damage in the brain, liver, kidney, and serum of a rat model of acute hypermethioninemia. Young Wistar rats were divided into four groups: I (control), II (TA 30 mg/kg), III (methionine (Met) 0.4 g/kg + methionine sulfoxide (MetO) 0.1 g/kg), and IV (TA/Met + MetO). Rats in groups II and IV received TA orally for seven days, and rats of groups I and III received an equal volume of water. After pretreatment with TA, rats from groups II and IV received a single subcutaneous injection of Met + MetO, and were euthanized 3 h afterwards. In specific brain structures and the kidneys, we observed that Met + MetO led to increased reactive oxygen species (ROS), nitrite, and lipid peroxidation levels, followed by a reduction in thiol content and antioxidant enzyme activity. On the other hand, pretreatment with TA prevented both oxidative and nitrosative damage. In the serum, Met + MetO caused a decrease in the activity of antioxidant enzymes, which was again prevented by TA pretreatment. In contrast, in the liver, there was a reduction in ROS levels and an increase in total thiol content, which was accompanied by a reduction in catalase and superoxide dismutase activities in the Met + MetO group, and pretreatment with TA was able to prevent only the reduction in catalase activity. Conclusively, pretreatment with TA has proven effective in preventing oxidative and nitrosative changes caused by the administration of Met + MetO, and may thus represent an adjunctive therapeutic approach for treatment of hypermethioninemia.

Hypermethioninemia induces memory deficits and morphological changes in hippocampus of young rats: implications on pathogenesis.

The aim of this study was to investigate the effect of the chronic administration of methionine (Met) and/or its metabolite, methionine sulfoxide (MetO), on the behavior and neurochemical parameters of young rats. Rats were treated with saline (control), Met (0.2-0.4 g/kg), MetO (0.05-0.1 g/kg), and/or a combination of Met + MetO, subcutaneously twice a day from postnatal day 6 (P6) to P28. The results showed that Met, MetO, and Met + MetO impaired short-term and spatial memories (P < 0.05), reduced rearing and grooming (P < 0.05), but did not alter locomotor activity (P > 0.05). Acetylcholinesterase activity was increased in the cerebral cortex, hippocampus, and striatum following Met and/or MetO (P < 0.05) treatment, while Na+, K+-ATPase activity was reduced in the hippocampus (P < 0.05). There was an increase in the level of thiobarbituric acid reactive substances (TBARS) in the cerebral cortex in Met-, MetO-, and Met + MetO-treated rats (P < 0.05). Met and/or MetO treatment reduced superoxide dismutase, catalase, and glutathione peroxidase activity, total thiol content, and nitrite levels, and increased reactive oxygen species and TBARS levels in the hippocampus and striatum (P < 0.05). Hippocampal brain-derived neurotrophic factor was reduced by MetO and Met + MetO compared with the control group. The number of NeuN-positive cells was decreased in the CA3 in Met + MetO group and in the dentate gyrus in the Met, MetO, and Met + MetO groups compared to control group (P < 0.05). Taken together, these findings further increase our understanding of changes in the brain in hypermethioninemia by elucidating behavioral alterations, biological mechanisms, and the vulnerability of brain function to high concentrations of Met and MetO.

Antidepressant Effect and Modulation of the Redox System Mediated by Tannic Acid on Lipopolysaccharide-Induced Depressive and Inflammatory Changes in Mice.

Depression is an emotional disorder that causes mental and physical changes, and has limited pharmacotherapy. Tannic acid (TA) is a polyphenol with previously described antioxidant and neuroprotective properties. The aim of this study was to evaluate the effects of TA on lipopolysaccharide (LPS)-induced depressive-like behavior, as well as oxidative stress parameters and TNF-α levels in the brains of mice. Animals were pretreated once daily, with TA (30 or 60 mg/kg), fluoxetine (20 mg/kg) or vehicle for 7 days. On the 7th day, the animals received a single injection of LPS (830 µg/kg). After 24 h, open field, forced swimming, tail suspension, and splash tests were conducted. The endotoxin induced depressive-like behavior in these mice and this was attenuated by TA. In the cerebral cortex, hippocampus, and striatum, LPS increased lipid peroxidation and reactive oxygen species production, and this was also prevented by TA administration. TA treatment also prevented a decrease in catalase activity within the striatum. Further, LPS administration caused increased levels of TNF-α in all brain structures, and this was prevented in the cortex by TA treatment. In conclusion, TA shows many neuroprotective properties, with demonstrated antioxidant, anti-inflammatory and antidepressant effects in this animal model of acute depressive-like behavior. Therefore, this compound could provide an alternative therapeutic approach for the treatment of depression.

