Hydroalcoholic Extract of Centella asiatica and Madecassic Acid Reverse Depressive-Like Behaviors, Inflammation and Oxidative Stress in Adult Rats Submitted to Stress in Early Life.

Major depressive disorder (MDD) is a severe disorder that causes enormous loss of quality of life, and among the factors underlying MDD is stress in maternal deprivation (MD). In addition, classic pharmacotherapy has presented severe adverse effects. Centella asiatica (C. asiatica) demonstrates a potential neuroprotective effect but has not yet been evaluated in MD models. This study aimed to evaluate the effect of C. asiatica extract and the active compound madecassic acid on possible depressive-like behavior, inflammation, and oxidative stress in the hippocampus and serum of young rats submitted to MD in the first days of life. Rats (after the first day of birth) were separated from the mother for 3 h a day for 10 days. When adults, these animals were divided into groups and submitted to treatment for 14 days. After subjecting the animals to protocols of locomotor activity in the open field and behavioral despair in the forced swimming test, researchers then euthanized the animals. The hippocampus and serum were collected and analyzed for the inflammatory cytokines and oxidative markers. The C. asiatica extract and active compound reversed or reduced depressive-like behaviors, inflammation in the hippocampus, and oxidative stress in serum and hippocampus. These results suggest that C. asiatica and madecassic acid have potential antidepressant action, at least partially, through anti-inflammatory and antioxidant profiles.

Prevalence of cognitive impairment and associated factors in older people.

BACKGROUND: Older people are the fastest-growing age group, with the highest risk of cognitive impairment. This study assessed the prevalence and associated factors with cognitive impairment in community-dwelling older people. METHODS: Older people were interviewed and accomplished through sociodemographic and health questionnaires. The quantitative variables were described by mean and standard deviation or median and interquartile range. The significance level adopted was 5 % (p < 0.05). The association between the quantitative variables was evaluated using the Pearson or Spearman correlation coefficients. RESULTS: The research population comprised 165 long-lived adults aged ≥80. The youngest one was 80, and the oldest one was 94 years old. The participants were 84.8 ± 3.6 years old, female (63 %) with a mean of education of 2.9 ± 1.8 years. A poor performance in the Mini-Mental State Examination (MMSE) was found in 58 (35.2 %) individuals when adjusted for educational level. After adjustment for confounding factors, body mass index (BMI) (p = 0.09), total older adults' income (up to 1 minimum wage [mw], p = 0.023; over 1 to 2 mw, p = 0.023), functional disability (Moderate dependence 75 %, p = 0.038; Moderate dependence 50 %, p = 0.081; Moderate dependence 25 %, p = 0.054), and the anxiety scale (p = 0.032), remained associated with cognitive impairment. CONCLUSIONS: This study showed that BMI, total older adults' income, functional disability, and anxiety are related to cognitive impairment in long-lived adults. This study has some limitations, such as the fact that it is a cross-sectional study, the reduced number of individuals, and the fact that there were no comparisons among different ages and populations.

Role of BDNF signaling in the neuroprotective and memory-enhancing effects of flavonoids in Alzheimer's Disease.

INTRODUCTION: Foods rich in flavonoids are associated with a reduced risk of various chronic diseases, including Alzheimer's disease (AD). In fact, growing evidence suggests that consuming flavonoid-rich foods can beneficially affect normal cognitive function. Animal models have shown that many flavonoids prevent the development of AD-like pathology and improve cognitive deficits. RESULT: Flavonoid-rich foods, such as green tea and blueberries, must exert their effect through the direct interaction of absorbed flavonoids and their metabolites with cellular and molecular targets. CONCLUSION: Based on the most recent scientific literature, this review article critically examines the therapeutic role of dietary flavonoids in ameliorating and preventing the progression of AD and focuses on the role of the BDNF signaling pathway in the neuroprotective effects of flavonoids.

