Sodium Propionate Oral Supplementation ameliorates Depressive-Like Behavior through Gut Microbiome and Histone 3 Epigenetic Regulation.

Major Depressive Disorder (MDD) is a global health concern, affecting over 250 million individuals worldwide. In recent years, the gut-brain axis has emerged as a promising field for understanding the pathophysiology of MDD. Microbial metabolites, such as Short-Chain Fatty Acids (SCFAs) - acetate, butyrate, and propionate -, have gained attention for their potential to influence epigenetic modifications within the host brain. However, the precise mechanisms through which these metabolites participate in MDD pathophysiology remain elusive. This study was designed to investigate the effects of oral SCFA supplementation in adult male Wistar rats subjected to Chronic Unpredictable Mild Stress (CUMS). A subset of control and CUMS-exposed rats received different supplementations: sodium acetate (NaOAc) at a concentration of 60 mM, sodium butyrate (NaB) at 40 mM, sodium propionate (NaP) at 50 mM, or a mixture of these SCFAs. The gut microbiome was assessed through 16S rRNA sequencing, and epigenetic profiling was performed using Western blot analysis. Results demonstrated that NaP supplementation significantly alleviated anhedonia in stressed animals, as evidenced by improved performance in the sucrose consumption test. This ameliorative effect was potentially associated with the modulation of gut bacterial communities, accompanied by the attenuation of the region-specific epigenetic dysregulation in the brain of the animals exposed to chronic stress. These findings suggest a potential association between gut dysbiosis and stress response, and NaP could be a promising target for future MDD interventions. However, further studies are needed to fully elucidate the underlying mechanisms of these effects.

Early-life trauma, impulsivity and suicide attempt: a systematic review and meta-analysis.

INTRODUCTION: Suicide is a worldwide health concern and up to date there is no good predictor of it except a previous suicide attempt. Therefore, there are increasing efforts in the understanding of which factors, genetic or environmental, are associated with suicide behaviour. OBJECTIVE: To review evidence of the effect of childhood trauma and impulsivity on suicidal behavior through a systematic review and meta-analysis. METHODS: Searches were conducted on the 12th of June 2021 in the PubMed, Scopus, and Web of Science databases. Two reviewers evaluated each record for eligibility and discussed upon disagreement, when no consensus was reached, a third reviewer was involved to make a decision. RESULTS: A total of 11,530 records were identified through the searches. After duplicates were removed, 6,595 records remained to be screened. The full text was sought for 1,561 records. Our qualitative synthesis included 22 studies, from which 9 were included in the meta-analyses. We found a significant effect of sexual abuse, physical abuse, emotional abuse and physical neglect on suicide attempts in the prisoners, and Substance Use Diorder (SUD) subgroups. Moreover, there was a significant effect of Childhood Trauma Questionnaire (CTQ) total score and emotional neglect dimension for all the subgroups. CONCLUSION: The present study has provided an overview of the state-of-the-art research on childhood trauma and impulsivity and their association with suicidal behavior and quantified their effects on suicide attempts. Hopefully this evidence will be considered in future research and harnessed for clinical gain in detection and treatment of suicide behaviour.

Excess of body weight is associated with accelerated T-cell senescence in hospitalized COVID-19 patients.

