RESUMO
BACKGROUND: A periodontal lesion is a consequence of chronic inflammatory processes, itself triggered by a bacterial infection of the pulpal and endodontic microenvironment. Evidence suggests that periodontal lesion induction could alter inflammatory cytokines leading to behavior changes. These effects in the context of anxiety and depressive behavior have been not full investigated. We aimed to observe anxiety- and depressive-like behavioral in rodent subjected to periapical dental lesions. METHODS: Pro-inflammatory cytokines levels also were investigated in the frontal cortex and hippocampus. Parameters related to hypothalamic-pituitary-adrenal (HPA) axis activation also were evaluated. Wistar rats were divided in groups: control/saline; control/imipramine; periapical lesion/saline; and periapical lesion/imipramine. Three weeks after induction of the periapical dental lesion, they were subjected to behavioral tests. RESULTS: In the periapical lesion group was demonstrated anhedonic behavior and depressive-like behavior. In the elevated plus-maze test the periapical lesion group had an increase in the number of entries and spent more time in the closed arms. Imipramine treatment was able to reverse depressive- and anxiety-like behaviors. In the hippocampus and frontal cortex tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and serum adrenocorticotropic hormone (ACTH) levels were higher in the periapical lesion group. However, rats treated with imipramine had lower IL-1ß and ACTH levels. CONCLUSIONS: Our results revealed depressive- and anxiety-like behaviors following induction of a specific dental lesion. These effects could be associated to higher levels of brain pro-inflammatory cytokines and HPA axis changes. Antidepressants treatments could be an alternative to treat comorbidities associated to periodontal lesions.
Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Antidepressivos Tricíclicos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Imipramina/farmacologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Doenças Periapicais/complicações , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Ansiedade/psicologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Depressão/etiologia , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Comportamento Alimentar/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Doenças Periapicais/metabolismo , Ratos WistarRESUMO
The aim of this study was to investigate the effects of lithium on brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) expression in the hippocampus and on memory in experimental pneumococcal meningitis. The mood-stabilizer lithium is known as a neuroprotective agent with many effects on the brain. In this study, animals received either artificial cerebrospinal fluid or Streptococcus pneumoniae suspension at a concentration of 5 × 109 CFU/mL. Eighteen hours after induction, all animals received ceftriaxone. The animals received saline or lithium (47.5 mg/kg) or tamoxifen (1 mg/kg) as adjuvant treatment, and they were separated into six groups: control/saline, control/lithium, control/tamoxifen, meningitis/saline, meningitis/lithium, and meningitis/tamoxifen. Ten days after meningitis induction, animals were subjected to open-field habituation and the step-down inhibitory avoidance tasks. Immediately after these tasks, the animals were killed and their hippocampus was removed to evaluate the expression of BDNF, NGF, and GDNF. In the meningitis group, treatment with lithium and tamoxifen resulted in improvement in memory. Meningitis group showed decreased expression of BDNF and GDNF in the hippocampus while lithium reestablished the neurotrophin expression. Lithium was able to prevent memory impairment and reestablishes hippocampal neurotrophin expression in experimental pneumococcal meningitis.
Assuntos
Hipocampo/metabolismo , Lítio/uso terapêutico , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Meningite Pneumocócica/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
Pneumococcal meningitis is a life-threatening infection of the central nervous system (CNS) with a high mortality rate. In addition to causing severe neurological sequelae infectious diseases of the CNS can play a significant role in the pathogenesis of neuropsychiatric disorders. In this study infant Wistar rats, postnatal day 11, received intracerebroventricular (i.c.v.) either artificial cerebrospinal fluid (CSF) or a Streptococcus pneumoniae suspension to a concentration of 1 × 106 colony-forming units (CFU). 18 h later animals received antibiotic treatment as usual during 7 days. On postnatal day 46, the animals received imipramine intraperitoneal (i.p.) or sterile NaCl during 14 days (postnatal days 46-60). Then, on postnatal days 59-60 we evaluated the consumption of sweet food (an index of anhedonia). On postnatal day 60 the animals were submitted to the forced swimming task. 60 min after this task the animals were decapitated and the blood was collected to evaluate adrenocorticotropic hormone (ACTH) and corticosterone. Immediately after blood collection the hippocampus was removed to evaluate brain-derived neurotropic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). The meningitis group exhibited depressive-like behavior as evidenced by decreased sucrose intake and increased immobility time in the forced swimming task, and BDNF and GDNF decrease in the hippocampus. ACTH levels were increased in the blood. Imipramine treatment reversed depressive-like behaviors, re-established hippocampal BDNF and GDNF expression, and normalized ACTH levels in the blood. Here we demonstrate that meningitis during early life period can trigger depressive-like behavior in adult life of rats.