Move Your Body toward Healthy Aging: Potential Neuroprotective Mechanisms of Irisin in Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia in older adults, having a significant global burden and increasing prevalence. Current treatments for AD only provide symptomatic relief and do not cure the disease. Physical activity has been extensively studied as a potential preventive measure against cognitive decline and AD. Recent research has identified a hormone called irisin, which is produced during exercise, that has shown promising effects on cognitive function. Irisin acts on the brain by promoting neuroprotection by enhancing the growth and survival of neurons. It also plays a role in metabolism, energy regulation, and glucose homeostasis. Furthermore, irisin has been found to modulate autophagy, which is a cellular process involved in the clearance of protein aggregates, which are a hallmark of AD. Additionally, irisin has been shown to protect against cell death, apoptosis, oxidative stress, and neuroinflammation, all of which are implicated in AD pathogenesis. However, further research is needed to fully understand the mechanisms and therapeutic potential of irisin in AD. Despite the current gaps in knowledge, irisin holds promise as a potential therapeutic target for slowing cognitive decline and improving quality of life in AD patients.

Bacillus strains prevent lipopolysaccharide-induced inflammation in gut and blood of male mice.

AIMS: The protective effects of Bacillus amyloliquefaciens(CCT7935), Bacillus subtilis(CCT7935), Bacillus licheniformis (CCT 7836), and Bacillus coagulans (CCT 0199) against lipopolysaccharide (LPS)-induced intestinal inflammation were investigated. METHODS AND RESULTS: Male Swiss mice were assigned into six groups: control group, LPS group, LPS + B. subtilis (CCT7935) group, LPS +   B. licheniformis (CCT 7836) group, LPS +   B. amyloliquefaciens (CCT7935) group, and LPS   + B. coagulans (CCT 0199) group. Each mouse of the groups Bacillus received 1 × 109 colony-forming units of Bacillus once daily by oral gavage during 30 days. Twenty-four hours after the last dose of Bacillus, all groups, except the control group, were intraperitoneally injected with LPS in the single dose of 15 mg kg-1. The mice were euthanized 24 h after the LPS administration. Histological alterations, myeloperoxidase activity, and nitrite levels were analyzed in the gut of mice and the inflammatory cytokines were analyzed in the gut and in the blood. The results demonstrate that the mice challenged with LPS presented the villi shortened and damaged, which were significantly protected by B. coagulans and B. amyloliquefaciens. Furthermore, all Bacillus tested were effective in preventing against the increase of myeloperoxidase activity, while B. amyloliquefaciens and B. subtilis prevented the increase of nitrite and IL-1ß levels in the gut of mice induced with LPS was decreased only B. subtilis. LPS also elevated the IL-1 ß, IL-6, and IL-10 levels in the blood, and these alterations were significantly suppressed by Bacillus, especially by B. subtilis. CONCLUSIONS: The study suggests that the Bacillus investigated in this study might be effective therapeutic agents for preventing intestinal inflammation, because they decrease the inflammatory process an protect against tissue damage.

Inflammatory stimulus worsens the effects of UV-A exposure on J774 cells.

UV-A radiation affects skin homeostasis by promoting oxidative distress. Endogenous photosensitizers in the dermis and epidermis of human skin absorb UV-A radiation forming excited states (singlet and triplet) and reactive oxygen species (ROS) producing oxidized compounds that trigger biological responses. The activation of NF-kB induces the expression of pro-inflammatory cytokines and can intensify the generation of ROS. However, there is no studies evaluating the cross talks between inflammatory stimulus and UV-A exposure on the levels of redox misbalance and inflammation. In here, we evaluated the effects of UV-A exposure on J774 macrophage cells previously challenged with LPS in terms of oxidative distress, release of pro-inflammatory cytokines, and activation of regulated cell death pathways. Our results showed that LPS potentiates the dose-dependent UV-A-induced oxidative distress and cytokine release, in addition to amplifying the regulated (autophagy and apoptosis) and non-regulated (necrosis) mechanisms of cell death, indicating that a previous inflammatory stimulus potentiates UV-A-induced cell damage. We discuss these results in terms of the current-available skin care strategies.

The shared molecular mechanisms underlying aging of the brain, major depressive disorder, and Alzheimer's disease: The role of circadian rhythm disturbances.