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

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

Hypolipidemic and anti-inflammatory properties of phenolic rich Butia odorata fruit extract: potential involvement of paraoxonase activity.

Aim: This study investigated the effects of polar Butia odorata fruit extract on metabolic, inflammatory, and oxidative stress parameters in rats submitted to a hyperlipidaemia condition induced by tyloxapol.Methods: Animals were divided into 3 groups: saline, saline plus tyloxapol, and B. odorata extract plus tyloxapol. Animals were treated for 15 days with a saline solution or B. odorata fruit extract and after hyperlipidaemia was induced by tyloxapol.Results: Treatment with B. odorata extract reduced serum triglyceride, total cholesterol, C-reactive protein, and adenosine deaminase and butyrylcholinesterase activities when compared to the tyloxapol group. HDL-cholesterol and paraoxonase 1 activity were higher in B. odorata extract treated animals when compared to tyloxapol-treated animals. No differences were observed in hepatic oxidative stress parameters. Phenolic compounds present in B. odorata fruit extract were identified and quantified by LC-MS/MS.Conclusion: These findings indicated that phenolic rich B. odorata extract has hypolipidemic and anti-inflammatory effects in hyperlipidemic rats.

High levels of methionine and methionine sulfoxide: Impact on adenine nucleotide hydrolysis and redox status in platelets and serum of young rats.

We investigated acute and chronic effects administration of methionine (Met) and/or methionine sulfoxide (MetO) on ectonucleotidases and oxidative stress in platelets and serum of young rats. Wistar rats were divided into four groups: control, Met, MetO, and Met + MetO. In acute treatment, the animals received a single subcutaneous injection of amino acid(s) and were euthanized after 1 and 3 hours. In chronic protocol, Met and/or MetO were administered twice a day with an 8-hour interval from the 6th to the 28th day of life. Nucleoside triphosphate phosphohydrolase and 5'-nucleotidase activities were reduced in platelets and serum by Met, MetO, and Met + MetO after 3 hours and 21 days. Adenosine deaminase activity reduced in platelets at 3 hours after MetO and Met + MetO administration and increased after 21 days in animals treated with Met + MetO. Superoxide dismutase and catalase activities decreased in platelets in MetO and Met + MetO groups after 3 hours, while reactive oxygen species (ROS) levels increased in same groups. Catalase activity in platelets decreased in all experimental groups after chronic treatment. Met, MetO, and Met + MetO administration increased plasmatic ROS levels in acute and chronic protocols; glutathione S-transferase activity increased by MetO and Met + MetO administration at 3 hours, and ascorbic acid decreased in all experimental groups in acute and chronic protocols. Thiobarbituric acid reactive substances increased, superoxide dismutase and catalase activities reduced in the Met and/or MetO groups at 3 hours and in chronic treatment. Our data demonstrated that Met and/or MetO induced changes in adenine nucleotide hydrolysis and redox status of platelets and serum, which can be associated with platelet dysfunction in hypermethioninemia.

2-(2-Methoxyphenyl)-3-((Piperidin-1-yl)ethyl)thiazolidin-4-One-Loaded Polymeric Nanocapsules: In Vitro Antiglioma Activity and In Vivo Toxicity Evaluation.

Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.

Combined actions of blueberry extract and lithium on neurochemical changes observed in an experimental model of mania: exploiting possible synergistic effects.

Bipolar disorder is a psychiatric disease characterized by recurrent episodes of mania and depression. Blueberries contain bioactive compounds with important pharmacological effects such as neuroprotective and antioxidant actions. The aim of this study was to investigate the effects of blueberry extract and/or lithium on oxidative stress, and acetylcholinesterase (AChE) and Na+, K+-ATPase activity in an experimental ketamine-induced model of mania. Male Wistar rats were pretreated with vehicle, blueberry extract (200 mg/kg), and/or lithium (45 mg/kg or 22.5 mg/kg twice daily) for 14 days. Between the 8th and 14th days, the animals also received an injection of ketamine (25 mg/kg) or vehicle. On the 15th day the animals received a single injection of ketamine; after 30 min, the locomotor activity was evaluated in an open field test. Ketamine administration induced an increase in locomotor activity. In the cerebral cortex, hippocampus and striatum, ketamine also induced an increase in reactive oxygen species, lipid peroxidation and nitrite levels, as well a decrease in antioxidant enzyme activity. Pretreatment with blueberry extract or lithium was able to prevent this change. Ketamine increased the AChE and Na+, K+-ATPase activity in brain structures, while the blueberry extract partially prevented these alterations. In addition, our results showed that the neuroprotective effect was not potentiated when lithium and blueberry extract treatment were given together. In conclusion, our findings suggest that blueberry extract has a neuroprotective effect against an experimental model of mania. However, more studies should be performed to evaluate its effects as an adjuvant therapy.