Assuntos
Comportamento Animal/fisiologia , Encéfalo/fisiopatologia , Depressão/fisiopatologia , Meningite Pneumocócica/fisiopatologia , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/sangue , Depressão/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Imipramina/farmacologia , Masculino , Meningite Pneumocócica/induzido quimicamente , Meningite Pneumocócica/metabolismo , Ratos Wistar , TempoRESUMO
INTRODUCTION: Mortality and morbidity from bacterial meningitis in African adults is significantly higher than those in better resourced settings. At the same time, the periodontal diseases are highly prevalent and can affect up to 90% of the population. Dental caries in Uganda was recorded in 40% and 62.5% of the children and adults, respectively. We hypothesize that pneumococcal meningitis could interfere in the development of periapical lesion. The aim of this study was to evaluate periapical lesion in Wistar rats subjected to pneumococcal meningitis. MATERIALS AND METHODS: The animals were divided in control, control/periapical lesion, meningitis, and meningitis/periapical lesion groups. The surgical exposure of molars and the infection of the dental pulp were from the oral environment. Pulp necrosis was induced on the left mandibular first molars during adulthood. Dental pulps were exposed by drilling cavities on the central portion of the occlusal surface with a 1011 HL round bur in high speed to a depth nearly equal to the bur diameter. Animals were subjected to behavioral task and evaluation of the size of periodontal ligament. Data from periodontal ligament space and open field task were reported as mean ± SEM and analysed by Two-way ANOVA and paired Student's t-test, respectively. RESULTS AND CONCLUSION: Meningitis/periapical increased the periodontal ligament space by 61% when compared with control/periapical. In the open-field task, there were no differences in the number of crossings and rearing movements between training and test session in meningitis and periapical lesion groups demonstrating habituation memory impairment. Bacterial meningitis and periapical lesion may play an important role in development of cognitive impairment.
RESUMO
Pneumococcal meningitis is characterized by high rates of mortality and long-term cognitive impairment. In this study, we evaluated the effects of interleukin (IL)-1ß receptor antagonist (IL-1Ra) on memory, cytokine, and brain-derived neurotrophic factor (BDNF) levels in hippocampus after experimental pneumococcal meningitis. In a first experiment the animals were divided into four groups: control/saline, control treated with IL-1Ra, meningitis/saline, and meningitis treated with IL-1Ra. In the meningitis/saline group IL-1ß and cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels increased at 24 h post-infection; adjuvant treatment with IL-1Ra reversed the increased levels in the hippocampus. The levels of tumour necrosis factor-alpha (TNF-α), IL-4, IL-6, IL-10, and BDNF did not change in all groups at 24 h post-infection. In a second experiment, the animals were subjected to behavioural tasks (open field, step-down inhibitory avoidance task, and object recognition task), cytokine, and BDNF levels analysis 10 days after experimental meningitis induction. In the open-field task, the meningitis/saline group did not exhibit difference between the training and test sessions, in the motor and exploratory activity indicating memory injury. The meningitis/IL-1Ra group presented difference between training and test session indicating habituation memory. The meningitis/saline group showed impairment in long-term memory for novel object recognition and in aversive memory. The adjuvant treatment with IL-1Ra prevented memory impairment. After behavioural tasks the hippocampus was evaluated. The levels of IL-4, IL-6, IL-10, and BDNF were maintained elevated 10 days post-infection. CINC-1 levels were elevated only in meningitis/saline group and IL-1ß decreased in meningitis/IL-Ra group. The levels of TNF-α did not change at 10 days post-infection. These findings illustrate the anti-inflammatory activity of IL-1Ra inhibitor in the first hours after meningitis induction. Adjuvant treatment with IL-1ß receptor antagonist could be a new avenue as therapeutic target during bacterial meningitis.
