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Preclinical evidence on the role of glucagon-like peptide-1 receptor (GLP-1r) agonists in the brain led to an increased interest in repurposing these compounds as a therapy for central nervous system (CNS) disorders and associated comorbidities. We aimed to investigate the neuroprotective effects of acute treatment with exendin (EX)-4, a GLP-1r agonist, in an animal model of inflammation. We evaluated the effect of different doses of EX-4 on inflammatory, neurotrophic, and oxidative stress parameters in the hippocampus and serum of lipopolysaccharide (LPS)-injected animals. Male Wistar rats were injected with LPS (0.25 mg/kg i.p.) and treated with different doses of EX-4 (0.1, 0.3, or 0.5 µg/kg i.p.). Sickness behavior was assessed by locomotor activity and body weight, and depressive-like behavior was also evaluated using forced swim test (FST). Brain-derived neurotrophic factor (BDNF), thiobarbituric acid reactive species (TBARS), and interleukin (IL)-6 were quantified in the serum and hippocampus. Glycemia was also analyzed pre- and post-EX-4 treatment. LPS groups exhibited decreased frequency of crossing and reduced body weight (p < 0.001), while alterations on FST were not observed. The higher dose of EX-4 reduced IL-6 in the hippocampus of LPS-injected animals (p = 0.018), and EX-4 per se reduced TBARS serum levels with a modest antioxidant effect in the LPS groups (p ≤ 0.005). BDNF hippocampal levels seemed to be increased in the LPS+EX-4 0.5 group compared with LPS+Saline (p > 0.05). Our study provides evidence on acute anti-inflammatory effects of EX-4 in the hippocampus of rats injected with LPS, contributing to future studies on repurposing compounds with potential neuroprotective properties.

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Objective: To evaluate whether an animal model of mania induced by lisdexamfetamine dimesylate (LDX) has an inflammatory profile and whether immune activation by lipopolysaccharides (LPS) has a cumulative effect on subsequent stimuli in this model. We also evaluated the action of lithium (Li) on inflammatory and neurotrophic factors. Methods: Adult male Wistar rats were subjected to an animal model of mania. After the open-field test, they were given LPS to induce systemic immune activation. Subsequently, the animals' blood was collected, and their serum levels of brain-derived neurotrophic factor and inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-6, IL-1β, IL-10, and inducible nitric oxide synthase [iNOS]) were measured. Results: LDX induced hyperactivity in the animals, but no inflammatory marker levels increased except brain-derived neurotrophic factor (BDNF). Li had no effect on serum BDNF levels but prevented iNOS levels from increasing in animals subjected to immune activation. Conclusion: Although Li prevented an LPS-induced increase in serum iNOS levels, its potential anti-inflammatory effects in this animal model of mania were conflicting.

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BACKGROUND: Innate immune system dysfunction has been recognized as an important element in the pathophysiology of bipolar disorder (BD). We aimed to investigate whether there are differences in the response of macrophages derived from patients in the early stages and late stages of BD and healthy subjects. METHODS: Human monocytes purified from peripheral blood mononuclear cells (PBMCs) of patients with BD type I (n = 18)-further classified into early- and late stage BD patients according to their functioning- and from healthy individuals (n = 10) were differentiated into macrophages in vitro. Monocyte-derived macrophages (M) were exposed to IFNγ plus LPS-M(IFNγ + LPS)- or IL-4-M(IL-4)-to induce their polarization into the classical (also called M1) or alternative (also called M2) activation phenotypes, respectively; or either Mψ were not exposed to any stimuli characterizing the resting state (denominated M0). In vitro secretion of cytokines, such as IL-1ß, IL-6, IL-10, and TNF-α, was used as an index of macrophage activity. RESULTS: M(IFNγ + LPS) from late-stage BD patients produced less amount of IL-1ß, IL-6, and IL-10 when compared to early-stage BD patients and healthy controls. Following alternative activation, M(IL-4) derived from late-stage patients secreted less IL-6 compared to the other groups. TNFα was less secreted by all macrophage phenotypes derived from late-stage patients when compared to healthy controls only (p < 0.005). Mψ from late-stage patients exhibited lower production of IL-1ß and IL-10 compared to macrophages from healthy subjects and early-stage patients respectively. Interestingly, cytokines secretion from M(IFNγ + LPS), M(IL-4) and Mψ were similar between early-stage patients and healthy controls. CONCLUSION: Our results suggest a progressive dysfunction in the response of peripheral innate immune cells of BD patients in the late stages of the illness. This failure in the regulation of the immune system function may be implicated in the multisystemic progression of BD.

