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Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low-density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood-brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr -/- ) mice. We noticed that microgliosis was more severe in the hippocampus of middle-aged LDLr -/- mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr -/- mice already showed increased microgliosis and decreased immunocontent of claudin-5 in the prefrontal cortex (PFC). Subsequently, 6-month-old male C57BL/6 wild-type and LDLr -/- mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr -/- mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non-treated LDLr -/- mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region-specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6-month-old LDLr -/- mice exhibited a slight but not significant increase in IBA-1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr -/- mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH., (© 2023 International Society for Neurochemistry.)

Understanding the complex biological processes of cells in culture, particularly those related to metabolism, can be biased by culture conditions, since the choice of energy substrate impacts all of the main metabolic pathways. When glucose is replaced by galactose, cells decrease their glycolytic flux, working as an in vitro model of limited nutrient availability. However, the effect of these changes on related physiological processes such as redox control is not well documented, particularly in endothelial cells, where mitochondrial oxidation is considered to be low. We evaluated the differences in mitochondrial dynamics and function in endothelial cells exposed to galactose or glucose culture medium. We observed that cells maintained in galactose-containing medium show a higher mitochondrial oxidative capacity, a more fused mitochondrial network, and higher intercellular coupling. These factors are documented to impact the cellular response to oxidative stress. Therefore, we analyzed the levels of two main redox regulators and found that bovine aortic endothelial cells (BAEC) in galactose media had higher levels of FOXO3 and lower levels of Nrf2 than those in glucose-containing media. Thus, cultures of endothelial cells in a galactose-containing medium may provide a more suitable target for the study of in vitro mitochondrial-related processes than those in glucose-containing media; the medium deeply influences redox signaling in these cells.

Gut dysbiosis is linked to metabolic and neurodegenerative diseases and comprises a plausible link between high-fat diet (HFD) and brain dysfunction. Here we show that gut microbiota modulation by either antibiotic treatment for 5 weeks or a brief 3-day fecal microbiota transplantation (FMT) regimen from low-fat (control) diet-fed mice decreased weight gain, adipose tissue hypertrophy, and glucose intolerance induced by HFD in C57BL/6 male mice. Notably, gut microbiota modulation by FMT completely reversed impaired recognition memory induced by HFD, whereas modulation by antibiotics had less pronounced effect. Improvement in recognition memory by FMT was accompanied by decreased HFD-induced astrogliosis in the hippocampal cornu ammonis region. Gut microbiome composition analysis indicated that HFD diminished microbiota diversity compared to control diet, whereas FMT partially restored the phyla diversity. Our findings reinforce the role of the gut microbiota on HFD-induced cognitive impairment and suggest that modulating the gut microbiota may be an effective strategy to prevent metabolic and cognitive dysfunction associated with unfavorable dietary patterns., (© 2024 International Society for Neurochemistry.)

High-fat diet-induced metabolic changes are not restricted to the onset of cardiovascular diseases, but also include effects on brain functions related to learning and memory. This study aimed to evaluate mitochondrial markers and function, as well as cognitive function, in a rat model of metabolic dysfunction. Eight-week-old male Wistar rats were subjected to either a control diet or a two-hit protocol combining a high fat diet (HFD) with the nitric oxide synthase inhibitor L-NAME in the drinking water. HFD plus L-NAME induced obesity, hypertension, and increased serum cholesterol. These rats exhibited bioenergetic dysfunction in the hippocampus, characterized by decreased oxygen (O 2 ) consumption related to ATP production, with no changes in H 2 O 2 production. Furthermore, OPA1 protein expression was upregulated in the hippocampus of HFD + L-NAME rats, with no alterations in other morphology-related proteins. Consistently, HFD + L-NAME rats showed disruption of performance in the Morris Water Maze Reference Memory test. The neocortex did not exhibit either bioenergetic changes or alterations in H 2 O 2 production. Calcium uptake rate and retention capacity in the neocortex of HFD + L-NAME rats were not altered. Our results indicate that hippocampal mitochondrial bioenergetic function is disturbed in rats exposed to a HFD plus L-NAME, thus disrupting spatial learning, whereas neocortical function remains unaffected., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Familial hypercholesterolemia (FH) is a metabolic condition caused mainly by a mutation in the low-density lipoprotein (LDL) receptor gene (LDLR), which is highly prevalent in the population. Besides being an important causative factor of cardiovascular diseases, FH has been considered an early risk factor for Alzheimer's disease. Cognitive and emotional behavioral impairments in LDL receptor knockout (LDLr -/- ) mice are associated with neuroinflammation, blood-brain barrier dysfunction, impaired neurogenesis, brain oxidative stress, and mitochondrial dysfunction. Notably, today, LDLr -/- mice, a widely used animal model for studying cardiovascular diseases and atherosclerosis, are also considered an interesting tool for studying dementia. Here, we reviewed the main findings in LDLr -/- mice regarding the relationship between FH and brain dysfunctions and dementia development., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The impact of overnutrition early in life is not restricted to the onset of cardiovascular and metabolic diseases, but also affects critical brain functions related to cognition. This study aimed to evaluate the relationship between peripheral metabolic and bioenergetic changes induced by a two-hit protocol and their impact on cognitive function in juvenile mice. Three-week-old male C57BL/6 mice received a high-fat diet (HFD) or control diet for 7 weeks, associated with two low doses of streptozotocin (STZ) or vehicle. Despite the absence of obesity, HFD+STZ impaired glucose metabolism and induced a trend towards cholesterol increase. The two-hit protocol impaired recognition and spatial memories in juvenile mice, without inducing a depressive-like behavior. HFD+STZ mice presented increased immunoreactivity for GFAP and a trend towards a decrease in NeuN in the hippocampus. The treatment caused a bioenergetic impairment in the hippocampus, characterized by a decrease in both O 2 consumption related to ATP production and in the maximum respiratory capacity. The thermogenic capacity of brown adipose tissue was impaired by the two-hit protocol, here verified through the absence of a decrease in O 2 consumption after uncoupled protein-1 inhibition and an increase in the reserve respiratory capacity. Impaired mitochondrial function was also observed in the liver of HFD+STZ juvenile mice, but not in their heart. These results indicate that exposure to HFD+STZ early in life has a detrimental impact on the bioenergetic and mitochondrial function of tissues with metabolic and thermogenic activities, which is likely related to hippocampal metabolic changes and cognitive impairment., Competing Interests: Declaration of competing Interest The authors declare that they have no other competing financial interests or personal relationships that could have influenced this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We hypothesized that norbixin, which is a carotenoid used as an orange/red natural food coloring additive, has anti-atherogenic properties. An in vitro oxidation assay with human LDL and a rabbit model of atherosclerosis were used to test this hypothesis. Norbixin inhibited the oxidation of isolated human LDL in a concentration-dependent manner. In the in vivo assay, rabbits were fed with a regular chow (control) or an atherogenic diet (0.5% cholesterol) alone or supplemented with norbixin (10, 30 or 100 mg/kg b.w.) for 60 days. Norbixin supplementation (30 and 100 mg/kg b.w.) increased HDL levels and reduced triglyceride levels and the atherogenic index of rabbits. This effect was associated with the decrease of serum levels of oxidized LDL, oxidized LDL antibodies and aortic tissue levels of lipid and protein oxidation in the atherogenic rabbits supplemented with norbixin. Atherogenic diet increased enzymatic (superoxide dismutase, catalase, glutathione reductase, and thioredoxin reductase-1) and non-enzymatic (non-protein thiol groups content) antioxidant defense systems in the aortic tissue but reduced the activity of paraoxonase-1 in the serum. All these changes were prevented by norbixin supplementation (10, 30 and 100 mg/kg b.w.). These results suggest that norbixin has atheroprotective potential by improving serum lipid profile and preventing oxidative modifications of circulating LDL and aortic tissue. Norbixin may, therefore, be beneficial in the control of atherosclerosis risk factors and can be further investigated as a candidate to be used not only as a functional food ingredient but also for therapeutic applications and in the nutraceutical industry., (Copyright © 2022. Published by Elsevier Ltd.)