An association with circadian clock function and pathophysiology of aging, major depressive disorder (MDD), and Alzheimer's disease (AD) is well established and has been proposed as a factor in the development of these diseases. Depression and changes in circadian rhythm have been increasingly suggested as the two primary overlapping and interpenetrating changes that occur with aging. The relationship between AD and depression in late life is not completely understood and probably is complex. Patients with major depression or AD suffer from disturbed sleep/wake cycles and altered rhythms in daily activities. Although classical monoaminergic hypotheses are traditionally proposed to explain the pathophysiology of MDD, several clinical and preclinical studies have reported a strong association between circadian rhythm and mood regulation. In addition, a large body of evidence supports an association between disruption of circadian rhythm and AD. Some clock genes are dysregulated in rodent models of depression. If aging, AD, and MDD share a common biological basis in pathophysiology, common therapeutic tools could be investigated for their prevention and treatment. Nitro-oxidative stress (NOS), for example, plays a fundamental role in aging, as well as in the pathogenesis of AD and MDD and is associated with circadian clock disturbances. Thus, development of therapeutic possibilities with these NOS-related conditions is advisable. This review describes recent findings that link disrupted circadian clocks to aging, MDD, and AD and summarizes the experimental evidence that supports connections between the circadian clock and molecular pathologic factors as shared common pathophysiological mechanisms underlying aging, AD, and MDD.

Vitamin D3 improves spatial memory and modulates cytokine levels in aged rats.

Vitamin D3 deficiency is associated with an increased risk of dementia. An association between vitamin D3 deficiency and subjective cognitive complaints in geriatric patients has been previously reported. This study aimed to evaluate the effects of two doses of vitamin D3 on spatial memory (using the Radial Maze) and cytokine levels [tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-10 (IL-10)] on 2-, 6-, 13-, 22-, and 31-month-old male Wistar rats. Animals were supplemented with vitamin D3 at doses of 42 IU/kg and 420 IU/kg for 21 days. A radial maze test was performed to evaluate spatial memory. After the behavioral test, the frontal cortex and hippocampus were dissected for enzyme immunoassay analyses to measure the cytokine levels (TNFα, IL-1ß, IL-6, and IL-10). Our results showed that vitamin D3 supplementation reversed spatial memory impairment at the supplemented doses (42 and 420 IU/kg) in 6-, 13-, and 22-month-old animals and at a dose of 420 IU/kg in 31-month-old animals. The lower dose (42 IU/kg) regulates both pro- and anti-inflammatory cytokines mainly in the frontal cortex. Our results suggest that vitamin D3 has a modulatory action on pro- and anti-inflammatory cytokines, since older animals showed increased cytokine levels compared to 2-month-old animals, and that vitamin D3 may exert an immunomodulatory effect on aging.

Long-term administration of soft drink causes memory impairment and oxidative damage in adult and middle-aged rats.

INTRODUCTION: The consumption of soft drinks has increased considerably in recent decades, mainly cola soft drinks. Excessive consumption of cola-based soft drinks is associated with several diseases and cognitive decline, particularly memory impairment. Furthermore, diets with high sugar can promote insulin resistance, metabolic syndrome, and dyslipidemia. AIM: Thus, the present study aimed to evaluate the effect of cola soft drink intake on behavioral alterations and oxidative damage in 2-, 8- and 14- month-old male Wistar rats. METHODS: The soft drink groups drank soft drink and/or water ad libitum during 67 days, the control groups ingested only water. Radial-arm maze and Y-maze were used to evaluate spatial memory, open-field to evaluate the habituation memory, and inhibitory avoidance to evaluate aversive memory. The behavioral tests started at the day 57 and finished at day 67 of treatment. At 68th day, the rats were killed; frontal cortex and hippocampus were dissected to the analysis of antioxidants enzymes catalase (CAT) and superoxide dismutase (SOD); and the oxidative markers thiobarbituric acid reactive substances (TBARS) and dichloro-dihydro-fluorescein diacetate (DCFH) were measured in the hippocampus. RESULTS AND DISCUSSION: The cola-based soft drink intake caused memory impairment in the radial-arm maze, Y-maze task, and open-field in the 2- and 8-month-old rat, but not in the 14-month-old. There were no difference among groups in the inhibitory avoidance test. In the frontal cortex, soft drink intake reduced CAT activity in the 8-month-old rats and SOD activity in the 8- and 14-month-old rats. In the hippocampus, the soft drink increased CAT activity in 2- and 8-month-old rats, increased DCFH levels at all ages, and increased TBARS levels in 2-month-rats. Therefore, the results show that long-term soft drink intake leads to memory impairment and oxidative stress. The younger seems to be more susceptible to the soft drink alterations on behavior; however, soft drink caused alterations in the oxidative system at all ages evaluated.

