RESUMO
Traumatic brain injury (TBI) remains a major health concern which causes long-term neurological disability particularly in war veterans, athletes and young adults. In spite of intense clinical and research investigations, there is no effective therapy to cease the pathogenesis of the disease. It is believed that axonal injury during TBI is potentiated by neuroinflammation and demyelination and/or failure to remyelination. This study highlights the use of naturally available cinnamein, also chemically known as benzyl cinnamate, in inhibiting neuroinflammation, promoting remyelination and combating the disease process of controlled cortical impact (CCI)-induced TBI in mice. Oral delivery of cinnamein through gavage brought down the activation of microglia and astrocytes to decrease the expression of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) in hippocampus and cortex of TBI mice. Cinnamein treatment also stimulated remyelination in TBI mice as revealed by PLP and A2B5 double-labeling, luxol fast blue (LFB) staining and axonal double-labeling for neurofilament and MBP. Furthermore, oral cinnamein reduced the size of lesion cavity in the brain, improved locomotor functions and restored memory and learning in TBI mice. These results suggest a new neuroprotective property of cinnamein that may be valuable in the treatment of TBI.
Assuntos
Lesões Encefálicas Traumáticas , Modelos Animais de Doenças , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/metabolismo , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Sepsis is associated with several comorbidities in survivors, such as posttraumatic stress disorder (PTSD). This study investigated whether rats that survive sepsis develop the generalization of fear memory as a model of PTSD. Responses to interventions that target the endothelin-1 (ET-1)/cannabinoid system and glial activation in the initial stages of sepsis were evaluated. As a control, we evaluated hyperalgesia before fear conditioning. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. CLP-induced sepsis with one or three punctures resulted in fear generalization in the survivors 13 and 20 days after the CLP procedure, a process that was not associated with hyperalgesia. Septic animals were intracerebroventricularly treated with vehicle, the endothelin receptor A (ETA) antagonist BQ123, the cannabinoid CB1 and CB2 receptor antagonists AM251 and AM630, respectively, and the glial blocker minocycline 4 h after CLP. The blockade of either CB1 or ETA receptors increased the survival rate, but only the former reversed fear memory generalization. The endothelinergic system blockade is important for improving survival but not for fear memory. Treatment with the CB2 receptor antagonist or minocycline also reversed the generalization of fear memory but did not increase the survival rate that was associated with CLP. Minocycline treatment also reduced tumor necrosis factor-α levels in the hippocampus suggesting that neuroinflammation is important for the generalization of fear memory induced by CLP. The influence of CLP on the generalization of fear memory was not related to Arc protein expression, a regulator of synaptic plasticity, in the dorsal hippocampus.
Assuntos
Canabinoides , Sepse , Transtornos de Estresse Pós-Traumáticos , Ratos , Animais , Receptores de Canabinoides , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Ratos Wistar , Doenças Neuroinflamatórias , Minociclina , Hiperalgesia , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Sepse/metabolismoRESUMO
COVID-19 is associated with oxidative stress, peripheral hyper inflammation, and neuroinflammation, especially in individuals with a more severe form of the disease. Some studies provide evidence on the onset or exacerbation of major depressive disorder (MDD), among other psychiatric disorders due to COVID-19. Oxidative stress and neuroinflammation are associated conditions, especially in the more severe form of MDD and in refractoriness to available therapeutic strategies. Inflammatory cytokines in the COVID-19 hyper inflammation process can activate the hypothalamic-pituitary-adrenal (HPA) axis and the indoleamine-2,3-dioxygenase (IDO) enzyme. IDO activation can reduce tryptophan and increase toxic metabolites of the kynurenine pathway, which increases glial activation, neuroinflammation, toxicity, and neuronal death. This review surveyed a number of studies and analyzed the mechanisms of oxidative stress, inflammation, and neuroinflammation involved in COVID-19 and depression. Finally, the importance of more protocols that can help elucidate the interaction between these mechanisms underlying COVID-19 and MDD and the possible therapeutic strategies involved in the interaction of these mechanisms are highlighted.
