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Our study focused on a mouse model of obesity induced by a high-fat diet (HFD). We administered Semaglutide intraperitoneally (Ozempic ®-0.05 mg/Kg-translational dose) every seven days for six weeks. HFD-fed mice had higher blood glucose, lipid profile, and insulin resistance. Moreover, mice fed HFD showed high gut levels of TLR4, NF-kB, TNF-α, IL-1β, and nitrotyrosine and low levels of occludin, indicating intestinal inflammation and permeability, culminating in higher serum levels of IL-1β and LPS. Treatment with semaglutide counteracted the dyslipidemia and insulin resistance, reducing gut and serum inflammatory markers. Structural changes in gut microbiome were determined by 16S rRNA sequencing. Semaglutide reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes. Meanwhile, semaglutide dramatically changed the overall composition and promoted the growth of acetate-producing bacteria (Bacteroides acidifaciens and Blautia coccoides), increasing hypothalamic acetate levels. Semaglutide intervention increased the number of hypothalamic GLP-1R+ neurons that mediate endogenous action on feeding and energy. In addition, semaglutide treatment reversed the hypothalamic neuroinflammation HDF-induced decreasing TLR4/MyD88/NF-κB signaling and JNK and AMPK levels, improving the hypothalamic insulin resistance. Also, semaglutide modulated the intestinal microbiota, promoting the growth of acetate-producing bacteria, inducing high levels of hypothalamic acetate, and increasing GPR43+ /POMC+ neurons. In the ARC, acetate activated the GPR43 and its downstream PI3K-Akt pathway, which activates POMC neurons by repressing the FoxO-1. Thus, among the multifactorial effectors of hypothalamic energy homeostasis, possibly higher levels of acetate derived from the intestinal microbiota contribute to reducing food intake., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interests. Ethics approval and consent to participate: All experiments were conducted by the Ethical Principles in Animal Experimentation and were accepted by the Ethics Committee on the Use of Animals of the Aggeu Magalhães Institute (CEUA 135/2018—IAM). Consent for publication: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Previous research has demonstrated that Prebiotics can influence the composition of the gut microbiota, consequently impacting mood regulation. This study aimed to assess the effects of Prebiotics, specifically Fructooligosaccharides (FOS) and Galactooligosaccharides (GOS) on neuroinflammation, depression, and anxiety-like behavior in a mouse model fed a high-fat diet (HFD). Initially, mice were divided into two groups: a control group on a standard diet (n = 15) and a group on an HFD for 18 weeks (n = 45). By the 13th week, the HFD group was further divided into experimental groups: Control (n = 15), HFD (n = 15), HFD receiving Prebiotics (n = 15), and HFD receiving Fluoxetine (n = 15). From the 13th week onward, the HFD + Prebiotics group received both the high-fat diet and a combination of FOS and GOS, while the HFD + Fluoxetine group received Fluoxetine in their drinking water. In the 18th week, all mice underwent tests to evaluate behavior, including the Tail Suspension Test (TST), Forced Swimming Test (FST), Sucrose Preference Test (SPT), and the Plus Maze Test (PMT), after which they were euthanized. Mice on the HFD exhibited increased body weight, abdominal size, blood glucose, triglyceride levels, cholesterol, insulin, HOMA index, and higher serum IL-1β. These obese mice also displayed an increased number of microglia and astrocytes, activation of the TLR4 pathway, and elevated levels of neuroinflammatory markers like TNF-α, IL-1β, and COX-2. Moreover, obese mice showed increased activation of the IDO pathway and decreased levels of NMDA receptors. Additionally, markers of neurogenesis and synaptic plasticity, such as PSD, SAP 102, CREB-p, and BDNF, were lower. Treatment with FOS and GOS reversed symptoms of depression and anxiety in mice subjected to HD. This improvement in behavior resulted from a reduction in dysbiosis with an increase in acetate-producing bacteria (B. acidifaciens and B. dorei) and intestinal permeability, leading to a decrease in chronic peripheral and central inflammation. Furthermore, the modulation of the gut-brain axis by FOS and GOS promoted elevated acetate and GPR43 levels in the brain and a reduction in the levels of pro-inflammatory cytokines, positively impacting signaling pathways of neuronal proliferation and survival in the hippocampus and prefrontal cortex., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Studies have shown that gut dysbiosis is associated with the steatotic liver disease associated with metabolic dysfunction (MALSD) and its severity. This study evaluated the effects of two commercially available prebiotics fructooligosaccharides (FOS) and galactooligosaccharides(GOS) on hepatic adipogenesis, inflammation, and gut microbiota in high-fat diet-induced MALSD. The results indicated that FOS and GOS effectively reduced insulin resistance, hyperglycaemia, triglyceridemia, cholesterolaemia, and IL-1β serum levels. Moreover, FOS and GOS modulated the lipogenic (SREBP-1c, ACC, and FAS) and lipolytic (ATGL) signalling pathways, and reduced inflammatory markers such as p-NFκB-65, IL-6, iNOS, COX-2, TNF-α, IL-1β, and nitrotyrosine. FOS and GOS also enhanced the abundance of acetate producers' bacteria Bacteroides acidifaciens and Bacteroides dorei . FOS and GOS also induced positive POMC/GPR43 neurons at the arcuate nucleus, indicating hypothalamic signalling modulation. Our results suggest that FOS and GOS attenuated MALSD by reducing the hepatic lipogenic pathways and intestinal permeability through the gut microbiota-brain axis.