Assuntos
Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Meningites Bacterianas/complicações , Fármacos Neuroprotetores/uso terapêutico , Análise de Variância , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Inibição Psicológica , Masculino , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Streptococcus pneumoniae/patogenicidadeRESUMO
Objective: To evaluate the influence of environmental enrichment (EE) on memory, cytokines, and brain-derived neurotrophic factor (BDNF) in the brain of adult rats subjected to experimental pneumococcal meningitis during infancy. Methods: On postnatal day 11, the animals received either artificial cerebrospinal fluid (CSF) or Streptococcus pneumoniae suspension intracisternally at 1 × 106 CFU/mL and remained with their mothers until age 21 days. Animals were divided into the following groups: control, control + EE, meningitis, and meningitis + EE. EE began at 21 days and continued until 60 days of age (adulthood). EE consisted of a large cage with three floors, ramps, running wheels, and objects of different shapes and textures. At 60 days, animals were randomized and subjected to habituation to the open-field task and the step-down inhibitory avoidance task. After the tasks, the hippocampus and CSF were isolated for analysis. Results: The meningitis group showed no difference in performance between training and test sessions of the open-field task, suggesting habituation memory impairment; in the meningitis + EE group, performance was significantly different, showing preservation of habituation memory. In the step-down inhibitory avoidance task, there were no differences in behavior between training and test sessions in the meningitis group, showing aversive memory impairment; conversely, differences were observed in the meningitis + EE group, demonstrating aversive memory preservation. In the two meningitis groups, IL-4, IL-10, and BDNF levels were increased in the hippocampus, and BDNF levels in the CSF. Conclusions: The data presented suggest that EE, a non-invasive therapy, enables recovery from memory deficits caused by neonatal meningitis. .
Assuntos
Animais , Masculino , Fator Neurotrófico Derivado do Encéfalo/sangue , Transtornos Cognitivos/terapia , Citocinas/sangue , Exposição Ambiental , Transtornos da Memória/terapia , Meningite Pneumocócica/terapia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Ratos Wistar , Recuperação de Função Fisiológica , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the influence of environmental enrichment (EE) on memory, cytokines, and brain-derived neurotrophic factor (BDNF) in the brain of adult rats subjected to experimental pneumococcal meningitis during infancy. METHODS: On postnatal day 11, the animals received either artificial cerebrospinal fluid (CSF) or Streptococcus pneumoniae suspension intracisternally at 1 × 10(6) CFU/mL and remained with their mothers until age 21 days. Animals were divided into the following groups: control, control + EE, meningitis, and meningitis + EE. EE began at 21 days and continued until 60 days of age (adulthood). EE consisted of a large cage with three floors, ramps, running wheels, and objects of different shapes and textures. At 60 days, animals were randomized and subjected to habituation to the open-field task and the step-down inhibitory avoidance task. After the tasks, the hippocampus and CSF were isolated for analysis. RESULTS: The meningitis group showed no difference in performance between training and test sessions of the open-field task, suggesting habituation memory impairment; in the meningitis + EE group, performance was significantly different, showing preservation of habituation memory. In the step-down inhibitory avoidance task, there were no differences in behavior between training and test sessions in the meningitis group, showing aversive memory impairment; conversely, differences were observed in the meningitis + EE group, demonstrating aversive memory preservation. In the two meningitis groups, IL-4, IL-10, and BDNF levels were increased in the hippocampus, and BDNF levels in the CSF. CONCLUSIONS: The data presented suggest that EE, a non-invasive therapy, enables recovery from memory deficits caused by neonatal meningitis.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Transtornos Cognitivos/terapia , Citocinas/sangue , Exposição Ambiental , Transtornos da Memória/terapia , Meningite Pneumocócica/terapia , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Masculino , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Ratos Wistar , Recuperação de Função Fisiológica , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
Pneumococcal meningitis is a relevant clinical disease characterized by an intense inflammatory reaction into the subarachnoid and ventricular spaces, leading to blood-brain barrier breakdown, hearing loss, and cognitive impairment. Matrix metalloproteinases (MMPs) are capable of degrading components of the basal laminin, thus contributing to BBB damage and neuronal injury. In the present study, we evaluated the effects of MMP-2, MMP-9, and MMP-2/9 inhibitors on BBB integrity, learning, and memory in Wistar rats subjected to pneumococcal meningitis. The animals underwent a magna cistern tap and received either 10 µL sterile saline as a placebo or an equivalent volume of a Streptococcus pneumoniae suspension at a concentration of 5 × 10(9)cfu/mL. The rats were randomized into different groups that received adjuvant treatment with MMP-2, MMP-9 or MMP-2/9 inhibitors. The BBB integrity was evaluated, and the animals were habituated to open-field and object recognition tasks 10 days after meningitis induction. Adjuvant treatments with inhibitors of MMP-2 or MMP-2/9 prevented BBB breakdown in the hippocampus, and treatments with inhibitors of MMP-2, MMP-9 or MMP-2/9 prevented BBB breakdown in the cortex. Ten days after meningitis induction, the animals that received adjuvant treatment with the inhibitor of MMP-2/9 demonstrated that animals habituated to the open-field task faster and enhanced memory during short-term and long-term retention test sessions in the object recognition task. Further investigation is necessary to provide support for MMP inhibitors as an alternative treatment for bacterial meningitis; however, these findings suggest that the meningitis model could be a good research tool for studying the biological mechanisms involved in the behavioral alterations associated with pneumococcal meningitis.