Inflammatory Cascade in Alzheimer's Disease Pathogenesis: A Review of Experimental Findings.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta (Aß) aggregation and deposition are critical pathogenic processes in AD, leading to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptic degeneration, and dementia. In LOAD, the causes of Aß accumulation and neuronal loss are not completely clear. Importantly, the blood-brain barrier (BBB) disruption seems to present an essential role in the induction of neuroinflammation and consequent AD development. In addition, we propose that the systemic inflammation triggered by conditions like metabolic diseases or infections are causative factors of BBB disruption, coexistent inflammatory cascade and, ultimately, the neurodegeneration observed in AD. In this regard, the use of anti-inflammatory molecules could be an interesting strategy to treat, delay or even halt AD onset and progression. Herein, we review the inflammatory cascade and underlying mechanisms involved in AD pathogenesis and revise the anti-inflammatory effects of compounds as emerging therapeutic drugs against AD.

Treatment with isolated gold nanoparticles reverses brain damage caused by obesity.

In this study, we performed two experiments. In the first experiment, the objective was to link gold nanoparticles (GNPs) with sodium diclofenac and/or soy lecithin and to determine their concentration in tissues and their toxicity using hepatic and renal analyzes in mice to evaluate their safety as therapeutic agents in the subsequent treatment of obesity. In the second experiment, we evaluated the effect of GNPs on inflammatory and biochemical parameters in obese mice. In the first experiment, we synthesized and characterized 18 nm GNPs that were administered intraperitoneally in isolation or in association with sodium diclofenac and/or soy lecithin in mice once daily for 1 or 14 days. Twenty-four hours after the single or final administration, the animals were euthanized, following which the tissues were removed for evaluating the concentration of GNPs, and serum samples were collected for hepatic and renal analysis. Hepatic damage was evaluated based on the levels of alanine aminotransferase (ALT), whereas renal damage was evaluated based on creatinine levels. A higher concentration of GNPs was detected in the tissues upon administration for 14 days, and there were no signs of hepatic or renal damage. In the second experiment, the mice were used as animal models of obesity and were fed a high-fat diet (obese group) and control diet (control group). After eight weeks of high-fat diet administration, the mice were treated with saline or with GNPs (average size of 18 nm) at a concentration of 70 mg/L (70 mg/kg) once a day, for 14 days, for 10 weeks. Body weight and food intake were measured frequently. After the experiment ended, the animals were euthanized, serum samples were collected for glucose and lipid profile analysis, the mesenteric fat content was weighed, and the brains were removed for inflammatory and biochemical analysis. In obese mice, although GNP administration did not reduce body and mesenteric fat weight, it reduced food intake. The glucose levels were reversed upon administration of GNPs, whereas the lipid profile was not altered in any of the groups. GNPs exerted a beneficial effect on inflammation and oxidative stress parameters, without reverting mitochondrial dysfunction. Our results indicate that the intraperitoneal administration of GNPs for 14 days results in a significant GNP concentration in adipose tissues, which could be an interesting finding for the treatment of inflammation associated with obesity. Based on the efficacy of GNPs in reducing dietary intake, inflammation, and oxidative stress, they can be considered potential alternative agents for the treatment of obesity.

Oral administration of D-galactose increases brain tricarboxylic acid cycle enzymes activities in Wistar rats.