Increasing evidence has indicated that prebiotics as an alternative treatment for neuropsychiatric diseases. This study evaluated the prebiotics Fructooligosaccharides (FOS) and Galactooligosaccharides (GOS) on the modulation of neuroinflammation and cognition in an experimental model of mice high-fat diet fed. Initially, mice were distributed in the following groups: (A) control standard diet (n = 15) and (B) HFD for 18 weeks (n = 30). In the 13th week, the mice were later divided into the following experimental groups: (A) Control (n = 15); (B) HFD (n = 14); and (C) HFD + Prebiotics (n = 14). From the 13th week, the HFD + Prebiotics group received a high-fat diet and a combination of FOS and GOS. In the 18th week, all animals performed the T-maze and Barnes Maze, and were later euthanized. Biochemical and molecular analyzes were performed to assess neuroinflammation, neurogenesis, synaptic plasticity, and intestinal inflammation. Mice fed HFD had higher blood glucose, triglyceridemia, cholesterolemia, and higher serum IL-1β associated with impaired learning and memory. These obese mice also showed activation of microglia and astrocytes and significant immunoreactivity of neuroinflammatory and apoptosis markers, such as TNF-α, COX-2, and Caspase-3, in addition to lower expression of neurogenesis and synaptic plasticity markers, such as NeuN, KI-67, CREB-p, and BDNF. FOS and GOS treatment significantly improved the biochemistry profile and decreased serum IL-1β levels. Treatment with FOS and GOS also reduced TNF-α, COX-2, Caspase-3, Iba-1, and GFAP-positive cells in the dentate gyrus, decreasing neuroinflammation and neuronal death caused by chronic HFD consumption. In addition, FOS and GOS promoted synaptic plasticity by increasing NeuN, p-CREB, BDNF, and KI-67, restoring spatial learning ability and memory. Moreover, FOS and GOS on HFD modulated the insulin pathway, which was proved by up-regulating IRS/PI3K/AKT signaling pathway, followed by a decreasing Aβ plate and Tau phosphorylation. Furthermore, the prebiotic intervention reshaped the HFD-induced imbalanced gut microbiota by modulating the composition of the bacterial community, markedly increasing Bacteroidetes. In addition, prebiotics decreased intestinal inflammation and leaky gut. In conclusion, FOS and GOS significantly modulated the gut microbiota and IRS/PI3K/AKT signaling pathway, decreased neuroinflammation, and promoted neuroplasticity improving spatial learning and memory. Schematic summarizing of the pathways by FOS and GOS improves memory and learning through the gut-brain axis. FOS and GOS improve the microbial profile, reducing intestinal inflammation and leaky gut in the distal colon. Specifically, the administration of FOS and GOS decreases the expression of TLR4, TNF-α, IL-1β, and MMP9 and increases the expression of occludin and IL-10. Prebiotics inhibit neuroinflammation, neuronal apoptosis, and reactive gliosis in the hippocampus but restore synaptic plasticity, neuronal proliferation, and neurogenesis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Parkinson's disease (PD) remains a disease of little known etiology. In addition to the motor symptoms, depression is present in about 40% of patients, contributing to the loss of quality of life. Recently, the involvement of the autophagy mechanism in the pathogenesis of depression has been studied, in addition to its involvement in PD as well. In this study, we tested the effects of metformin, an antidiabetic drug also with antidepressant effects, on depressive-like behavior in a rotenone-induced PD model and on the autophagy process. Mice 8-week-old male C57BL/6 were induced with rotenone for 20 consecutive days (2.5 mg/kg/day) and treated with metformin (200 mg/kg/day) from the 5th day of induction. All the animals were submitted to rotarod, sucrose preference and tail suspension tests. After euthanasia, the substantia nigra and hippocampus were removed for analysis by western blotting or fixed and analyzed by immunofluorescence. The results show that there was an impairment of autophagy in animals induced by rotenone both in nigral and extranigral regions as well as a depressive-like behavior. Metformin was able to inhibit depressive-like behavior and increase signaling pathway proteins, transcription factors and autophagosome-forming proteins, thus inducing autophagy in both the hippocampus and the substantia nigra. In conclusion, we show that metformin has an antidepressant effect in a rotenone-induced PD model, which may result, at least in part, from the induction of the autophagy process., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Extracellular Vesicles (EVs) are tiny vesicles used by cells as means of cellular communication, through which the function and state of a given cell can be changed. A body of evidence has suggested that EVs could be culprits in the development and progression of various types of diseases, including neurodegenerative diseases such as Multiple Sclerosis (MS) and Alzheimer's Disease (AD). Unsurprisingly, EVs have also been implicate in mood, anxiety and neurodevelopmental disorders, such as Major Depressive Disorder (MDD), anxiety disorder and Autism-Spectrum Disorder (ASD), respectively. Here, we review the state-of-art regarding the roles of EVs in the aforementioned diseases and focus on the mechanisms by which they can cause and worsen disease. Harnessing the knowledge of EVs is