Assuntos
Transtornos Cognitivos/prevenção & controle , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Meningite Pneumocócica/tratamento farmacológico , Animais , Barreira Hematoencefálica/microbiologia , Barreira Hematoencefálica/fisiopatologia , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Meningite Pneumocócica/complicações , Meningite Pneumocócica/metabolismo , Ratos , Ratos Wistar , Streptococcus pneumoniaeRESUMO
Klebsiella pneumoniae meningitis has recently become an increasingly common cause of central nervous system infection. The invasion of bacteria within the subarachnoid space stimulates the release of pro-inflammatory cytokines and chemokines, triggering a host immune response. The aim of the present study was to evaluate memory and pro-inflammatory mediators at different times in the brains of adult Wistar rats with K. pneumoniae meningitis. The animals were sacrificed at 6, 12, 24, 48 and 96 h after meningitis induction. The hippocampus, frontal cortex and cerebrospinal fluid were isolated to determine the cytokine, chemokine and brain-derived neurotrophic factor (BDNF) levels. In the first 6 and 24 h following meningitis induction, there was a significant increase of the TNF-α, IL-1ß, IL-6, cytokine-induced neutrophil chemoattractant-1 and BDNF levels in the central nervous system. Ten days after meningitis induction, cognitive memory was evaluated using an open-field task and step-down inhibitory avoidance task. In the control group, significant differences in behaviour were observed between the training and testing sessions for both tasks, demonstrating habituation and aversive memory. However, the meningitis group did not exhibit any difference between the training and testing sessions in either task, demonstrating memory impairment. As a result of these observations, we believe that the meningitis model may be a good research tool to study the biological mechanisms involved in the pathophysiology of this illness, while recognizing that animal models should be interpreted with caution before extrapolation to the clinic.
Assuntos
Sistema Nervoso Central/patologia , Citocinas/análise , Infecções por Klebsiella/complicações , Infecções por Klebsiella/patologia , Transtornos da Memória/etiologia , Meningites Bacterianas/complicações , Meningites Bacterianas/patologia , Animais , Fator Neurotrófico Derivado do Encéfalo/análise , Sistema Nervoso Central/imunologia , Córtex Cerebral/química , Córtex Cerebral/patologia , Líquido Cefalorraquidiano/química , Modelos Animais de Doenças , Hipocampo/química , Hipocampo/patologia , Klebsiella pneumoniae/crescimento & desenvolvimento , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Neonatal meningitis is a severe acute infectious disease of the central nervous system and an important cause of morbidity and mortality worldwide. The inflammatory reaction involves the meninges, the subarachnoid space and the brain parenchymal vessels and contributes to neuronal injury. Neonatal meningitis leads to deafness, blindness, cerebral palsy, seizures, hydrocephalus or cognitive impairment in approximately 25-50â% of survivors. Bacterial pathogens can reach the blood-brain barrier and be recognized by antigen-presenting cells through the binding of Toll-like receptors. They induce the activation of NFκB or mitogen-activated protein kinase pathways and subsequently upregulate leukocyte populations and express numerous proteins involved in inflammation and the immune response. Many brain cells can produce cytokines, chemokines and other pro-inflammatory molecules in response to bacterial stimuli, and polymorphonuclear leukocytes are attracted, activated and released in large amounts of superoxide anion and nitric oxide, leading to peroxynitrite formation and generating oxidative stress. This cascade leads to lipid peroxidation, mitochondrial damage and breakdown of the blood-brain barrier, thus contributing to cell injury during neonatal meningitis. This review summarizes information on the pathophysiology and adjuvant treatment of acute bacterial meningitis in neonates.