D-galactose (D-gal) is a carbohydrate widely distributed in regular diets. However, D-gal administration in rodents is associated with behavioral and neurochemical alterations similar to features observed in aging. In this regard, this study aimed to investigate the effects of D-gal exposure, in different periods, in rats' brain regions' activities of creatine kinase (CK) and tricarboxylic acid (TCA) cycle enzymes. Male adult Wistar rats received D-gal (100 mg/kg, gavage) for 1, 2, 4, 6 or 8 weeks. CK and TCA enzymes' activities were evaluated in rats' prefrontal cortex and hippocampus. In general, the results showed an increase in citrate synthase (CS) and succinate dehydrogenase (SDH) activities in animals treated with D-gal compared to the control group in the prefrontal cortex and hippocampus. Also, in the fourth week, the malate dehydrogenase (MD) activity increased in the hippocampus of rats that received D-gal compared to control rats. In addition, we observed an increase in the CK activity in the prefrontal cortex and hippocampus in the first and eighth weeks of treatment in the D-gal group compared to the control group. D-gal administration orally administered modulated TCA cycle enzymes and CK activities in the prefrontal cortex and hippocampus, which were also observed in aging and neurodegenerative diseases. However, more studies using experimental models are necessary to understand better the impact and contribution of these brain metabolic abnormalities associated with D-gal consumption for aging.

Folic acid prevents habituation memory impairment and oxidative stress in an aging model induced by D-galactose.

The present study aimed to evaluate the effect of folic acid treatment in an animal model of aging induced by D-galactose (D-gal). For this propose, adult male Wistar rats received D-gal intraperitoneally (100 mg/kg) and/or folic acid orally (5 mg/kg, 10 mg/kg or 50 mg/kg) for 8 weeks. D-gal caused habituation memory impairment, and folic acid (10 mg/kg and 50 mg/kg) reversed this effect. However, folic acid 50 mg/kg per se caused habituation memory impairment. D-gal increased the lipid peroxidation and oxidative damage to proteins in the prefrontal cortex and hippocampus from rats. Folic acid (5 mg/kg, 10 mg/kg, or 50 mg/kg) partially reversed the oxidative damage to lipids in the hippocampus, but not in the prefrontal cortex, and reversed protein oxidative damage in the prefrontal cortex and hippocampus. D-gal induced synaptophysin and BCL-2 decrease in the hippocampus and phosphorylated tau increase in the prefrontal cortex. Folic acid was able to reverse these D-gal-related alterations in the protein content. The present study shows folic acid supplementation as an alternative during the aging to prevent cognitive impairment and brain alterations that can cause neurodegenerative diseases. However, additional studies are necessary to elucidate the effect of folic acid in aging.

Folic Acid Supplementation in the Gestational Phase of Female Rats Improves Age-Related Memory Impairment and Neuroinflammation in Their Adult and Aged Offspring.

Folic acid (FA) supplementation is important during pregnancy to avoid malformations in the offspring. However, it is unknown if it can affect the offspring throughout their lives. To evaluate the offspring, female mother rats (dams) were separated into 5 groups: Four groups received the AIN-93 diet, divided into control and FA (5, 10, and 50 mg/kg), and an additional group received a FA-deficient diet, and the diet was performed during pregnancy and lactation. We evaluated the female offspring of these dams (at 2 and 18 months old). The aged offspring fed with FA-deficient diet presented habituation, spatial and aversive memory impairment and the FA maternal supplementation prevented this. The natural aging caused an increase in the TNF-α and IL-1ß levels in the hippocampus from 18-month-old offspring. FA maternal supplementation was able to prevent the increase of these cytokines. IL-4 levels decreased in the prefrontal cortex from aged control rats and FA prevented it. FA deficiency decreased the levels of IL-4 in the hippocampus of the young offspring. In addition, natural aging and FA deficiency decreased brain-derived neurotrophic factor levels in the hippocampus and nerve growth factor levels in the prefrontal cortex and FA supplementation prevented it. Thus, the present study shows for the first time the effect of FA maternal supplementation on memory, cytokines, and neurotrophins in the aged offspring.

Stress and signaling pathways regulating autophagy: From behavioral models to psychiatric disorders.