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test. In addition, YAC128 mice exhibited cognitive deficits in the Swimming T-maze Test during the late symptomatic stage. Except for a reduction in basal mitochondrial respiration, no significant deficits in the mitochondrial respiratory rates were observed in the hippocampus of late symptomatic YAC128 mice. In agreement, YAC128 animals did not present robust alterations in mitochondrial ultrastructural morphology. However, light and electron microscopy analysis revealed the presence of dark neurons characterized by the intense staining of granule cell bodies and shrunken nuclei and cytoplasm in the hippocampal dentate gyrus (DG) of late symptomatic YAC128 mice. Furthermore, structural alterations in the rough endoplasmic reticulum and Golgi apparatus were detected in the hippocampal DG of YAC128 mice by electron microscopy. These results clearly show a degenerative process in the hippocampal DG in late symptomatic YAC128 animals.

Methylmercury (MeHg) is a ubiquitous environmental neurotoxicant whose mechanisms of action involve oxidation of endogenous nucleophilic groups (mainly thiols and selenols), depletion of antioxidant defenses, and disruption of neurotransmitter homeostasis. Diphenyl diselenide-(PhSe) 2 -a model diaryl diselenide, has been reported to display significant protective effects against MeHg-induced neurotoxicity under both in vitro and in vivo experimental conditions. In this study, we compared the protective effects of (PhSe) 2 with those of RC513 (4,4'-diselanediylbis(2,6-di-tert-butylphenol), a novel diselenide-probucol-analog) against MeHg-induced toxicity in the neuronal (hippocampal) cell line HT22. Although both (PhSe) 2 and RC513 significantly mitigated MeHg- and tert-butylhydroperoxide (t-BuOOH)-cytotoxicity, the probucol analog exhibited superior protective effects, which were observed earlier and at lower concentrations compared to (PhSe) 2 . RC513 treatment (at either 0.5 µM or 2 µM) significantly increased glutathione peroxidase (GPx) activity, which has been reported to counteract MeHg-toxicity. (PhSe) 2 was also able to increase GPx activity, but only at 2 µM. Although both compounds increased the Gpx1 transcripts at 6 h after treatments, only RC513 was able to increase mRNA levels of Prx2, Prx3, Prx5, and Txn2, which are also involved in peroxide detoxification. RC513 (at 2 µM) significantly increased GPx-1 protein expression in HT22 cells, although (PhSe) 2 displayed a minor (nonsignificant) effect in this parameter. In agreement, RC513 induced a faster and superior capability to cope with exogenously-added peroxide (t-BuOOH). In summary, when compared to the prototypical organic diaryl diselenide [(PhSe) 2 ], RC513 displayed superior protective properties against MeHg-toxicity in vitro; this was paralleled by a more pronounced upregulation of defenses related to detoxification of peroxides, which are well-known MeHg-derived intermediate oxidant species., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Methylglyoxal (MG) is a reactive metabolite derived from different physiological pathways. Its production can be harmful to cells via glycation reactions of lipids, DNA, and proteins. But, the effects of MG on mitochondrial functioning and bioenergetic responses are still elusive. Then, the effects of MG on key parameters of mitochondrial functionality were examined here. Isolated rat liver mitochondria were exposed to 0.1-10 mM of MG to determine its toxicity in the mitochondrial viability, membrane potential (Δψm), swelling and the superoxide (O 2 •- ) production. Besides, mitochondrial oxidative phosphorylation parameters were analyzed by high-resolution respiratory (HRR) assay. In this set of experiments, routine state, PM state (pyruvate/malate), oxidative phosphorylation (OXPHOS), LEAK respiration, electron transport system (ETS) and oxygen residual (ROX) states were evaluated. HRR showed that PM state, OXPHOS CI-Linked, LEAK respiration, ETS CI/CII-Linked and ETS CII-Linked/ROX were significantly inhibited by MG exposure. MG also inhibited the complex II activity, and decreased Δψm and the viability of mitochondria. Taken together, our data indicates that MG is an inductor of mitochondrial dysfunctions and impairs important steps of respiratory chain, effects that can alter bioenergetics responses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Worldwide, and especially in Western civilizations, most of the staple diets contain high amounts of fat and refined carbohydrates, leading to an increasing number of obese individuals. In addition to inducing metabolic disorders, energy dense food intake has been suggested to impair brain functions such as cognition and mood control. Here we demonstrate an impaired memory function already 3 days after the start of a high-fat diet (HFD) exposure, and depressive-like behavior, in the tail suspension test, after 5 days. These changes were followed by reduced synaptic density, changes in mitochondrial function and astrocyte activation in the hippocampus. Preceding or coinciding with the behavioral changes, we found an induction of the proinflammatory cytokines TNF-α and IL-6 and an increased permeability of the blood-brain barrier (BBB), in the hippocampus. Finally, in mice treated with a TNF-α inhibitor, the behavioral and BBB alterations caused by HFD-feeding were mitigated suggesting that inflammatory signaling was critical for the changes. In summary, our findings suggest that HFD rapidly triggers hippocampal dysfunction associated with BBB disruption and neuroinflammation, promoting a progressive breakdown of synaptic and metabolic function. In addition to elucidating the link between diet and cognitive function, our results might be relevant for the comprehension of the neurodegenerative process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Paula, Brunetta, Engel, Gaspar, Velloso, Engblom, de Oliveira and de Bem.)

Cryopreservation of ovarian tissue followed by transplantation represents a strategy to restore ovarian function and fertility. Stress from cryopreservation-thawing processes can lead to alterations and/or damage to mitochondrial structure and functionality. High resolution respirometry and histological analysis were used to evaluate the effect of cryopreservation and transplantation on ovarian tissue. Four different conditions were performed: Fresh non-transplanted tissue, Fresh transplanted tissue, Cryopreserved non-transplanted tissue and Cryopreserved transplanted tissue. All groups were able to respond to the substrates-uncoupler-inhibitor protocol. We found a dramatic decrease in general oxygen consumption in hemi-ovaries submitted to cryopreservation and/or transplantation. The effect of cryopreservation on mitochondrial metabolism was less intense than effect of transplantation, since the transplantation affected all of the mitochondrial states. A total of 2644 follicles were analyzed. Of these, 2198 were classified as morphologically normal. The percentage of morphologically normal follicles was significantly lower in the Cryopreserved transplanted group when compared to the Cryopreserved non-transplanted group and the Fresh transplanted group (p-value < 0.05). Despite decreased follicular viability and mitochondrial activity, the cryopreservation followed by transplantation of ovarian tissue proved feasible for attempts to restore ovarian function., (© 2021. The Author(s).)

