ABSTRACT
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.
Subject(s)
Animals , Male , Bipolar Disorder/immunology , Disease Models, Animal , Lisdexamfetamine Dimesylate , Lithium/pharmacology , Anti-Inflammatory Agents/pharmacology , Nerve Growth Factors/drug effects , Time Factors , Bipolar Disorder/physiopathology , Bipolar Disorder/chemically induced , Enzyme-Linked Immunosorbent Assay , Lipopolysaccharides/pharmacology , Reproducibility of Results , Cytokines/blood , Treatment Outcome , Rats, Wistar , Brain-Derived Neurotrophic Factor/blood , Nitric Oxide Synthase Type II/blood , Locomotion/drug effectsABSTRACT
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.