BACKGROUND: Several risk factors have been involved in the poor clinical progression of coronavirus disease-19 (COVID-19), including ageing, and obesity. SARS-CoV-2 may compromise lung function through cell damage and paracrine inflammation; and obesity has been associated with premature immunosenescence, microbial translocation, and dysfunctional innate immune responses leading to poor immune response against a range of viruses and bacterial infections. Here, we have comprehensively characterized the immunosenescence, microbial translocation, and immune dysregulation established in hospitalized COVID-19 patients with different degrees of body weight. RESULTS: Hospitalised COVID-19 patients with overweight and obesity had similarly higher plasma LPS and sCD14 levels than controls (all p < 0.01). Patients with obesity had higher leptin levels than controls. Obesity and overweight patients had similarly higher expansions of classical monocytes and immature natural killer (NK) cells (CD56+CD16-) than controls. In contrast, reduced proportions of intermediate monocytes, mature NK cells (CD56+CD16+), and NKT were found in both groups of patients than controls. As expected, COVID-19 patients had a robust expansion of plasmablasts, contrasting to lower proportions of major T-cell subsets (CD4 + and CD8+) than controls. Concerning T-cell activation, overweight and obese patients had lower proportions of CD4+CD38+ cells than controls. Contrasting changes were reported in CD25+CD127low/neg regulatory T cells, with increased and decreased proportions found in CD4+ and CD8+ T cells, respectively. There were similar proportions of T cells expressing checkpoint inhibitors across all groups. We also investigated distinct stages of T-cell differentiation (early, intermediate, and late-differentiated - TEMRA). The intermediate-differentiated CD4 + T cells and TEMRA cells (CD4+ and CD8+) were expanded in patients compared to controls. Senescent T cells can also express NK receptors (NKG2A/D), and patients had a robust expansion of CD8+CD57+NKG2A+ cells than controls. Unbiased immune profiling further confirmed the expansions of senescent T cells in COVID-19. CONCLUSIONS: These findings suggest that dysregulated immune cells, microbial translocation, and T-cell senescence may partially explain the increased vulnerability to COVID-19 in subjects with excess of body weight.

Transgenerational inheritance of methylmercury and vitamin A-induced toxicological effects in a Wistar rats environmental-based model.

Mercury (Hg) and vitamin A (VitA) are two environmental factors with potential health impacts, especially during pregnancy and early childhood. Fish and seafood may present elevated levels of methylmercury (MeHg), the major Hg derivative, and VitA. This study aimed to evaluate the transgenerational effects of exposure to MeHg and/or VitA on epigenetic and toxicological parameters in a Wistar rat model. Our findings revealed persistent toxicological effects in generations F1 and F2 following low/mild doses of MeHg and/or VitA exposure during dams' (F0) gestation and breastfeeding. Toxicological effects observed in F2 included chronic DNA damage, bone marrow toxicity, altered microglial content, reduced neuronal signal, and diminished male longevity. Sex-specific patterns were also observed. Co-exposure to MeHg and VitA showed both synergistic and antagonistic effects. Additionally, the study demonstrated that MeHg and VitA affected histone methylation and caused consistent effects in F2. While MeHg exposure has been associated with transgenerational inheritance effects in other organisms, this study provides the first evidence of transgenerational inheritance of MeHg and VitA-induced toxicological effects in rodents. Although the exact mechanism is not yet fully understood, these findings suggest that MeHg and VitA may perpetuate their impacts across generations. The study highlights the need for remedial policies and interventions to mitigate the potential health problems faced by future generations exposed to MeHg or VitA. Further research is warranted to investigate the transgenerational effects beyond F2 and determine the matrilineal or patrilineal inheritance patterns.

Histone 3 Trimethylation Patterns are Associated with Resilience or Stress Susceptibility in a Rat Model of Major Depression Disorder.

Major Depressive Disorder (MDD) is a severe and multifactorial psychiatric condition. Evidence has shown that environmental factors, such as stress, significantly explain MDD pathophysiology. Studies have hypothesized that changes in histone methylation patterns are involved in impaired glutamatergic signaling. Based on this scenario, this study aims to investigate histone 3 involvement in depression susceptibility or resilience in MDD pathophysiology by investigating cellular and molecular parameters related to i) glutamatergic neurotransmission, ii) astrocytic functioning, and iii) neurogenesis. For this, we subjected male Wistar rats to the Chronic Unpredictable Mild Stress (CUMS) model of depression. We propose that by evaluating the sucrose consumption, open field, and object recognition test performance from animals submitted to CUMS, it is possible to predict with high specificity rats with susceptibility to depressive-like phenotype and resilient to the depressive-like phenotype. We also demonstrated, for the first time, that patterns of H3K4me3, H3K9me3, H3K27me3, and H3K36me3 trimethylation are strictly associated with the resilient or susceptible to depressive-like phenotype in a brain-region-specific manner. Additionally, susceptible animals have reduced DCx and GFAP and resilient animals present increase of AQP-4 immunoreactivity. Together, these results provide evidence that H3 trimethylations are related to the development of the resilient or susceptible to depressive-like phenotype, contributing to further advances in the pathophysiology of MDD and the discovery of mechanisms behind resilience.