Oxidized LDL (oxLDL) plays a pivotal role on atherosclerosis development, mainly in the formation of lipid-laden macrophage "foam cells". As a consequence, substances that can modulate LDL oxidation have a pharmacological and therapeutic relevance. Based in previous findings showing the ability of Syzigium cumini leaf extract (ScExt) in preventing LDL oxidation in vitro, this study was aimed to assess the effects of ScExt on oxLDL-mediated toxicity in murine J774 macrophages-like cells. For biochemical analyses, LDL isolated from fresh human plasma and oxidized with CuSO 4 was incubated with ScExt pre-treated macrophages. Our results demonstrated that ScExt was efficient in preventing the overproduction of reactive oxygen/nitrogen species (ROS/RNS), the loss of macrophage's viability and the foam cells formation induced by oxLDL. These protective effects of ScExt make it a promising antioxidant for future trials toward atherogenesis., (Copyright © 2020. Published by Elsevier Masson SAS.)

Obesity is a global health problem with high prevalence and defined by a high body mass index (BMI). Several comorbidities affecting the central nervous system (CNS) are associated with obesity (e.g., neurodegenerative diseases, cognitive deficit, and psychobehavioral disturbs). The zebrafish (Danio rerio) has been considered a suitable model organism to investigate the neurobehavioral features of various human diseases. Here, we verify the impact of a high-fat diet (HFD) on the CNS by specifically assessing the effects of short-term HFD on anxiety-like responses, aggression, social preference, and memory, which are essential behaviors for survival and reproduction. Animals were separated in three experimental groups. The standard diet group (SD) received 7.5 mg/fish of dry food, while HFD groups received 5 mg/fish dry food plus 7.5 (HFD-7.5) or 15 mg/fish (HFD-15) of chicken egg yolk daily. Dietary fat content (w/w) was approximately 6.5%, 16.9%, and 21.1%, respectively. We performed behavioral tests and morphometric analyses after two weeks of HFD. In comparison to SD animals, HFD groups showed typical obesogenic responses with increases in BMI, abdominal length, and body weight. HFD individuals also showed increased aggression and anxiety-like behaviors in the mirror-induced aggression and novel tank diving tests, respectively. Interestingly, HFD did not change the social preference behavior, mean swimming speed or spontaneous activity levels, while the HFD-15 group showed cognitive deficits in the inhibitory avoidance test. Collectively, this "proof-of-concept" study is the first report to characterize the effects of short-term HFD on different behavioral domains of zebrafish with high degree of face validity. Moreover, our data reinforce the growing utility of zebrafish to explore the neurobehavioral basis of obesity, providing clinically translatable data, complementing the existing rodent models and supporting future mechanistic studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hypercholesterolemia has been linked to neurodegenerative disease development. Previously others and we demonstrated that high levels of plasma cholesterol-induced memory impairments and depressive-like behavior in mice. More recently, some evidence reported that a hypercholesterolemic diet led to motor alterations in rodents. Peripheral inflammation, blood-brain barrier (BBB) dysfunction, and neuroinflammation seem to be the connective factors between hypercholesterolemia and brain disorders. Herein, we aimed to investigate whether treatment with gold nanoparticles (GNPs) can prevent the inflammation, BBB disruption, and behavioral changes related to neurodegenerative diseases and depression, induced by hypercholesterolemic diet intake in mice. Adult Swiss mice were fed a standard or a high cholesterol diet for eight weeks and concomitantly treated with either vehicle or GNPs by the oral route. At the end of treatments, mice were subjected to behavioral tests. After that, the blood, liver, and brain structures were collected for biochemical analysis. The high cholesterol diet-induced an increase in the plasma cholesterol levels and body weight of mice, which were not modified by GNPs treatment. Hypercholesterolemia was associated with enhanced liver tumor necrosis factor- α (TNF-α), BBB dysfunction in the hippocampus and olfactory bulb, memory impairment, cataleptic posture, and depressive-like behavior. Notably, GNPs administration attenuated liver inflammation, BBB dysfunction, and improved behavioral and memory deficits in hypercholesterolemic mice. Also, GNPs increased mitochondrial complex I activity in the prefrontal cortex of mice. It is worth highlight that GNPs' administration did not cause toxic effects in the liver and kidney of mice. Overall, our results indicated that GNPs treatment potentially mitigated peripheral, brain, and memory impairments related to hypercholesterolemia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: While chronic feeding with high-fat or high-sugar diets is known related to obesity and type 2 diabetes, later data have indicated that it is also related to depression and anxiety appearance. In this regard, multi-target drugs raise considerable interest as promising therapeutic solutions to complex diseases. Considering the pharmacological effects of the imidazopyridine-derivative moiety imidazo[1,2-a]pyridine and the organoselenium molecules, the combination of both could be a feasible strategy to develop efficient drugs to handle obesity and related comorbidities, for example dyslipidemia and mood disorders., Methods: The antidepressant- and anxiolytic-like properties of a selanylimidazopyridine compound, 2-Phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine (3-SePh-IP), were evaluated on high-fat/high-fructose diet (HFFD)-fed female Swiss mice., Key Findings: Our results showed that a short-term HFFD (16 days) could promote a significant body weight gain, hypercholesterolemia, glucose intolerance, and anxiety- and depressive-like behaviour in mice. Concomitant treatment with 3-SePh-IP (10 mg/kg; i.p.) attenuated the HFFD-induced increase in cholesterol levels and blunted the anxiety- and depressive-like behaviour in mice., Conclusions: 3-SePh-IP holds multimodal pharmacological properties, which provide a rationale for further studies, for example to assess the underlying mechanisms linked to its anxiolytic- and antidepressive-like activities., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Methylglyoxal (MGO) is an endogenous toxin, mainly produced as a by-product of glycolysis that has been associated to aging, Alzheimer's disease, and inflammation. Cell culture studies reported that MGO could impair the glyoxalase, thioredoxin, and glutathione systems. Thus, we investigated the effect of in vivo MGO administration on these systems, but no major changes were observed in the glyoxalase, thioredoxin, and glutathione systems, as evaluated in the prefrontal cortex and the hippocampus of mice. A previous study from our group indicated that MGO administration produced learning/memory deficits and depression-like behavior. Confirming these findings, the tail suspension test indicated that MGO treatment for 7 days leads to depression-like behavior in three different mice strains. MGO treatment for 12 days induced working memory impairment, as evaluated in the Y maze spontaneous alternation test, which was paralleled by low dopamine and serotonin levels in the cerebral cortex. Increased DARPP32 Thr75/Thr34 phosphorylation ratio was observed, suggesting a suppression of phosphatase 1 inhibition, which may be involved in behavioral responses to MGO. Co-treatment with a dopamine/noradrenaline reuptake inhibitor (bupropion, 10 mg/kg, p.o.) reversed the depression-like behavior and working memory impairment and restored the serotonin and dopamine levels in the cerebral cortex. Overall, the cerebral cortex monoaminergic system appears to be a preferential target of MGO toxicity, a new potential therapeutic target that remains to be addressed.