Assuntos
COVID-19 , Transtorno Depressivo Maior , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação , Cinurenina/metabolismo , Cinurenina/uso terapêutico , Doenças Neuroinflamatórias , Estresse OxidativoRESUMO
Addiction is a chronic and potentially deadly disease considered a global health problem. Nevertheless, there is still no ideal treatment for its management. The alterations in the reward system are the most known pathophysiological mechanisms. Dopamine is the pivotal neurotransmitter involved in neuronal drug reward mechanisms and its neuronal mechanisms have been intensely investigated in recent years. However, neuroglial interactions and their relation to drug addiction development and maintenance of drug addiction have been understudied. Many reports have found that most neuroglial cells express dopamine receptors and that dopamine activity may induce neuroimmunomodulatory effects. Furthermore, current research has also shown that pro- and anti-inflammatory molecules modulate dopaminergic neuron activity. Thus, studying the immune mechanisms of dopamine associated with drug abuse is vital in researching new pathophysiological mechanisms and new therapeutic targets for addiction management.
Assuntos
Comportamento Aditivo , Transtornos Relacionados ao Uso de Substâncias , Dopamina , Neurônios Dopaminérgicos , Humanos , Neuroglia , RecompensaRESUMO
The experimental autoimmune encephalomyelitis (EAE) is a model that mimics multiple sclerosis in rodents. Evidence has suggested that the activation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway (KP), plays a crucial role in inflammation-related diseases. The present study aimed to investigate the involvement of the inflammatory process and KP components in a model of EAE in mice. To identify the role of KP in EAE pathogenesis, mice received IDO inhibitor (INCB024360) at a dose of 200 mg/kg (per oral) for 25 days. We demonstrated that IDO inhibitor mitigated the clinical signs of EAE, in parallel with the reduction of cytokine levels (brain, spinal cord, spleen and lymph node) and ionized calcium-binding adaptor protein-1 (Iba-1) gene expression in the central nervous system of EAE mice. Besides, IDO inhibitor causes a significant decrease in the levels of tryptophan, kynurenine and neurotoxic metabolites of KP, such as 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) in the prefrontal cortex, hippocampus, spinal cord, spleen and lymph node of EAE mice. The mRNA expression and enzyme activity of IDO and kynurenine 3-monooxygenase (KMO) were also reduced by IDO inhibitor. These findings indicate that the inflammatory process concomitant with the activation of IDO/KP is involved in the pathogenic mechanisms of EAE. The modulation of KP is a promising target for novel pharmacological treatment of MS.
Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/enzimologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/metabolismo , Cinurenina/análogos & derivados , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/metabolismo , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Oximas/uso terapêutico , Fragmentos de Peptídeos , Ácido Quinolínico/metabolismo , Sulfonamidas/uso terapêutico , Triptofano/metabolismoRESUMO
Lesions of peripheral nerves lead to pain, hyperalgesia, and psychological comorbidities. However, the relationship between mood disorders and neuropathic pain is unclear, as well as the underlying mechanisms related to these disorders. Therefore, we investigated if nerve injury induces depression, anxiety, and cognitive impairment and if there were changes in cytokines, growth factors, and glial cell activation in cortical sites involved in processing pain and mood in animals with nerve injury. Nerve injury was induced by partial sciatic nerve ligation (PSNL) in male Swiss mice and compared to sham-operated animals. Nociceptive behavioral tests to mechanical and thermal (heat and cold) stimuli confirmed the development of hyperalgesia. We further examined mood disorders and memory behaviors. We show nerve injury induces a decrease in mechanical withdrawal thresholds and thermal latency to heat and cold. We also show that nerve injury causes depressive-like and anxiety-like behaviors as well as impairment in short-term memory in mice. There were increases in proinflammatory cytokines as well as Brain-Derived Neurotrophic Factor (BDNF) in the injured nerve. In the spinal cord, there were increases in both pro and anti-inflammatory cytokines, as well as of BDNF and Nerve Growth Factor (NGF). Further, in our data was a decrease in the density of microglia and astrocytes in the hippocampus and increased microglial density in the prefrontal cortex, areas associated with neuropathic pain conditions.