Glioprotective Effects of Lingonberry Extract Against Altered Cellular Viability, Acetylcholinesterase Activity, and Oxidative Stress in Lipopolysaccharide-Treated Astrocytes.

Altered astrocytic function is a contributing factor to the development of neurological diseases and neurodegeneration. Berry fruits exert neuroprotective effects by modulating pathways involved in inflammation, neurotransmission, and oxidative stress. The aim of this study was to examine the effects of the lingonberry extract on cellular viability and oxidative stress in astrocytes exposed to lipopolysaccharide (LPS). In the reversal protocol, primary astrocytic cultures were first exposed to 1 µg/mL LPS for 3 h and subsequently treated with lingonberry extract (10, 30, 50, and 100 µg/mL) for 24 and 48 h. In the prevention protocol, exposure to the lingonberry extract was performed before treatment with LPS. In both reversal and prevention protocols, the lingonberry extracts, from 10 to 100 µg/mL, attenuated LPS-induced increase in reactive oxygen species (around 55 and 45%, respectively, P < 0.01), nitrite levels (around 50 and 45%, respectively, P < 0.05), and acetylcholinesterase activity (around 45 and 60%, respectively, P < 0.05) in astrocytic cultures at 24 and 48 h. Also, in both reversal and prevention protocols, the lingonberry extract also prevented and reversed the LPS-induced decreased cellular viability (around 45 and 90%, respectively, P < 0.05), thiol content (around 55 and 70%, respectively, P < 0.05), and superoxide dismutase activity (around 50 and 145%, respectively, P < 0.05), in astrocytes at both 24 and 48 h. Our findings suggested that the lingonberry extract exerted a glioprotective effect through an anti-oxidative mechanism against LPS-induced astrocytic damage.

Southern Brazilian native fruit shows neurochemical, metabolic and behavioral benefits in an animal model of metabolic syndrome.

In this work, we evaluated the effects of Psidium cattleianum (Red Type) (PcRT) fruit extract on metabolic, behavioral, and neurochemical parameters in rats fed with a highly palatable diet (HPD) consisted of sucrose (65% carbohydrates being 34% from condensed milk, 8% from sucrose and 23% from starch, 25% protein and 10% fat). Animals were divided into 4 groups: standard chow, standard chow + PcRT extract (200 mg/Kg/day by gavage), HPD, HPD + extract. The animals were treated for 150 days. Concerning chemical profiling, LC/PDA/MS/MS analysis revealed cyanidin-3-O-glucoside as the only anthocyanin in the PcRT extract. Our results showed that the animals exposed to HPD presented glucose intolerance, increased weight gain and visceral fat, as well as higher serum levels of glucose, triacylglycerol, total cholesterol, LDL-cholesterol and interleukin-6. These alterations were prevented by PcRT. In addition, HPD caused an increase in immobility time in a forced swimming test and the fruit extract prevented this alteration, indicating an antidepressant-like effect. PcRT treatment also prevented increased acetylcholinesterase activity in the prefrontal cortex caused by HPD consumption. Moreover, PcRT extract was able to restore Ca2+-ATPase activity in the prefrontal cortex, hippocampus, and striatum, as well as Na+,K+-ATPase activity in the prefrontal cortex and hippocampus. PcRT treatment decreased thiobarbituric acid-reactive substances, nitrite, and reactive oxygen species levels and prevented the reduction of superoxide dismutase activity in all cerebral structures of the HPD group. Additionally, HPD decreased catalase in the hippocampus and striatum. However, the extract prevented this change in the hippocampus. Our results showed that this berry extract has antihyperglycemic and antihyperlipidemic effects, and neuroprotective properties, proving to be a potential therapeutic agent for individuals with metabolic syndrome.