not only important to deliver different cargos to cells in a specific manner to treat these diseases, but also to establish reliable disease biomarkers, which will aid in the early disease diagnosis and treatment, increasing the chance of successful treatment., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Thereabout 30-40% of patients with Parkinson's Disease (PD) also have depression contributing to the loss of quality of life. Among the patients who treat depression, about 50% do not show significant improvement due to the limited efficacy of the treatment. So far, there are no effective disease-modifying treatments that can impede its progression. The current clinical approach is based on symptom management. Nonetheless, the reuse of drugs with excellent safety profiles represents an attractive alternative strategy for treating of different clinical aspects of PD. In this study, we evaluated the effects of metformin separately and associated with fluoxetine on depressive like-behavior and motor alterations in experimental Parkinson's disease. C57BL6 mice were induced with rotenone (2.5 mg/kg/day) for 20 days and treated with metformin (200 mg/kg/day) and fluoxetine (10 mg/kg/day) from the 5th day of induction. The animals were submitted to Sucrose Preference, Tail Suspension, and rotarod tests. Hippocampus, prefrontal cortex, and substantia nigra were dissected for molecular and morphological analysis. Metformin and fluoxetine prevented depressive-like behavior and improved motor impairment and increased TH nigral positive cells. Metformin and fluoxetine also reduced IBA-1 and GFAP positive cells in the hippocampus. Moreover, metformin reduced the phospho-NF-kB, IL-1β in the prefrontal cortex and iNOS levels in the hippocampus. Both metformin and fluoxetine increased neurogenesis by increasing KI67, but only the combined treatment increased neuronal survival by NeuN positive cells in the hippocampus. In addition, fluoxetine reduced cell death, decreasing caspase-3 and PARP-1 levels. Lastly, metformin potentiated the effect of fluoxetine on neuroplasticity by increasing BDNF positive cells. Metformin has antidepressant and antiparkinsonian potential due to anti-inflammatory neurogenic, and neuroplasticity-inducing effects when combined with fluoxetine., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The disruption of the gut microbial composition, defined as dysbiosis, has been associated with many neurological disorders with inflammatory components. The alteration of the gut microbiota leads to an increase in pro-inflammatory cytokines that are associated with metabolic diseases (such as obesity and type 2 diabetes), autoimmune arthritis, and neuropsychiatric diseases. Prebiotics are defined as non-digestible carbohydrates and promote the growth of beneficial bacteria such as bifidobacteria and lactobacillus, exert beneficial effects on improving dysbiosis and its associated inflammatory state. Preclinical and clinical data indicated that some prebiotics also have positive impacts on the central nervous system (CNS) due to the modulation of neuroinflammation and thus may have a key role in the modulation of cognitive impairment, anxiety, and depression. The present manuscript reviews the state-of-art of the effects of prebiotics in cognitive impairment, anxiety, and depressive disorders. Data from clinical studies are still scarce, and further clinical trials are needed to corroborate the potential therapeutic cognitive, antidepressant, and anxiolytic of prebiotics. Prebiotics may provide patients suffering from cognitive deficits, depression, and anxiety with a new tool to minimize disease symptoms and increase the quality of life., Competing Interests: Conflict of interest The authors declare no conflict of interests regarding the publication of this paper., (Copyright © 2020. Published by Elsevier B.V.)

Neuroschistosomiasis is a severe form of presentation of schistosomiasis in which Schistosoma spp. affects the central nervous system. This is the first study performed to analyze whether there is any relationship between physical effort and the appearance of neuroschistosomiasis, through clinical, molecular and immunological evaluations. An experimental controlled study using 64 male Balb/c inbred mice divided into four groups according to presence or absence of S. mansoni infection and submitted to physical effort or resting was conducted. Thirteen weeks after exercise training, S. mansoni DNA was detected in the brain or spinal cord in about 30% of the infected animals moreover, only S. mansoni-positive samples showed positive labeling for S. mansoni antigens in the brain or spinal cord, with a striking reaction inside the microglia. However, the behavioral tests did not show any clinical symptoms of neuroschistosomiasis in animals submitted to physical effort or in resting. In animals with S. mansoni-positive DNA, immunohistochemical data revealed astrogliosis and microgliosis, elevated IL-10 levels and decreased TNF-α expression. This study demonstrated that isometric exercise does not promote neuroschistosomiasis, furthermore, ectopic forms of schistosomiasis in the central nervous system were largely asymptomatic and exhibited a Th2 immune response profile. More experimental studies are necessary in order to characterize the pathological process of experimental neuroschistosomiasis., (Copyright © 2019. Published by Elsevier Inc.)