The incidence of metabolic disorders, as well as of neurodegenerative diseases-mainly the sporadic forms of Alzheimer's and Parkinson's disease-are increasing worldwide. Notably, obesity, diabetes, and hypercholesterolemia have been indicated as early risk factors for sporadic forms of Alzheimer's and Parkinson's disease. These conditions share a range of molecular and cellular features, including protein aggregation, oxidative stress, neuroinflammation, and blood-brain barrier dysfunction, all of which contribute to neuronal death and cognitive impairment. Rodent models of obesity, diabetes, and hypercholesterolemia exhibit all the hallmarks of these degenerative diseases, and represent an interesting approach to the study of the phenotypic features and pathogenic mechanisms of neurodegenerative disorders. We review the main pathological aspects of Alzheimer's and Parkinson's disease as summarized in rodent models of obesity, diabetes, and hypercholesterolemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Bem, Krolow, Farias, de Rezende, Gelain, Moreira, Duarte and de Oliveira.)

Most pharmacological studies concerning the beneficial effects of organoselenium compounds have focused on their ability to mimic glutathione peroxidase (GPx). However, mechanisms other than GPx-like activity might be involved on their biological effects. This study was aimed to investigate and compare the protective effects of two well known [(PhSe) 2 and PhSeZnCl] and two newly developed (MRK Picolyl and MRK Ester) organoselenium compounds against oxidative challenge in cultured neuronal HT22 cells. The thiol peroxidase and oxidase activities were performed using the glutathione reductase (GR)-coupled assay. In order to evaluate protective effects of the organoselenium compounds against oxidative challenge in neuronal HT22 cells, experiments based on glutamate-induced oxytosis and SIN-1-mediated peroxynitrite generation were performed. The thiol peroxidase activities of the studied organoselenium compounds were smaller than bovine erythrocytes GPx enzyme. Besides, (PhSe) 2 and PhSeZnCl showed higher thiol peroxidase and lower thiol oxidase activities compared to the new compounds. MRK Picolyl and MRK Ester, which showed lower thiol peroxidase activity, showed higher thiol oxidase activity. Both pre- or co-treatment with (PhSe) 2 , PhSeZnCl, MRK Picolyl and MRK Ester protected HT22 cells against glutamate-induced cytotoxicity. (PhSe) 2 and MRK Picolyl significantly prevented peroxinitrite-induced dihydrorhodamine oxidation, but this effect was observed only when HT22 were pre-treated with these compounds. The treatment with (PhSe) 2 increased the protein expression of antioxidant defences (Prx3, CAT and GCLC) in HT22 cells. Taking together, our results suggest that the biological effects elicited by these compounds are not directly related to their GPx-mimetic and thiol oxidase activities, but might be linked to the up-regulation of endogenous antioxidant defences trough their thiol-modifier effects.

Voluntary wheel running is widely used as a physical activity (PA) model in rodents, but most studies investigate the beneficial effects of this intervention in socially isolated mice. Social isolation stress (SIS) is associated with vulnerability to oxidative stress and reduced mitochondrial activity. Thus, the aim of this study was to investigate the effects of free access to a running wheel for 21 days on the various markers of the cellular redox/antioxidant status as well as mitochondrial function of mice subjected to SIS or maintained in groups of 3 in the homecage. SIS increased thiobarbituric acid reactive substance (TBARS) levels in the cerebral cortex, and PA intervention was not able to reverse such alteration. PA reduced TBARS levels in the liver of grouped mice and gastrocnemius of socially isolated mice. PA increased nonprotein thiol (NPSH) levels in the cerebral cortex of grouped mice. Furthermore, socially isolated mice presented lower glutathione peroxidase (GPx) activity in the cerebellum and gastrocnemius, and glutathione reductase (GR) activity in the cerebral cortex and liver. By contrast, SIS induced higher GPx activity in the cerebral cortex and heart. PA reduced GPx (cerebral cortex) and GR (cerebral cortex and liver) activities of socially isolated mice. SIS caused higher activity of mitochondrial complexes I and II in the cerebral cortex, and the PA paradigm was not able to alter this effect. Interestingly, the PA produced antidepressant-like effect at both SIS and control groups. In conclusion, the results showed the influence of SIS for the effects of PA on the antioxidant status, but not on the mitochondrial function and emotionality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Amyloid-β (Aβ) peptides play a significant role in the pathogenesis of Alzheimer's disease (AD). Neurotoxic effects promoted by Aβ peptides involve glutamate transmission impairment, decrease of neurotrophic factors, mitochondrial dysfunction, oxidative stress, synaptotoxicity, and neuronal degeneration. Here, we assessed the early events evoked by Aβ 1-40 on the hippocampus. Additionally, we sought to unravel the molecular mechanisms of atorvastatin preventive effect on Aβ-induced hippocampal damage. Mice were treated orally (p.o.) with atorvastatin 10 mg/kg/day during 7 consecutive days before the intracerebroventricular (i.c.v.) infusion of Aβ 1-40 (400 pmol/site). Twenty-four hours after Aβ 1-40 infusion, a reduced content of mature BDNF/proBDNF ratio was observed in Aβ-treated mice. However, there is no alteration in synaptophysin, PSD-95, and doublecortin immunocontent in the hippocampus. Aβ 1-40 promoted an increase in reactive oxygen species (ROS) and nitric oxide (NO) generation in hippocampal slices, and atorvastatin prevented this oxidative burst. Mitochondrial OXPHOS was measured by high-resolution respirometry. At this time point, Aβ 1-40 did not alter the O 2 consumption rates (OCR) related to phosphorylating state associated with complexes I and II, and the maximal OCR. However, atorvastatin increased OCR of phosphorylating state associated with complex I and complexes I and II, maximal OCR of complexes I and II, and OCR associated with mitochondrial spare capacity. Atorvastatin treatment improved mitochondrial function in the rodent hippocampus, even after Aβ infusion, pointing to a promising effect of improving brain mitochondria bioenergetics. Therefore, atorvastatin could act as an adjuvant in battling the symptoms of AD to preventing or delaying the disease progression.

NAD(P) + transhydrogenase (NNT) links redox states of the mitochondrial NAD(H) and NADP(H) via a reaction coupled to proton-motive force across the inner mitochondrial membrane. NNT is believed to be ubiquitously present in mammalian cells, but its expression may vary substantially in different tissues. The present study investigated the tissue distribution and possible roles of NNT in the mouse brain. The pons exhibited high NNT expression/activity, and immunohistochemistry revealed intense NNT labeling in neurons from brainstem nuclei. In some of these regions, neuronal NNT labeling was strongly colocalized with enzymes involved in the biosynthesis of 5-hydroxytryptamine (5-HT) and nitric oxide (NO), which directly or indirectly require NADPH. Behavioral tests were performed in mice lacking NNT activity (Nnt -/- , mice carrying the mutated Nnt C57BL/6J allele from the C57BL/6J strain) and the Nnt +/+ controls. Our data demonstrated that aged Nnt -/- mice (18-20 months old), but not adult mice (3-4 months old), showed an increased immobility time in the tail suspension test that was reversed by fluoxetine treatment, providing evidence of depressive-like behavior in these mice. Aged Nnt -/- mice also exhibited behavioral changes and impaired locomotor activity in the open field and rotarod tests. Despite the colocalization between NNT and NO synthase, the S-nitrosation and cGMP levels were independent of the Nnt genotype. Taken together, our results indicated that NNT is unevenly distributed throughout the brain and associated with 5-THergic and NOergic neurons. The lack of NNT led to alterations in brain functions related to mood and motor behavior/performance in aged mice., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr-/-), a mouse model of familial hypercholesterolemia., Objective: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr-/-mice., Methods: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr-/-mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice's prefrontal cortices and hippocampi., Results: A tenfold elevation in plasma cholesterol levels of LDLr-/-mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr-/-mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr-/-mice treated with a hypercholesterolemic diet. The LDLr-/-mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr-/-mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice., Conclusion: Therefore, LDLr-/-mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.