Bioavailable Phenolic Compounds from Olive Pomace Present Anti-Neuroinflammatory Potential on Microglia Cells.

The neuroinflammatory process is considered one of the main characteristics of central nervous system diseases, where a pro-inflammatory response results in oxidative stress through the generation of reactive oxygen and nitrogen species (ROS and RNS). Olive (Olea europaea L.) pomace is a by-product of olive oil production that is rich in phenolic compounds (PCs), known for their antioxidant and anti-inflammatory properties. This work looked at the antioxidant and anti-neuroinflammatory effects of the bioavailable PC from olive pomace in cell-free models and microglia cells. The bioavailable PC of olive pomace was obtained through the process of in vitro gastrointestinal digestion of fractionated olive pomace (OPF, particles size < 2 mm) and micronized olive pomace (OPM, particles size < 20 µm). The profile of the PC that is present in the bioavailable fraction as well as its in vitro antioxidant capacity were determined. The anti-neuroinflammatory capacity of the bioavailable PC from olive pomace (0.03-3 mg L-1) was evaluated in BV-2 cells activated by lipopolysaccharide (LPS) for 24 h. The total bioavailable PC concentration and antioxidant activity against peroxyl radical were higher in the OPM than those observed in the OPF sample. The activation of BV-2 cells by LPS resulted in increased levels of ROS and nitric oxide (NO). The bioavailable PCs from both OPF and OPM, at their lowest concentrations, were able to reduce the ROS generation in activated BV-2 cells. In contrast, the highest PC concentration of OPF and OPM was able to reduce the NO levels in activated microglial cells. Our results demonstrate that bioavailable PCs from olive pomace can act as anti-neuroinflammatory agents in vitro, independent of particle size. Moreover, studies approaching ways to increase the bioavailability of PCs from olive pomace, as well as any possible toxic effects, are needed before a final statement on its nutritional use is made.

Bexarotene drives the self-renewing proliferation of adult neural stem cells, promotes neuron-glial fate shift, and regulates late neuronal differentiation.

Treatment with bexarotene, a selective retinoid X receptor (RXR) agonist, significantly improves behavioral dysfunctions in various neurodegenerative animal models. Additionally, it activates neurodevelopmental and plasticity pathways in the brains of adult mice. Our objective was to investigate the impact of RXR activation by bexarotene on adult neural stem cells (aNSC) and their cell lineages. To achieve this, we treated NSCs isolated from the subventricular zone (SVZ) of adult rat brains from the proliferative stage to the differentiated status. The results showed that bexarotene-treated aNSC exhibited increased BrdU incorporation, SOX2+ dividing cell pairs, and cell migration from neurospheres, revealing that the treatment promotes self-renewing proliferation and cell motility in SVZ-aNCS. Furthermore, bexarotene induced a cell fate shift characterized by a significant increase in GFAP+/S100B+ differentiated astrocytes, which uncovers the participation of activated-RXR in astrogenesis. In the neuronal lineage, the fate shift was counteracted by bexarotene-induced enhancement of NeuN+ nuclei together with neurite network outgrowth, indicating that the RXR agonist stimulates SVZ-aNCS neuronal differentiation at later stages. These findings establish new connections between RXR activation, astro- and neurogenesis in the adult brain, and contribute to the development of therapeutic strategies targeting nuclear receptors for neural repair.

Increased alpha-synuclein and neuroinflammation in the substantia nigra triggered by systemic inflammation are reversed by targeted inhibition of the receptor for advanced glycation end products (RAGE).