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OBJECTIVE: To evaluate whether an animal model of mania induced by lisdexamfetamine dimesylate (LDX) has an inflammatory profile and whether immune activation by lipopolysaccharides (LPS) has a cumulative effect on subsequent stimuli in this model. We also evaluated the action of lithium (Li) on inflammatory and neurotrophic factors. METHODS: Adult male Wistar rats were subjected to an animal model of mania. After the open-field test, they were given LPS to induce systemic immune activation. Subsequently, the animals' blood was collected, and their serum levels of brain-derived neurotrophic factor and inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-6, IL-1ß, IL-10, and inducible nitric oxide synthase [iNOS]) were measured. RESULTS: LDX induced hyperactivity in the animals, but no inflammatory marker levels increased except brain-derived neurotrophic factor (BDNF). Li had no effect on serum BDNF levels but prevented iNOS levels from increasing in animals subjected to immune activation. CONCLUSION: Although Li prevented an LPS-induced increase in serum iNOS levels, its potential anti-inflammatory effects in this animal model of mania were conflicting.

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Abstract Introduction The rationale of mesenchymal stem cells (MSCs) as a novel therapeutic approach in certain neurodegenerative diseases is based on their ability to promote neurogenesis. Hippocampal atrophy has been related to bipolar disorder (BD) in preclinical, imaging and postmortem studies. Therefore, the development of new strategies to stimulate the neurogenesis process in BD is crucial. Objectives To investigate the behavioral and neurochemical changes induced by transplantation of MSCs in a model of mania-like behavior induced by lisdexamfetamine dimesylate (LDX). Methods Wistar rats (n=65) received one oral daily dose of LDX (10 mg/kg) or saline for 14 days. On the 8th day of treatment, the animals additionally received intrahippocampal saline or MSC (1 µL containing 25,000 cells) or lithium (47.5 mg/kg) as an internal experimental control. Two hours after the last administration, behavioral and neurochemical analyses were performed. Results LDX-treated rats had increased locomotor activity compared to saline-saline rats (p=0.004), and lithium reversed LDX-related hyperactive behavior (p<0.001). In contrast, the administration of MSCs did not change hyperlocomotion, indicating no effects of this treatment on LDX-treated rats (p=0.979). We did not find differences between groups in BDNF levels (p>0.05) in the hippocampus of rats. Conclusion Even though these results suggest that a single intrahippocampal injection of MSCs was not helpful to treat hyperactivity induced by LDX and neither influenced BDNF secretion, we cannot rule out the possible therapeutic effects of MSCs. Further research is required to determine direct effects of LDX on brain structures as well as in other pathophysiological targets related to BD.

Resumo Introdução Células-tronco mesenquimais (CTMs) têm emergido como um promissor tratamento em diversas doenças neurodegenerativas devido a sua plasticidade e capacidade de regenerar tecidos. Estudos pré-clínicos, clínicos e de neuroimagem têm demonstrado a presença de atrofia hipocampal no transtorno bipolar (TB). Portanto, o desenvolvimento de tratamentos capazes de regenerar tecido lesado e estimular a neurogênese poderia ser útil. Objetivos Investigar mudanças comportamentais e neuroquímicas induzidas pelo transplante de CTMs no hipocampo de ratos em um modelo animal de mania induzido por dimesilato de lisdexanfetamina (LDX). Métodos Ratos Wistar (n=65) receberam LDX (10 mg/kg) ou solução salina por via oral durante 14 dias. No oitavo dia, os animais foram transplantados com injeção de CTMs ou solução salina (1 µL contendo 25.000 células) ou lítio (47,5 mg/kg) como controle interno do experimento. Duas horas após a última dose, foram realizadas análises comportamentais e neuroquímicas. Resultados Animais que receberam LDX tiveram um aumento da atividade locomotora comparados ao grupo que recebeu solução salina (p=0,004); já o lítio reverteu a hiperatividade locomotora desses animais (p<0,001). Os animais que receberam CTMs não apresentaram alterações no comportamento, indicando ausência de efeitos sobre hiperatividade locomotora. Os níveis de BDNF hipocampais não diferiram entre os grupos (p>0.05). Conclusão Não foi possível demonstrar efeitos neuroprotetores das CTMs, administradas em dose única, em um modelo animal de mania induzido por LDX. No entanto, não se pode descartar os possíveis efeitos terapêuticos das CTMs. Mais estudos são necessários para determinar os efeitos das CTMs em estruturas cerebrais e outros alvos fisiopatológicos relacionados ao TB.