Tyrosinemia type II is a genetic disorder characterized by elevated blood levels of the amino acid tyrosine caused by the deficiency of tyrosine aminotransferase enzyme, resulting in neurologic and developmental difficulties in the patients. Although neurological sequelae are common in Tyrosinemia type II patients, the mechanisms involved are still poorly understood. The oxidative stress appears to be, at least in part, responsible for neurological complication in this inborn error metabolism. We observed that an acute injection of tyrosine in rats caused a massive oxidative stress in different brain structures. The glutathione system and superoxide dismutase enzyme are relevant antioxidant strategies of the cells and tissues, including in the brain. Other important point is the strong relation between oxidative damage and inflammatory events. Herein, we investigated the effects of chronic administration of tyrosine in the hippocampus of young rats, with emphasis in the activity of GSH related enzymes and superoxide dismutase enzyme, and the astrocytosis. We observed that rats exposed to high levels of tyrosine presented an increased content of tyrosine, which was associated with an increment in the activity of glutathione peroxidase and glutathione reductase as well as with a diminished activity of superoxide dismutase. This antioxidant imbalance was accompanied by enhanced glial fibrillary acidic protein immunoreactivity, a marker of astrocytes, in the brain area studied. In conclusion, hippocampus astrogliosis is also a characteristic of brain alteration in Tyrosinemia. In addition, the chronic exposition to high levels of tyrosine is associated with an alteration in the activity of fundamental antioxidant enzymes.

Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/-), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer's disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein 1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/-mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels.

Zika virus (ZIKV) has a strong tropism for the nervous system and has been related to post-infection neurological syndromes. Once neuronal cells are infected, the virus is capable of modulating cell metabolism, leading to neurotoxicity and cellular death. The negative effect of ZIKV in neuron cells has been characterized. However, the description of molecules capable of reversing these cytotoxic effects is still under investigation. In this context, it has been largely demonstrated that docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, is highly neuroprotective. Here, we hypothesized that DHA's neuroprotective proprieties could have an influence on ZIKV-induced neurotoxicity in SH-SY5Y cells. Our data showed that pre-treatment of SH-SY5Y cells with DHA increased the cell viability and proliferation in ZIKV-infected cells. Moreover, DHA triggered an anti-inflammatory response in those infected cells. Besides, DHA was capable of restoring mitochondria function and number in ZIKV-infected SH-SY5Y cells. In addition, cells pre-treated with DHA prior to ZIKV infection presented a lower viral load at different times of infection. Taking together, these results demonstrated that DHA has a potential anti-inflammatory and neuroprotective effect against ZIKV infection in these neuron-like cells and could be a useful tool in the treatment against this virus.

Objective: In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis., Methods: We evaluated hippocampus-dependent behavior and neurogenesis in adult C57BL/6JRj and LDLr -/- mice. We investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro., Results: Behavioral tests revealed that adult LDLr -/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr -/- mice, suggesting a potential direct impact of LDLr mutation on NPC. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown., Conclusions: Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

New Findings: What is the central question of this study? What are the temporal responses of mitochondrial respiration and mitochondrial responsivity to insulin in soleus muscle fibres from mice during the development of obesity and insulin resistance? What is the main finding and its importance? Short- and long-term feeding with a high-fat diet markedly reduced soleus mitochondrial respiration and mitochondrial responsivity to insulin before any change in glycogen synthesis. Muscle glycogen synthesis and whole-body insulin resistance were present after 14 and 28 days, respectively. Our findings highlight the plasticity of mitochondria during the development of obesity and insulin resistance., Abstract: Recently, significant attention has been given to the role of muscle mitochondrial function in the development of insulin resistance associated with obesity. Our aim was to investigate temporal alterations in mitochondrial respiration, H 2 O 2 emission and mitochondrial responsivity to insulin in permeabilized skeletal muscle fibres during the development of obesity in mice. Male Swiss mice (5-6 weeks old) were fed with a high-fat diet (60% calories from fat) or standard diet for 7, 14 or 28 days to induce obesity and insulin resistance. Diet-induced obese (DIO) mice presented with reduced glucose tolerance and hyperinsulinaemia after 7 days of high-fat diet. After 14 days, the expected increase in muscle glycogen content after systemic injection of glucose and insulin was not observed in DIO mice. At 28 days, blood glucose decay after insulin injection was significantly impaired. Complex I (pyruvate + malate) and II (succinate)-linked respiration and oxidative phosphorylation (ADP) were decreased after 7 days of high-fat diet and remained low in DIO mice after 14 and 28 days of treatment. Moreover, mitochondria from DIO mice were incapable of increasing respiratory coupling and ADP responsivity after insulin stimulation in all observed periods. Markers of mitochondrial content were reduced only after 28 days of treatment. The mitochondrial H 2 O 2 emission profile varied during the time course of DIO, with a reduction of H 2 O 2 emission in the early stages of DIO and an increased emission after 28 days of treatment. Our data demonstrate that DIO promotes transitory alterations in mitochondrial physiology during the early and late stages of insulin resistance related to obesity., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

While chronic high-fat feeding has long been associated with the rising incidence of obesity/type 2 diabetes, recent evidence has established that it is also associated with deficits in hippocampus-dependent memory. In this regard, environmental enrichment (EE) is an animal housing technique composed of increased space, physical activity, and social interactions, which in turn increases sensory, cognitive, motor, and social stimulation. EE leads to improved cerebral health as defined by increased neurogenesis, enhanced learning and memory and resistance to external cerebral insults. In the present study, the impacts of environmental enrichment (EE) on Swiss mice fed a high-fat, cholesterol-enriched diet (HFECD; 20% fat and 1.5% cholesterol) were investigated. Here, we demonstrated that EE, when initiated 4 weeks after the beginning of HFECD in mice, prevents HFECD-induced spatial memory and object recognition impairment, which were tested in T-maze and object recognition tests. Although EE did not affect HFECD-induced weight gain or hypercholesterolaemia, it improved glucose tolerance. On the other hand, EE was unable to mitigate a decrease in brain-derived neurotrophic factor (BDNF) and IL-6 hippocampal levels induced by the HFECD. Overall, while our results reinforce the positive and neuroprotective effects of EE on cognition they do not support a role for EE in preventing the neurochemical changes induced by the HFECD. Based on clinical observations that nondiabetic individuals with mild forms of impaired glucose tolerance have a higher risk of cognitive impairments, one can speculate about the connection between the effects of EE on glucose intolerance and its effects on cognition., (Copyright © 2018 Elsevier B.V. All rights reserved.)