The receptor for advanced glycation end products (RAGE) is a protein of the immunoglobulin superfamily capable of regulating inflammation. Considering the role of this receptor in the initiation and establishment of neuroinflammation, and the limited understanding of the function of RAGE in the maintenance of this condition, this study describes the effects of RAGE inhibition in the brain, through an intranasal treatment with the antagonist FPS-ZM1, in an animal model of chronic neuroinflammation induced by acute intraperitoneal injection of lipopolysaccharide (LPS). Seventy days after LPS administration (2 mg/kg, i.p.), Wistar rats received, intranasally, 1.2 mg of FPS-ZM1 over 14 days. On days 88 and 89, the animals were submitted to the open-field test and were killed on day 90 after the intraperitoneal injection of LPS. Our results indicate that blockade of encephalic RAGE attenuates LPS-induced chronic neuroinflammation in different brain regions. Furthermore, we found that intranasal FPS-ZM1 administration reduced levels of gliosis markers, RAGE ligands, and α-synuclein in the substantia nigra pars compacta. Additionally, the treatment also reversed the increase in S100 calcium-binding protein B (RAGE ligand) in the cerebrospinal fluid and the cognitive-behavioral deficits promoted by LPS-less time spent in the central zone of the open-field arena (more time in the lateral zones), decreased total distance traveled, and increased number of freezing episodes. In summary, our study demonstrates the prominent role of RAGE in the maintenance of a chronic neuroinflammatory state triggered by a single episode of systemic inflammation and also points to possible future RAGE-based therapeutic approaches to treat conditions in which chronic neuroinflammation and increased α-synuclein levels could play a relevant role, such as in Parkinson's disease.

Sodium Butyrate Protects Against Intestinal Oxidative Damage and Neuroinflammation in the Prefrontal Cortex of Ulcerative Colitis Mice Model.

Inflammatory bowel diseases (IBD) cause increased inflammatory signalling and oxidative damage. IBDs are correlated with an increased incidence of brain-related disorders suggesting that the gut-brain-axis exerts a pivotal role in IBD. Butyrate is one of the main microbial metabolites in the colon, and it can cross the blood-brain barrier, directly affecting the brain. We induced ulcerative colitis (UC) in mice utilizing dextran sodium sulfate (DSS) in the drinking water for 7 days. Animals were divided into four groups, receiving water or DSS and treated with saline or 0,066 g/kg of Sodium Butyrate for 7 days. We also used an integrative approach, combining bioinformatics functional network and experimental strategies to understand how butyrate may affect UC. Butyrate was able to attenuate colitis severity and intestinal inflammation. Butyrate protected the colon against oxidative damage in UC and protected the prefrontal cortex from neuroinflammation observed in DSS group. Immunocontent of tight junction proteins Claudin-5 and Occludin were reduced in colon of DSS group mice and butyrate was able to restore to control levels. Occludin and Claudin-5 decrease in DSS group indicate that an intestinal barrier disruption may lead to the increased influx of gut-derived molecules, causing neuroinflammation in the prefrontal cortex, observed by increased IBA-1 marker. The probable protection mechanism of butyrate treatment occurs through NRF2 through Nrf2 and HIF-1α activation and consequent activation of catalase and superoxide dismutase. Our data suggest that systemic inflammation associated with intestinal barrier disruption in UC leads to neuroinflammation in the prefrontal cortex, which was atenuated by butyrate.

Coagulation biomarkers and coronavirus disease 2019 phenotyping: a prospective cohort study.