Autophagy is a process of degradation and recycling of cytoplasmatic components by the lysosomes. In the central nervous system (CNS), autophagy is involved in cell surveillance, neuroinflammation, and neuroplasticity. Neuropsychiatric conditions are associated with functional disturbances at molecular and cellular levels, causing significant impairments in cell homeostasis. Additionally, emerging evidence supports that dysfunctions in autophagy contribute to the pathophysiology of neurological diseases. However, the studies on autophagy in psychiatric disorders are highly heterogeneous and have several limitations, mainly to assess causality and determine the autophagy flux in animals and human samples. Besides, the role of this mechanism in non-neuronal cells in the CNS is only recently being explored. Thus, this review summarizes and discusses the changes in the autophagy pathway in animal models of psychiatric disorders and the limitations underlying the significant findings. Moreover, we compared these findings with clinical studies. Understanding the involvement of autophagy in psychiatric conditions, and the limitation of our current models may contribute to the development of more effective research approaches and possibly pharmacological therapies.

Lipoic Acid and Fish Oil Combination Potentiates Neuroinflammation and Oxidative Stress Regulation and Prevents Cognitive Decline of Rats After Sepsis.

Sepsis causes organ dysfunction due to an infection, and it may impact the central nervous system. Neuroinflammation and oxidative stress are related to brain dysfunction after sepsis. Both processes affect microglia activation, neurotrophin production, and long-term cognition. Fish oil (FO) is an anti-inflammatory compound, and lipoic acid (LA) is a universal antioxidant substance. They exert neuroprotective roles when administered alone. We aimed at determining the effect of FO+LA combination on microglia activation and brain dysfunction after sepsis. Microglia cells from neonatal pups were co-treated with lipopolysaccharide (LPS) and FO or LA, alone or combined, for 24 h. Cytokine levels were measured. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) and treated orally with FO, LA, or FO+LA. At 24 h after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of cytokines, myeloperoxidase (MPO) activity, protein carbonyls, superoxide dismutase (SOD), and catalase (CAT) activity. At 10 days after surgery, brain-derived neurotrophic factor (BDNF) levels were determined and behavioral tests were performed. The combination diminished in vitro levels of pro-inflammatory cytokines. The combination reduced TNF-α in the cortex, IL-1ß in the prefrontal cortex, as well as MPO activity, and decreased protein carbonyls formation in all structures. The combination enhanced catalase activity in the prefrontal cortex and hippocampus, elevated BDNF levels in all structures, and prevented behavioral impairment. In summary, the combination was effective in preventing cognitive damage by reducing neuroinflammation and oxidative stress and increasing BDNF levels.

Sodium Butyrate and Indole-3-propionic Acid Prevent the Increase of Cytokines and Kynurenine Levels in LPS-induced Human Primary Astrocytes.

The crosstalk between central nervous system (CNS) and gut microbiota plays key roles in neuroinflammation and chronic immune activation that are common features of all neurodegenerative diseases. Imbalance in the microbiota can lead to an increase in the intestinal permeability allowing toxins to diffuse and reach the CNS, as well as impairing the production of neuroprotective metabolites such as sodium butyrate (SB) and indole-3-propionic acid (IPA). The aim of the present study was to evaluate the effect of SB and IPA on LPS-induced production of cytokines and tryptophan metabolites in human astrocytes. Primary cultures of human astrocytes were pre-incubated with SB or IPA for 1 hour before treatment with LPS. Cell viability was not affected at 24, 48 or 72 hours after pre-treatment with SB, IPA or LPS treatment. SB was able to significantly prevent the increase of GM-CSF, MCP-1, IL-6 IL-12, and IL-13 triggered by LPS. SB and IPA also prevented inflammation indicated by the increase in kynurenine and kynurenine/tryptophan ratio induced by LPS treatment. IPA pre-treatment prevented the LPS-induced increase in MCP-1, IL-12, IL-13, and TNF-α levels 24 hours after pre-treatment, but had no effect on tryptophan metabolites. The present study showed for the first time that bacterial metabolites SB and IPA have potential anti-inflammatory effect on primary human astrocytes with potential therapeutic benefit in neurodegenerative disease characterized by the presence of chronic low-grade inflammation.