All four FOXO isoforms have been shown to respond to changes in the cellular redox status of the cell, and regulate the expression of target genes that in turn can modulate the cellular oxidative status. However, the mechanisms involved are still controversial. It is clear though that redox regulation of FOXO factors occurs at different levels. The proteins themselves are redox-sensitive and their capacity to bind their target sites seems to be at least partially dependent on their oxidative status. Importantly, several of the cofactors that are known to regulate FOXO transcriptional activity are also sensitive to changes in the cellular redox status, in particular the deacetylase SirT1 is activated in response to reduced levels of reducing equivalents (increased NAD + /NADH + ratio) and the coactivator PGC-1α is induced in response to increased cellular oxidative stress. Furthermore, nuclear localization of FOXO factors is also regulated by proteins that, like AKT, are themselves regulated directly or indirectly by the cellular levels of reactive oxygen and nitrogen species. In this technical review, we aim to update the current status of our knowledge of how to handle redox-regulated FOXO factor research in order to better understand FOXO biology.

Oxidative stress and mitochondrial dysfunction are critical events in neurodegenerative diseases; therefore, molecules that increase cellular antioxidant defenses represent a future pharmacologic strategy to counteract such conditions. The aim of this study was to investigate the potential protective effect of (PhSe) 2 on mouse hippocampal cell line (HT22) exposed to tert-BuOOH (in vitro model of oxidative stress), as well as to elucidate potential mechanisms underlying this protection. Our results showed that tert-BuOOH caused time- and concentration-dependent cytotoxicity, which was preceded by increased oxidants production and mitochondrial dysfunction. (PhSe) 2 pre-incubation significantly prevented these cytotoxic events and the observed protective effects were paralleled by the upregulation of the cellular glutathione-dependent antioxidant system: (PhSe) 2 increased GSH levels (> 60%), GPx activity (6.9-fold) and the mRNA expression of antioxidant enzymes Gpx1 (3.9-fold) and Gclc (2.3-fold). Of note, the cytoprotective effect of (PhSe) 2 was significantly decreased when cells were treated with mercaptosuccinic acid, an inhibitor of GPx, indicating the involvement of GPx modulation in the observed protective effect. In summary, the present findings bring out a new action mechanism concerning the antioxidant properties of (PhSe) 2 . The observed upregulation of the glutathione-dependent antioxidant system represents a future pharmacologic possibility that goes beyond the well-known thiol-peroxidase activity of this compound., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent studies have shown that probucol (PB), a hipocholesterolemic agent with antioxidant and anti-inflammatory properties, presents neuroprotective properties. On the other hand, adverse effects have limited PB's clinical application. Thus, the search for PB derivatives with no or less adverse effects has been a topic of research. In this study, we present a novel organoselenium PB derivative (RC513) and investigate its potential protective activity in an in vitro experimental model of oxidative toxicity induced by tert-butyl hydroperoxide (tBuOOH) in HT22 neuronal cells, as well as exploit potential protective mechanisms. tBuOOH exposure caused a significant decrease in the cell viability, which was preceded by (i) increased reactive species generation and (ii) decreased mitochondrial maximum oxygen consumption rate. RC513 pretreatment (48 h) significantly prevented the tBuOOH-induced decrease of cell viability, RS generation, and mitochondrial dysfunction. Of note, RC513 significantly increased glutathione peroxidase (GPx) activity and mRNA expression of GPx1, a key enzyme involved in peroxide detoxification. The use of mercaptosuccinic acid, an inhibitor of GPx, significantly decreased the protective activity of RC513 against tBuOOH-induced cytotoxicity in HT22 cells, highlighting the importance of GPx upregulation in the observed protection. In summary, the results showed a significant protective activity of a novel PB derivative against tBuOOH-induced oxidative stress and mitochondrial dysfunction, which was related to the upregulation of GPx. Our results point to RC513 as a promising neuroprotective molecule, even though studies concerning potential beneficial effects and safety aspects of RC513 under in vivo conditions are well warranted.

The present study evaluated the effects of hypercholesterolemia in response to conditioned aversive stimuli in mice. Specifically, (a) young (3 months old) and aged (24 months old) female C57Bl/6 mice were fed daily for 4 weeks with a standard rodent diet or an enriched cholesterol diet (ECD) and then subjected to the contextual fear conditioning test. In another experimental set, 3-month-old C576Bl/6 female mice, fed daily during the 4 weeks with the standard rodent diet or ECD, were subjected to the contextual fear conditioning test and received vehicle or scopolamine (0.37 mg/kg; intraperitoneally) immediately after the training session. (b) 12-month-old C576Bl/6 and low-density lipoprotein receptor knockout mice (LDLr) female mice were subjected to the contextual fear conditioning test. In another experimental set, they were subjected to the contextual fear conditioning test and received vehicle or donepezil (3.0 mg/kg; intraperitoneally) immediately after the training session. The present results show that (a) the ECD specifically impaired retrieval of contextual fear memory in aged mice; (b) an ineffective dose of scopolamine impaired fear memory consolidation in young mice fed the ECD; (c) LDLr mice presented impaired contextual fear memory retrieval; and (d) boosting cholinergic neurotransmission with a single donepezil administration at the consolidation window led to improved fear memory consolidation in LDLr mice. These findings suggest that high levels of cholesterol induced by either an ECD or a genetic deletion of LDLr decreased freezing behavior on the contextual fear conditioning test, which seemed to involve dysfunction of the cholinergic system.

Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction and neuronal lost in specific brain areas including hippocampus, resulting in memory/learning deficits and cognitive impairments. In addition, non-cognitive symptoms are reported in AD patients, such as anxiety, apathy and depressed mood. The current antidepressant drugs present reduced efficacy to improve depressive symptoms in AD patients. Here, we investigated the ability of creatine, a compound with neuroprotective and antidepressant properties, to counteract amyloid β 1-40 peptide-induced depressive-like behavior in mice. Moreover, we addressed the participation of the intracellular signaling pathway mediated by glycogen synthase kinase-3β (GSK-3β)/nuclear factor erythroid-2-related factor 2 (Nrf 2 ) in the creatine effects. Aß 1-40 administration (400 pmol/mouse, i.c.v.) increased the immobility time in the tail suspension test and decreased the grooming time and increased latency to grooming in the splash test, indicative of depressive-like behavior. These impairments were attenuated by creatine (0.01 and 10 mg/kg, p.o.) and fluoxetine (10 mg/kg, p.o., positive control). No significant alterations on locomotor performance were observed in the open field. Aß 1-40 administration did not alter hippocampal phospho-GSK-3β (Ser 9 )/total GSK-3β, total GSK-3β and heme oxygenase-1 (HO-1) immunocontents. However, Aß 1-40 -infused mice treated with creatine (0.01 mg/kg) presented increased phosphorylation of GSK-3β(Ser 9 ) and HO-1 immunocontent in the hippocampus. Fluoxetine per se increased GSK-3β(Ser 9 ) phosphorylation, but did not alter HO-1 levels. In addition, Aß 1-40 administration increased hippocampal glutathione (GSH) levels as well as glutathione reductase (GR) and thioredoxin reductase (TrxR) activities, and these effects were abolished by creatine and fluoxetine. This study provides the first evidence of the antidepressive-like effects of creatine in Aß 1-40 -treated mice, which were accompanied by hippocampal inhibition of GSK-3β and modulation of antioxidant defenses. These findings indicate the potential of creatine for the treatment of depression associated with AD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor with cholesterol-lowering, anti-inflammatory, and antioxidant properties. Increasing evidence show atorvastatin acts as a protective agent against insults in the central nervous system (CNS). The regular use of statins has been associated with a reduced risk of Parkinson's disease (PD) development. Here, we evaluated early events involved in the neurotoxicity induced by intranasal (i.n.) infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rats and the potential of atorvastatin to prevent these early toxic events. Male Wistar rats were pretreated orally with atorvastatin (10 mg/kg/day) or vehicle once a day during seven consecutive days. Twenty-four hours after atorvastatin administration, animals received a single bilateral i.n. infusion of MPTP (1 mg/nostril), and 6 h later, the striatum and the hippocampus were collected to evaluate early oxidative stress parameters and inflammatory cytokines. Atorvastatin prevented MPTP-induced increase in reactive species (RS) generation and in glutathione levels in the striatum. Atorvastatin also prevented the reduction in mitochondrial respiratory chain complex I and II activities evoked by MPTP in the striatum. Atorvastatin per se reduced the levels of the cytokines TNF-α and IL-1β, and surprisingly, it reduced IL-10 and nerve growth factor levels in the striatum. However, the anti-inflammatory IL-10 levels increased in the striatum following atorvastatin plus MPTP treatment. These effects were not observed in the hippocampus. Our findings reinforce and extend the notion of the neuroprotective effects of atorvastatin in a PD model and indicate the modulation of oxidative and inflammatory responses as the mechanisms associated with therapeutic action of atorvastatin in PD.