BACKGROUND: Because severe acute respiratory syndrome coronarivus 2 (SARS-CoV-2) leads to severe conditions and thrombus formation, evaluation of the coagulation markers is important in determining the prognosis and phenotyping of patients with COVID-19. METHODS: In a prospective study that included 213 COVID-19 patients admitted to the intensive care unit (ICU) the levels of antithrombin, C-reactive protein (CRP); factors XI, XII, XIII; prothrombin and D-dimer were measured. Spearman's correlation coefficient was used to assess the pairwise correlations between the biomarkers. Hierarchical and non-hierarchical cluster analysis was performed using the levels of biomarkers to identify patients´ phenotypes. Multivariate binary regression was used to determine the association of the patient´s outcome with clinical variables and biomarker levels. RESULTS: The levels of factors XI and XIII were significantly higher in patients with less severe COVID-19, while factor XIII and antithrombin levels were significantly associated with mortality. These coagulation biomarkers were associated with the in-hospital survival of COVID-19 patients over and above the core clinical factors on admission. Hierarchical cluster analysis showed a cluster between factor XIII and antithrombin, and this hierarchical cluster was extended to CRP in the next step. Furthermore, a non-hierarchical K-means cluster analysis was performed, and two phenotypes were identified based on the CRP and antithrombin levels independently of clinical variables and were associated with mortality. CONCLUSION: Coagulation biomarkers were associated with in-hospital survival of COVID-19 patients. Lower levels of factors XI, XII and XIII and prothrombin were associated with disease severity, while higher levels of both CRP and antithrombin clustered with worse prognosis. These results suggest the role of coagulation abnormalities in the development of COVID-19 and open the perspective of identifying subgroups of patients who would benefit more from interventions focused on regulating coagulation.

RAGE Against the Glycation Machine in Synucleinopathies: Time to Explore New Questions.

Oligomerization and aggregation of misfolded forms of α-synuclein are believed to be key molecular mechanisms in Parkinson's disease (PD) and other synucleinopathies, so extensive research has attempted to understand these processes. Among diverse post-translational modifications that impact α-synuclein aggregation, glycation may take place at several lysine sites and modify α-synuclein oligomerization, toxicity, and clearance. The receptor for advanced glycation end products (RAGE) is considered a key regulator of chronic neuroinflammation through microglial activation in response to advanced glycation end products, such as carboxy-ethyl-lysine, or carboxy-methyl-lysine. The presence of RAGE in the midbrain of PD patients has been reported in the last decades and this receptor was proposed to have a role in sustaining PD neuroinflammation. However, different PD animal models demonstrated that RAGE is preferentially expressed in neurons and astrocytes, while recent evidence demonstrated that fibrillar, non-glycated α-synuclein binds to RAGE. Here, we summarize the available data on α-synuclein glycation and RAGE in the context of PD, and discuss about the questions yet to be answered that may increase our understanding of the molecular bases of PD and synucleinopathies.

Is it all the RAGE? Defining the role of the receptor for advanced glycation end products in Parkinson's disease.

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non-transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro-inflammatory signaling in microglia by binding to amyloid-ß peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain.

Amburana cearensis seed extract stimulates astrocyte glutamate homeostatic mechanisms in hippocampal brain slices and protects oligodendrocytes against ischemia.

BACKGROUND: Stroke is a leading cause of death and disability worldwide. A major factor in brain damage following ischemia is excitotoxicity caused by elevated levels of the neurotransmitter glutamate. In the brain, glutamate homeostasis is a primary function of astrocytes. Amburana cearensis has long been used in folk medicine and seed extract obtained with dichloromethane (EDAC) have previously been shown to exhibit cytoprotective activity in vitro. The aim of the present study was to analyse the activity of EDAC in hippocampal brain slices. METHODS: We prepared a dichloromethane extract (EDAC) from A. cearensis seeds and characterized the chemical constituents by 1H and 13C-NMR. Hippocampal slices from P6-8 or P90 Wistar rats were used for cell viability assay or glutamate uptake test. Hippocampal slices from P10-12 transgenic mice SOX10-EGFP and GFAP-EGFP and immunofluorescence for GS, GLAST and GLT1 were used to study oligodendrocytes and astrocytes. RESULTS: Astrocytes play a critical role in glutamate homeostasis and we provide immunohistochemical evidence that in excitotoxicity EDAC increased expression of glutamate transporters and glutamine synthetase, which is essential for detoxifying glutamate. Next, we directly examined astrocytes using transgenic mice in which glial fibrillary acidic protein (GFAP) drives expression of enhanced green fluorescence protein (EGFP) and show that glutamate excitotoxicity caused a decrease in GFAP-EGFP and that EDAC protected against this loss. This was examined further in the oxygen-glucose deprivation (OGD) model of ischemia, where EDAC caused an increase in astrocytic process branching, resulting in an increase in GFAP-EGFP. Using SOX10-EGFP reporter mice, we show that the acute response of oligodendrocytes to OGD in hippocampal slices is a marked loss of their processes and EDAC protected oligodendrocytes against this damage. CONCLUSION: This study provides evidence that EDAC is cytoprotective against ischemia and glutamate excitotoxicity by modulating astrocyte responses and stimulating their glutamate homeostatic mechanisms.