Adenosine and NMDA Receptors Modulate Neuroprotection-Induced NMDA Preconditioning in Mice.

The severity score of quinolinic acid (QA)-induced seizures was investigated after N-methyl-D-aspartate (NMDA) preconditioning associated with adenosine receptors. Also, the levels of adenosine A1 and A2A receptors and subunits of NMDA receptors in the hippocampi of mice were determined to define components of the resistance mechanism. Adult CF-1 mice were treated intraperitoneally with saline or NMDA (75 mg/kg), and some mice were treated intracerebroventricularly (i.c.v.) with 0.1 pmol of adenosine receptor antagonists 8-cyclopentyltheophylline (CPT; receptor A1) or ZM241385 (receptor A2A) 0, 1, or 6 h after NMDA administration. These adenosine receptor antagonists were administered to block NMDA's protective effect. Seizures and their severity scores were evaluated during convulsions induced by QA (36.8 nmol) that was administered i.c.v. 24 h after NMDA. The cell viability and content of subunits of the NMDA receptors were analyzed 24 h after QA administration. NMDA preconditioning reduced the maximal severity 6 displayed in QA-administered mice, inducing protection in 47.6% of mice after QA-induced seizures. CPT increased the latency of seizures when administered 0 or 6 h, and ZM241385 generated the same effect when administered 6 h after NMDA administration. The GluN1 content was lower in the hippocampi of the QA mice and the NMDA-preconditioned animals without seizures. GluN2A content was unaltered in all groups. The results demonstrated the components of resistance evoked by NMDA, in which adenosine receptors participate in a time-dependent mode. Similarly, the reduction on GluN1 expression in the hippocampus may contribute to this effect during the preconditioning period.

Microbiota Alterations in Alzheimer's Disease: Involvement of the Kynurenine Pathway and Inflammation.

Alzheimer's disease (AD) is a neurodegenerative disease considered the major cause of dementia in the elderly. The main pathophysiological features of the disease are neuronal loss (mainly cholinergic neurons), glutamatergic excitotoxicity, extracellular accumulation of amyloid beta, and intracellular neurofibrillary tangles. However, other pathophysiological features of the disease have emerged including neuroinflammation and dysregulation of the kynurenine pathway (KP). The intestinal microbiota is a large and diverse collection of microorganisms that play a crucial role in regulating host health. Recently, studies have highlighted that changes in intestinal microbiota contribute to brain dysfunction in various neurological diseases including AD. Studies suggest that microbiota compositions are altered in AD patients and animal models and that these changes may increase intestinal permeability and induce inflammation. Considering that microbiota can modulate the kynurenine pathway and in turn neuroinflammation, the gut microbiome may be a valuable target for the development of new disease-modifying therapies. The present review aims to link the interactions between AD, microbiota, and the KP.

Diet-induced obesity causes hypothalamic neurochemistry alterations in Swiss mice.

The aim of this study was to assess inflammatory parameters, oxidative stress and energy metabolism in the hypothalamus of diet-induced obese mice. Male Swiss mice were divided into two study groups: control group and obese group. The animals in the control group were fed a diet with adequate amounts of macronutrients (normal-lipid diet), whereas the animals in the obese group were fed a high-fat diet to induce obesity. Obesity induction lasted 10 weeks, at the end of this period the disease model was validated in animals. The animals in the obese group had higher calorie consumption, higher body weight and higher weight of mesenteric fat compared to control group. Obesity showed an increase in levels of interleukin 1ß and decreased levels of interleukin 10 in the hypothalamus. Furthermore, increased lipid peroxidation and protein carbonylation, and decreased level of glutathione in the hypothalamus of obese animals. However, there was no statistically significant difference in the activity of antioxidant enzymes, superoxide dismutase and catalase. The obese group had lower activity of complex I, II and IV of the mitochondrial respiratory chain, as well as lower activity of creatine kinase in the hypothalamus as compared to the control group. Thus, the results from this study showed changes in inflammatory markers, and dysregulation of metabolic enzymes in the pathophysiology of obesity.