The contribution of oxidative stress to the pathophysiology of depression has been described in numerous studies. Particularly, an increased production of reactive oxygen species (ROS) caused by mitochondrial dysfunction can lead to neuronal cell death. Human neuroblastoma SH-SY5Y cells were used to investigate the neuroprotective effect of the antidepressant duloxetine against rotenone-induced oxidative stress. SH-SY5Y cells were pretreated with duloxetine (1-5 µM) for 24 h followed by a 24-h rotenone exposure (10 µM). The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) inhibitor LY294002 (10 µM) and the heme oxygenase 1 (HO-1) inhibitor zinc protoporphyrin IX-ZnPP (5 µM) were added to cultures 1 h prior duloxetine treatments. After treatments cell viability and ROS generation were assessed. NF-E2-related factor-2 (Nrf2) nuclear translocation was assessed by immunofluorescent staining after 4 and 8 h of duloxetine incubation. Furthermore, the Nrf2 and HO-1 mRNA expression was carried out after 4-48 h of duloxetine treatment by qRT-PCR. Duloxetine pretreatment antagonized rotenone-induced overproduction of ROS and cell death in SH-SY5Y cells. In addition, a 1-h pretreatment with LY294002 abolished duloxetine's protective effect. Duloxetine also induced nuclear translocation of the Nrf2 and the expression of its target gene, HO-1. Finally, the HO-1 inhibitor, ZnPP, suppressed the duloxetine protective effect. Overall, these results indicate that the mechanism of duloxetine neuroprotective action against oxidative stress and cell death might rely on the Akt/Nrf2/HO-1 pathways.

Etnopharmacological Relevance: Syzygium cumini (L.) Skeels is a plant widely used in folk medicine to treat diabetes mellitus (DM). The tea from its leaves is frequently used by diabetics for lowering hyperglycemia. There is a close relationship between DM and atherosclerosis, a chronic immuno-inflammatory disease, were the early stages encompass oxidative and glycative modifications in the structure of low density lipoprotein (LDL)., Aim of This Study: To investigate the potential protective effects of aqueous-leaf extract from Syzygium cumini (S.cExt) against CuSO 4 -induced oxidation and methylglyoxal (MG)-induced glycation of human LDL in vitro., Materials and Methods: LDL oxidative changes were evaluated by measuring conjugated dienes (CD) formation, thiobarbituric acid reactive substances (TBARS) levels, quenching of tryptophan (Trp) fluorescence and structural modifications in LDL particle. In LDL glycated by MG (glyLDL), we determined the levels of fluorescent advanced glycation end products (AGEs) and mobility by agarose gel electrophoresis., Results: S.cExt blocked oxidative events induced by CuSO 4 in human LDL, plasma and serum. Fourier transform infrared spectroscopy (FT-IR) revealed that specific regions of apoB100 were oxidized by CuSO 4 in human LDL and that S.cExt reduced these oxidations. Unlike, the increased AGEs levels and eletrophoretic mobility observed in LDL MG-glycated were not modified by S.cExt., Conclusion: The findings herein indicate that S.cExt could be tested in atherogenesis models as potential protective agent against LDL oxidation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Sepsis survivors frequently develop late cognitive impairment. Because little is known on the mechanisms of post-septic memory deficits, there are no current effective approaches to prevent or treat such symptoms. Here, we subjected mice to severe sepsis induced by cecal ligation and puncture (CLP) and evaluated the sepsis-surviving animals in the open field, novel object recognition (NOR), and step-down inhibitory avoidance (IA) task at different times after surgery. Post-septic mice (30 days post-surgery) failed in the NOR and IA tests but exhibited normal performance when re-evaluated 45 days after surgery. Cognitive impairment in post-septic mice was accompanied by reduced hippocampal levels of proteins involved in synaptic plasticity, including synaptophysin, cAMP response element-binding protein (CREB), CREB phosphorylated at serine residue 133 (CREBpSer 133 ), and GluA1 phosphorylated at serine residue 845 (GluA1pSer 845 ). Expression of tumor necrosis factor α (TNF-α) was increased and brain insulin signaling was disrupted, as indicated by increased hippocampal IRS-1 phosphorylation at serine 636 (IRS-1pSer 636 ) and decreased phosphorylation of IRS-1 at tyrosine 465 (IRS-1pTyr 465 ), in the hippocampus 30 days after CLP. Phosphorylation of Akt at serine 473 (AktpSer 473 ) and of GSK3 at serine 9 (GSK3βpSer 9 ) were also decreased in hippocampi of post-septic animals, further indicating that brain insulin signaling is disrupted by sepsis. We then treated post-septic mice with liraglutide, a GLP-1 receptor agonist with insulinotropic activity, or TDZD-8, a GSK3β inhibitor, which rescued NOR memory. In conclusion, these results establish that hippocampal inflammation and disrupted insulin signaling are induced by sepsis and are linked to late memory impairment in sepsis survivors.