Calorie restriction mitigates metabolic, behavioral and neurochemical effects of cafeteria diet in aged male rats.

Besides metabolic dysfunctions, elderly individuals with obesity are at special risk of developing cognitive decline and psychiatric disturbances. Restricted calorie consumption could be an efficient strategy to improve metabolic function after obesity. However, its effects on anxiety-like behaviors in aged rats submitted to an obesogenic diet are unknown. For this purpose, 42 Wistar rats (18-months old) were divided into four groups: Control (CT), calorie restriction (CR), cafeteria diet (CAF), and CAF+CR (CAF/CR). CT, CR, and CAF groups received the diets for 8 weeks. CAF/CR group was submitted to the CAF menu for 7 weeks and then switched to a standard diet on a CR regimen, receiving 30% lower calories than consumed by the CT, for another 5 weeks. CAF's menu consisted of ultra-processed foods such as cookies, chocolate, sausage, and bologna. Body weight, visceral adiposity, and biochemical blood analysis were evaluated for obesity diagnosis. The profile of gut microbiota was investigated, along with circulating levels of LPS. Neurochemical parameters, such as neurotransmitter levels, were dosed. Anxiety-like behaviors were accessed using open field (OF) and elevated plus maze (EPM) tests. As expected, CR reduced weight gain and improved glucose homeostasis. Gut microbiome disturbance was found in CAF-fed animals accompanied by increased levels of LPS. However, CR after CAF mitigated several harmful responses. The obesogenic diet triggered anxiety-like manifestations in the OF and EPM tests that were not evidenced in the CAF/CR group. These findings indicate that CR can be a promising strategy for the neurological effects of obesity in aged rats.

Impact of cafeteria diet and n3 supplementation on the intestinal microbiota, fatty acids levels, neuroinflammatory markers and social memory in male rats.

OBJECTIVE: To assess the effects of omega-3 (n3) supplementation on intestinal microbiota, fatty acids profile, neuroinflammation, and social memory of cafeteria diet (CAF)-fed rats. METHODS: Male Wistar rats were fed with CAF for 20 weeks. Omega-3 (500 mg/kg/day) was supplemented between the 16th and 20th week. Colon morphology, intestinal microbiota composition, short-chain fatty acids (SCFA) and lipopolysaccharide (LPS) in the plasma, fatty acids profile, TLR-4 and claudin-5 expressions in the brain, and social memory were investigated. RESULTS: CAF reduced colon length, crypts' depth, and microbiota diversity, while n3 increased the Firmicutes/Bacteroidetes ratio. CAF increased SCFA plasma levels, but n3 reduced butyrate and isobutyrate in obese rats. LPS was increased in CAF-fed rats, and n3 decreased its levels. In the cerebral cortex, n3 increased caprylic, palmitic, stearic, tricosanoic, lignoceric, myristoleic, and linoleic acids. CAF increased palmitic acid and TLR-4 expression in the cerebral cortex while decreasing claudin-5 in the hippocampus. In the social memory test, CAF-fed animals showed greater social interaction with no effect of n3. CONCLUSIONS: The lack of n3 effect in some of the evaluated parameters may be due to the severity of the obesity caused by CAF. However, n3 reduced LPS levels, suggesting its ability to reverse endotoxemia.

Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization.

Molecular and functional abnormalities of astrocytes have been implicated in the etiology and pathogenesis of schizophrenia (SCZ). In this study, we examined the proteome, inflammatory responses, and secretome effects on vascularization of human induced pluripotent stem cell (hiPSC)-derived astrocytes from patients with SCZ. Proteomic analysis revealed alterations in proteins related to immune function and vascularization. Reduced expression of the nuclear factor kappa B (NF-κB) p65 subunit was observed in these astrocytes, with no incremental secretion of cytokines after tumor necrosis factor alpha (TNF-α) stimulation. Among inflammatory cytokines, secretion of interleukin (IL)-8 was particularly elevated in SCZ-patient-derived-astrocyte-conditioned medium (ASCZCM). In a chicken chorioallantoic membrane (CAM) assay, ASCZCM reduced the diameter of newly grown vessels. This effect could be mimicked with exogenous addition of IL-8. Taken together, our results suggest that SCZ astrocytes are immunologically dysfunctional and may consequently affect vascularization through secreted factors.

Neuroprotective effects of combined therapy with memantine, donepezil, and vitamin D in ovariectomized female mice subjected to dementia model.

Women older than 60 have a higher risk of dementia, aging-related cognitive decline, and Alzheimer's Disease (AD) than the rest of the population. The main reason is hormonal senescence after menopause, a period characterized by a decline in estrogen levels. Since the effectiveness of drugs currently approved for the treatment of AD is limited, it is necessary to seek the development of new therapeutic strategies. Vitamin D deficiency is prevalent in AD patients and individuals with dementia in general. The supplementation of this vitamin in dementia patients might be an interesting approach for increasing the effectiveness of pre-existing medications for dementia treatment. Thus, the present study aims to investigate the effect of vitamin D treatment associated with memantine and donepezil in female mice submitted to ovariectomy (OVX) for five months and subjected to a dementia animal model induced by intracerebroventricular injection of aggregated amyloid ßeta (Aß1-42). For this purpose, Balb/c mice were divided into five experimental groups, which received 17 days of combined therapy with vitamin D, donepezil, and memantine. Then, animals were subjected to behavioral tests. OVX groups exhibited reduced levels of estradiol (E2) in serum, which was not altered by the combined therapy. Higher levels of vitamin D3 were found in the OVX animals submitted to the triple-association treatment. Mice exposed to both OVX and the dementia animal model presented impairment in short and long-term spatial and habituation memories. Also, female mice exposed to Aß and OVX exhibited a reduction in brain-derived neurotrophic factor (BDNF) and interleukin-4 (IL-4) levels, and an increase in tumor necrose factor-α (TNFα) levels in the hippocampus. Besides, increased levels of IL-1ß in the hippocampus and cerebral cortex were observed, as well as a significant increase in immunoreactivity for glial fibrillary acidic protein (GFAP), an astrocytes marker, in the hippocampus. Notably, triple-association treatment reversed the effects of the exposition of mice to Aß and OVX in the long-term spatial and habituation memories impairment, as well as reversed changes in TNFα, IL-1ß, IL-4, and GFAP immunoreactivity levels in the hippocampus of treated animals. Our results indicate that the therapeutic association of vitamin D, memantine, and donepezil has beneficial effects on memory performance and attenuated the neuroinflammatory response in female mice subjected to OVX associated with a dementia animal model.

Zinc Supplementation Partially Decreases the Harmful Effects of a Cafeteria Diet in Rats but Does Not Prevent Intestinal Dysbiosis.