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INTRODUCTION: The rationale of mesenchymal stem cells (MSCs) as a novel therapeutic approach in certain neurodegenerative diseases is based on their ability to promote neurogenesis. Hippocampal atrophy has been related to bipolar disorder (BD) in preclinical, imaging and postmortem studies. Therefore, the development of new strategies to stimulate the neurogenesis process in BD is crucial. OBJECTIVES: To investigate the behavioral and neurochemical changes induced by transplantation of MSCs in a model of mania-like behavior induced by lisdexamfetamine dimesylate (LDX). METHODS: Wistar rats (n=65) received one oral daily dose of LDX (10 mg/kg) or saline for 14 days. On the 8th day of treatment, the animals additionally received intrahippocampal saline or MSC (1 µL containing 25,000 cells) or lithium (47.5 mg/kg) as an internal experimental control. Two hours after the last administration, behavioral and neurochemical analyses were performed. RESULTS: LDX-treated rats had increased locomotor activity compared to saline-saline rats (p=0.004), and lithium reversed LDX-related hyperactive behavior (p<0.001). In contrast, the administration of MSCs did not change hyperlocomotion, indicating no effects of this treatment on LDX-treated rats (p=0.979). We did not find differences between groups in BDNF levels (p>0.05) in the hippocampus of rats. CONCLUSION: Even though these results suggest that a single intrahippocampal injection of MSCs was not helpful to treat hyperactivity induced by LDX and neither influenced BDNF secretion, we cannot rule out the possible therapeutic effects of MSCs. Further research is required to determine direct effects of LDX on brain structures as well as in other pathophysiological targets related to BD.

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OBJECTIVE: Bipolar disorder is a chronic, severe and disabling disease; however, its pathophysiology remains poorly understood. Recent evidence has suggested that inflammation and immune dysregulation play a significant role in the pathophysiology of bipolar disorder. This review is aimed to highlight the importance of systemic inflammation in modulating the inflammatory response of microglia and hence its potential involvement with bipolar disorder. We also discuss novel therapeutic strategies that emerge from this new research. METHOD: This article presents a theoretical synthesis of the effects of systemic inflammation on the immune response of the central nervous system in bipolar disorder. The complex relationship between stress, pro-inflammatory cytokines and microglial dysfunction is summarized, emphasizing the role of the kynurenine pathway in this process and, consequently, their effects on neuronal plasticity. RESULTS: Bipolar patients demonstrate increased serum levels of pro-inflammatory cytokines (interleukin-1ß, interleukin-6 and tumor necrosis factor-α) and lower hypothalamic-pituitary-adrenal axis sensitivity. This imbalance in the immune system promotes a change in blood-brain barrier permeability, leading to an inflammatory signal spread in the central nervous system from the periphery, through macrophages activation (M1 polarization). Chronic microglial activation can result in neuronal apoptosis, neurogenesis inhibition, hippocampal volume reduction, lower neurotransmitters synthesis and cytotoxicity, by increasing glutamate production and kynurenine metabolism. CONCLUSIONS: This review provides an overview of the mechanisms involved in the immune system imbalance and its potential involvement in the pathophysiology of bipolar disorder. Consequently, new strategies that normalize the immune-inflammatory pathways may provide a valuable therapeutic target for the treatment of these disorders.

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