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 neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP + ), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP + (1.8-18 μg/mouse) in C57BL6 mice. MPP + administration at high dose (18 μg/mouse) altered motor parameters, since it increased the latency to leave the first quadrant and reduced crossing, rearing, and grooming responses in the open-field test and decreased rotarod latency time. MPP + administration at low dose (1.8 μg/mouse) caused specific nonmotor dysfunctions as it produced a depressive-like effect in the forced swim test and tail suspension test, loss of motivational and self-care behavior in the splash test, anxiety-like effect in the elevated plus maze test, and short-term memory deficit in the step-down inhibitory avoidance task, without altering ambulation. MPP + at doses of 1.8-18 μg/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 μg/mouse increased α-synuclein and decreased parkin immunocontent. The astrocytic calcium-binding protein S100B and glial fibrillary acidic protein (GFAP)/S100B ratio was decreased following MPP + administration (18 μg/mouse). At this highest dose, MPP + increased the ionized calcium-binding adapter molecule 1 (Iba-1) immunocontent, suggesting microglial activation. Also, MPP + at a dose of 18 μg/mouse increased thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and increased glutathione peroxidase (GPx) and hemeoxygenase-1 (HO-1) immunocontent, suggesting a significant role for oxidative stress in the MPP + -induced striatal damage. MPP + (18 μg/mouse) also increased striatal fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF) levels. Moreover, MPP + decreased tropomyosin receptor kinase B (TrkB) immunocontent. Finally, MPP + (1.8-18 μg/mouse) increased serum corticosterone levels and did not alter acetylcholinesterase (AChE) activity in the striatum but increased it in cerebral cortex and hippocampus. Collectively, these results indicate that MPP + administration at low doses may be used as a model of emotional and memory/learning behavioral deficit related to PD and that MPP + administration at high dose could be useful for analysis of striatal dysfunctions associated with motor deficits in PD.

Thiol homeostasis has a critical role in the maintenance of proper cellular functions and survival, being coordinated by the action of several reductive enzymes, including glutathione (GSH)/glutathione reductase (GR) and thioredoxin (Trx)/thioredoxin reductase (TrxR) systems. Here, we investigated the effects of the GR inhibitor 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA) on the activity of thiol reductases (GR and TrxR), redox balance and mitochondrial function of A172 glioblastoma cells. 2-AAPA inhibited cell GR (IC 50 =6.7μM) and TrxR (IC 50 =8.7μM). A significant decrease in the cellular ability to decompose cumene hydroperoxide was observed and associated to a greater susceptibility to this peroxide. The redox state of peroxiredoxins (Prx1, Prx2 and Prx3) was markedly shifted to dimer 30min after treatment with 100μM 2-AAPA, an event preceding 2-AAPA-induced decrease in cell viability. Furthermore, mitochondrial function was also severely impaired, leading to a decrease in the respiratory control ratio, reserve capacity, and ATP synthesis-coupled respiration, as well as an increase in mitochondrial membrane potential. Our results indicate that inhibition of GR and TrxR activities, disruption of the ability to detoxify peroxides, increased oxidation of Prxs, as well as compromised mitochondrial function represent early events mediating 2-AAPA toxicity to A172 glioblastoma cells., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Organoselenium compounds, such as diphenyl diselenide (PhSe) 2 and phenylselenium zinc chloride (PhSeZnCl), show protective activities related to their thiol peroxidase activity. However, depending on experimental conditions, organoselenium compounds can cause toxicity by oxidising thiol groups of proteins and induce the production of reactive oxygen species (ROS). Here, we analysed the toxicity of (PhSe) 2 and PhSeZnCl in yeast Saccharomyces cerevisiae. Cell growth of S. cerevisiae after 1, 2, 3, 4, 6, and 16 h of treatment with 2, 4, 6, and 10 μM of (PhSe) 2 was evaluated. For comparative purpose, PhSeZnCl was analysed only at 16 h of incubation at equivalent concentrations of selenium (i.e. 4, 8, 12, and 20 μM). ROS production (DCFH-DA), size, granularity, and cell membrane permeability (propidium iodide) were determined by flow cytometry. (PhSe) 2 inhibited cell growth at 2 h (10 μM) of incubation, followed by increase in cell size. The increase of cell membrane permeability and granularity (10 μM) was observed after 3 h of incubation, however, ROS production occurs only at 16 h of incubation (10 μM) with (PhSe) 2 , indicating that ROS overproduction is a more likely consequence of (PhSe) 2 toxicity and not its determinant. All tested parameters showed that only concentration of 20 μM induced toxicity in samples incubated with PhSeZnCl. In summary, the results suggest that (PhSe) 2 toxicity in S. cerevisiae is time and concentration dependent, presenting more toxicity when compared with PhSeZnCl.

Emerging evidence has pointed to mercury exposure as a risk factor for hypertension, atherosclerosis, myocardial infarction and coronary heart disease. However, the underlying mechanisms are not well understood. This study investigated potential toxic effects of low concentrations of methylmercury (MeHg) in cultured bovine aortic endothelial cells (BAECs) and the possible involvement of reactive species, particularly superoxide anion, in mediating such toxicity. MeHg treatment increased the oxidation of 2',7'-dichlorodihydrofluorescein diacetate (a general probe for reactive species) and dihydroethidium, a specific probe for superoxide anion. MeHg-induced 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium oxidations were significantly decreased by apocynin, an inhibitor of the enzyme NADPH oxidase, which represents a main source of superoxide anion in endothelial cells. MeHg treatment significantly disrupted mitochondrial membrane potential and this event was also reversed by apocynin. MeHg treatment also decreased glutathione levels and this event preceded glutathione peroxidase inhibition, which was observed only at 24h after treatment. These results indicate that MeHg induces oxidative stress in cultured BAECs and that this event is related to the production of superoxide anion. Moreover, the observed protective effects of apocynin in BAECs suggest the potential involvement of NADPH-oxidase in MeHg-induced endothelial dysfunction, which represents a pivotal event in most cardiovascular diseases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Guanosine, the endogenous guanine nucleoside, prevents cellular death induced by ischemic events and is a promising neuroprotective agent. During an ischemic event, nitric oxide has been reported to either cause or prevent cell death. Our aim was to evaluate the neuroprotective effects of guanosine against oxidative damage in hippocampal slices subjected to an in vitro ischemia model, the oxygen/glucose deprivation (OGD) protocol. We also assessed the participation of nitric oxide synthase (NOS) enzymes activity on the neuroprotection promoted by guanosine. Here, we showed that guanosine prevented the increase in ROS, nitric oxide, and peroxynitrite production induced by OGD. Moreover, guanosine prevented the loss of mitochondrial membrane potential in hippocampal slices subjected to OGD. Guanosine did not present an antioxidant effect per se. The protective effects of guanosine were mimicked by inhibition of neuronal NOS, but not of inducible NOS. The neuroprotective effect of guanosine may involve activation of cellular mechanisms that prevent the increase in nitric oxide production, possibly via neuronal NOS.

Although epidemiological studies have reported an association between hypercholesterolemia and mood disorders, there is a lack of data regarding depressive-like behavior in animal models of hypercholesterolemia. To address these questions, we assessed depressive-like behavior and hippocampal and cortical monoaminergic metabolism in three-month-old, low-density lipoprotein receptor knockout (LDLr(-/-)) and C57BL/6 wild-type mice. The LDLr(-/-) mice exhibited depressive-like behavior in the sucrose preference test, splash test, and tail suspension test. Increased monoamine oxidase (MAO) A and B activity was evidenced in the hippocampus of LDLr(-/-) mice. Furthermore, to address whether or not cholesterol modulates MAO activity, we exposed SH-SY5Y human neuroblastoma cells to human isolated low-density lipoprotein (LDL). Notably, LDL increased the activity of MAO-A and stimulated the reactive species generation in vitro. These findings indicate that depressive-like behavior in hypercholesterolemic mice is accompanied by alterations in the monoaminergic metabolism, providing new evidence about the association between hypercholesterolemia and depression., (Copyright © 2016. Published by Elsevier B.V.)