RESUMO
Neurobrucellosis, which is the most morbid form of brucellosis disease, presents with inflammatory signs and symptoms. Recent experimental evidence clearly indicates that deregulation of astrocytes and microglia caused by Brucella infection creates a microenvironment in the central nervous system (CNS) in which secretion of pro-inflammatory mediators lead to destabilization of the glial structure, the damage of the blood brain barrier (BBB) and neuronal demise. This review of Brucella interactions with cells of the CNS and the BBB is intended to present recent immunological findings that can explain, at least in part, the basis for the inflammatory pathogenesis of the nervous system that takes place upon Brucella infection.
Assuntos
Barreira Hematoencefálica/imunologia , Brucelose/imunologia , Sistema Nervoso Central/imunologia , Imunidade Inata/fisiologia , Fatores Imunológicos/imunologia , Animais , Barreira Hematoencefálica/metabolismo , Brucelose/metabolismo , Sistema Nervoso Central/metabolismo , Humanos , Fatores Imunológicos/metabolismoRESUMO
Chemotherapy-induced peripheral neuropathy is a disabling condition induced by several frequently used chemotherapeutic drugs including the front-line agent oxaliplatin (OXA). Symptoms are predominantly sensory with the development of neuropathic pain. Alternative dosing protocols and treatment discontinuation are the only available therapeutic strategies. The aim of our work was to evaluate the potential of a synthetic derivative of progesterone, 17α-hydroxyprogesterone caproate (HPGC), in the prevention and treatment of OXA-evoked painful neuropathy. We also evaluated glial activation at the dorsal root ganglia (DRG) and spinal cord levels as a possible target mechanism underlying HPGC actions. Male rats were injected with OXA and HPGC following a prophylactic (HPGCp) or therapeutic (HPGCt) scheme (starting either before or after chemotherapy). The development of hypersensitivity and allodynic pain and the expression of neuronal and glial activation markers were evaluated. When compared to control animals, those receiving OXA showed a significant decrease in paw mechanical and thermal thresholds, with the development of allodynia. Animals treated with HPGCp showed patterns of response similar to those detected in control animals, while those treated with HPGCt showed a suppression of both hypersensitivities after HPGC administration. We also observed a significant increase in the mRNA levels of activating transcription factor 3, the transcription factor (c-fos), glial fibrillary acidic protein, ionized calcium binding adaptor protein 1, interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNFα) in DRG and spinal cord of OXA-injected animals, and significantly lower levels in rats receiving OXA and HPGC. These results show that HPGC administration reduces neuronal and glial activation markers and is able to both prevent and suppress OXA-induced allodynia, suggesting a promising therapeutic strategy.
Assuntos
Caproato de 17 alfa-Hidroxiprogesterona/farmacologia , Antineoplásicos/farmacologia , Hiperalgesia , Neuralgia , Oxaliplatina/farmacologia , Doenças do Sistema Nervoso Periférico , Progestinas/farmacologia , Caproato de 17 alfa-Hidroxiprogesterona/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Masculino , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/prevenção & controle , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Progestinas/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
Evidence suggests that exercise can modulate neuroinflammation and neuronal damage. We evaluated if such effects of exercise can be detected with positron emission tomography (PET) in a rat model of Parkinson's disease (PD). Rats were unilaterally injected in the striatum with 6-hydroxydopamine (PD rats) or saline (controls) and either remained sedentary (SED) or were forced to exercise three times per week for 40 min (EX). Motor and cognitive functions were evaluated by the open field, novel object recognition, and cylinder tests. At baseline, day 10 and 30, glial activation and dopamine synthesis were assessed by [11C]PBR28 and [18F]FDOPA PET, respectively. PET data were confirmed by immunohistochemical analysis of microglial (Iba-1) / astrocyte (GFAP) activation and tyrosine hydroxylase (TH). [11C]PBR28 PET showed increased glial activation in striatum and hippocampus of PD rats at day 10, which had resolved at day 30. Exercise completely suppressed glial activation. Imaging results correlated well with post-mortem Iba-1 staining, but not with GFAP staining. [18F]FDOPA PET, TH staining and behavioral tests indicate that 6-OHDA caused damage to dopaminergic neurons, which was partially prevented by exercise. These results show that exercise can modulate toxin-induced glial activation and neuronal damage, which can be monitored noninvasively by PET.