Zinc (Zn) plays an important role in metabolic homeostasis and may modulate neurological impairment related to obesity. The present study aimed to evaluate the effect of Zn supplementation on the intestinal microbiota, fatty acid profile, and neurofunctional parameters in obese male Wistar rats. Rats were fed a cafeteria diet (CAF), composed of ultra-processed and highly caloric and palatable foods, for 20 weeks to induce obesity. From week 16, Zn supplementation was started (10 mg/kg/day). At the end of the experiment, we evaluated the colon morphology, composition of gut microbiota, intestinal fatty acids, integrity of the intestinal barrier and blood-brain barrier (BBB), and neuroplasticity markers in the cerebral cortex and hippocampus. Obese rats showed dysbiosis, morphological changes, short-chain fatty acid (SCFA) reduction, and increased saturated fatty acids in the colon. BBB may also be compromised in CAF-fed animals, as claudin-5 expression is reduced in the cerebral cortex. In addition, synaptophysin was decreased in the hippocampus, which may affect synaptic function. Our findings showed that Zn could not protect obese animals from intestinal dysbiosis. However, an increase in acetate levels was observed, which suggests a partial beneficial effect of Zn. Thus, Zn supplementation may not be sufficient to protect from obesity-related dysfunctions.

Gut microbiota modulation by prednisolone in a rat kindling model of pentylenetetrazol (PTZ)-induced seizure.

The gut microbiota is a complex community composed by several microorganisms that interact in the maintenance of homeostasis and contribute to physiological processes, including brain function. The relationship of the taxonomic composition of the gut microbiota with neurological diseases such as autism, Parkinson's, Alzheimer's, anxiety, and depression is widely recognized. The immune system is an important intermediary between the gut microbiota and the central nervous system, being one of the communication routes of the gut-brain axis. Although the complexity of the relationship between inflammation and epilepsy has not yet been elucidated, inflammatory processes are similar in many ways to the consequences of dysbiosis and contribute to disease progression. This study aimed to analyze the taxonomic composition of the gut microbiota of rats treated with prednisolone in a kindling model of epilepsy. Male Wistar rats (90 days, n = 24) divided into four experimental groups: sodium chloride solution 0.9 g%, diazepam 2 mg/kg, prednisolone 1 mg/kg, and prednisolone 5 mg/kg administered intraperitoneally (i.p.) for 14 days. The kindling model was induced by pentylenetetrazole (PTZ) 25 mg/kg i.p. on alternate days. The taxonomic profile was established by applying metagenomic DNA sequencing. There was no change in alpha diversity, and the composition of the gut microbiota between prednisolone and diazepam was similar. The significant increase in Verrucomicrobia, Saccharibacteria, and Actinobacteria may be related to the protective activity against seizures and inflammatory processes that cause some cases of epilepsy. Further studies are needed to investigate the functional influence that these species have on epilepsy and the inflammatory processes that trigger it.

High fat diet-induced obesity causes a reduction in brain tyrosine hydroxylase levels and non-motor features in rats through metabolic dysfunction, neuroinflammation and oxidative stress.

Obesity is a health problem that has been associated with neuroinflammation, decreased cognitive functions and development of neurodegenerative diseases. Parkinson's disease (PD) is a chronic neurodegenerative condition characterized by motor and non-motor abnormalities, increased brain inflammation, α-synuclein protein aggregation and dopaminergic neuron loss that is associated with decreased levels of tyrosine hydroxylase (TH) in the brain. Diet-induced obesity is a global epidemic and its role as a risk factor for PD is not clear. Herein, we showed that 25 weeks on a high-fat diet (HFD) promotes significant alterations in the nigrostriatal axis of Wistar rats. Obesity induced by HFD exposure caused a reduction in TH levels and increased TH phosphorylation at serine 40 in the ventral tegmental area. These effects were associated with insulin resistance, increased tumor necrosis factor-α levels, oxidative stress, astrogliosis and microglia activation. No difference was detected in the levels of α-synuclein. Obesity also induced impairment of locomotor activity, total mobility and anxiety-related behaviors that were identified in the open-field and light/dark tasks. There were no changes in motor coordination or memory. Together, these data suggest that the reduction of TH levels in the nigrostriatal axis occurs through an α-synuclein-independent pathway and can be attributed to brain inflammation, oxidative/nitrosative stress and metabolic disorders induced by obesity.