Assuntos
Neurônios Dopaminérgicos/patologia , Neuroglia/metabolismo , Doença de Parkinson/patologia , Condicionamento Físico Animal/fisiologia , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Oxidopamina/farmacologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/terapia , Tomografia por Emissão de Pósitrons/métodos , Ratos , Fatores de TempoRESUMO
The pathological hallmarks of Alzheimer's disease (AD) are amyloid-ß (Aß) plaques, neurofibrillary tangles, and glia activation. The pathology also includes vascular amyloidosis and cerebrovascular disease. Vascular compromise can result in hypoperfusion, local tissue hypoxia, and acidosis. Activated microglia and astrocytes can phagocytose Aß through membrane receptors that include scavenger receptors. Changes in glial cells induced by extracellular acidosis could play a role in the development of AD. Here, we assess whether extracellular acidosis changes glial cell properties relevant for Aß clearance capacity. Incubation of glial cells on acidified culture medium (pH 6.9 or 6.5) for 24-48âh resulted in decreased cell diameter, with thinner branches in astrocytes, slight reduction in cell body size in microglia, a transient decrease in astrocyte adhesion to substrates, and a persistent decrease in microglia adhesion compared with control media (pH 7.4). Astrocyte Aß phagocytosis decreased at pH 6.9 and 6.5, whereas microglia phagocytosis only transiently decreased in acidified media. Scavenger receptors class B member I (SR-BI) increased and scavenger receptors-macrophage receptors with collagenous structures (SR-MARCO) decreased in astrocytes cultured at pH 6.5. In contrast, in microglia exposed to pH 6.5, expression of SR-BI and SR-MARCO increased and fatty acid translocase (CD-36) decreased. In conclusion, the acidic environment changed the adhesiveness and morphology of both microglia and astrocytes, but only astrocytes showed a persistent decrease in Aß clearance activity. Expression of scavenger receptors was affected differentially in microglia and astrocytes by acidosis. These changes in scavenger receptor patterns can affect the activation of glia and their contribution to neurodegeneration.
Assuntos
Acidose/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Regulação da Expressão Gênica/fisiologia , Microglia/metabolismo , Fagocitose/fisiologia , Receptores Depuradores/genética , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Meios de Cultivo Condicionados/farmacologia , Meios de Cultivo Condicionados/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Microglia/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Fagocitose/efeitos dos fármacos , Ratos , Receptores Depuradores/metabolismo , Fatores de Tempo , Proteínas de Transporte Vesicular/metabolismoRESUMO
Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. Glial cell activation and cytokine production contribute to the pathology of central neuropathic syndromes. In this study we evaluated the effects of progesterone, a neuroactive steroid, on pain development and the spinal expression of IL-1ß, its receptors (IL-1RI and IL-1RII) and antagonist (IL-1ra), IL-6 and TNFα, and NR1 subunit of NMDAR. Our results show that progesterone, by modulating the expression of pro-inflammatory cytokines and neuronal IL-1RI/NR1 colocalization, emerges as a promising agent to prevent chronic pain after SCI.
Assuntos
Citocinas/metabolismo , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Animais , Citocinas/genética , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Neuralgia/etiologia , Limiar da Dor/efeitos dos fármacos , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Traumatismos da Medula Espinal/complicações , Fatores de TempoRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioral abnormalities is necessary. In previous studies, we have reported that the Chilean rodent Octodon degus could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O. degus brain. We report some histopathological markers associated with the onset progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and the expression of the peroxisome proliferative-activated receptor γ coactivator-1α (PGC-1α). With these results, we suggest that the O. degus could represent a new model for AD research and a powerful tool in the search for therapeutic strategies against AD.
Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Encéfalo/patologia , Adenilato Quinase/metabolismo , Envelhecimento/fisiologia , Animais , Apoptose/fisiologia , Astrócitos/patologia , Astrócitos/fisiologia , Comportamento Animal , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Interleucina-6/metabolismo , Microglia/patologia , Microglia/fisiologia , Neurônios/patologia , Neurônios/fisiologia , Octodon , Estresse Oxidativo/fisiologia , Fatores de Transcrição/metabolismoRESUMO
PURPOSE: The effect of a highly selective 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal system on the astroglial and microglial activation was analysed in adult Wistar rats after an unilateral striatal injection of the neurotoxin. METHODS: Male rats received an unilateral stereotaxical injection of the 6-OHDA in the left side of the neostriatum and were sacrificed 22 days later. Control animals received the injection of the solvent. The rotational behaviour was registered by a rotometer just before the sacrifice. Immunohistochemistry was employed for visualization of the tyrosine hydroxylase (TH) positive dopamine cells, glial fibrillary acidic protein (GFAP) immunolabeled astrocytes and OX42 immunoreactive microglia. Stereological method employing the optical disector was used to estimate the degree of the changes. RESULTS: The striatal injection of the 6-OHDA induced a massive disappearance (32% of control) of the TH immunoreactive terminals in a defined area within the striatum surrounding the injection site. A disappearance (54% of control) of dopamine cell bodies was observed in a small region of the ipsilateral pars compacta of the substantia nigra (SNc). The GFAP and OX42immunohistochemistry revealed astroglial and microglial reactions (increases in the number and size of the cells) in the ipsilateral neostriatum and SNc of the 6-OHDA injected rats. CONCLUSIONS: The striatal injection of 6-OHDA leads to retrograde degeneration as well as astroglial and microglial activation in the nigrostriatal dopamine pathway. Modulation of activated glial cells may be related to wound repair and to the trophic paracrine response in the lesioned nigrostriatal dopamine system.
OBJETIVO: O efeito de uma lesão altamente seletiva induzida pela 6-hidroxidopamina (6-OHDA) no sistema nigroestriatal dopaminérgico sobre a ativação astroglial e microglial foi analisado em ratos Wistar adultos após uma injeção unilateral da neurotoxina no estriado. MÉTODOS: Ratos receberam injeção estereotáxica unilateral de 6-OHDA no lado esquerdo do neoestriado e foram sacrificados 22 dias depois. Os animais controles receberam injeção de solvente. O comportamento rotacional foi registrado antes do sacrifício. A técnica da imunohistoquímica foi utilizada para a visualização das células dopaminérgicas positivas à tirosina hidroxilase (TH), dos astrócitos marcados pela proteína glial fibrilar ácida (GFAP) e da microglia imunorreativa ao OX42. O método estereológico empregando o dissector óptico foi usado para estimar o grau das mudanças no sistema nigroestriatal. RESULTADOS: A injeção estriatal de 6-OHDA induziu o desaparecimento massivo (32% do controle) de terminais imunorreativos à TH numa área definida dentro do estriado, ao redor do local da injeção. Desaparecimento de corpos celulares dopaminérgicos (54% do controle) foi observado em pequena região da porção compacta da substância negra (SNc) ipsilateral. A imunohistoquímica da GFAP e da OX42 revelou reação astroglial e microglial (aumentos no número e tamanho das células) no estriado ipsilateral e na SNc ipsilateral de ratos injetados com a 6-OHDA. CONCLUSÕES: A injeção estriatal de 6-OHDA leva à degeneração retrógrada, bem como à ativação astroglial e microglial na via nigroestriatal dopaminérgica. A modulação das células gliais ativadas pode estar relacionada à cicatrização e à resposta trófica parácrina no sistema nigroestriatal lesado.