Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 635
Filtrar
1.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361041

RESUMO

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6'-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Gliose/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Lesões Encefálicas Traumáticas/complicações , Cognição , Gliose/etiologia , Hipocampo/metabolismo , Fatores Imunológicos/farmacologia , Masculino , Memória , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Talidomida/farmacologia , Talidomida/uso terapêutico
2.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206635

RESUMO

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus callosum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke.


Assuntos
Corticosterona/administração & dosagem , Gliose/metabolismo , Gliose/patologia , Vias Neurais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Substância Branca/efeitos dos fármacos , Substância Branca/fisiologia , Animais , Axônios/metabolismo , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Gliose/tratamento farmacológico , Gliose/etiologia , Imuno-Histoquímica , Masculino , Camundongos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
3.
Biomolecules ; 11(4)2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921556

RESUMO

The available treatments for patients affected by Alzheimer's disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. In the present review, we briefly summarize the pathological mechanisms of AD known so far, based on which different therapeutic tools have been designed. Then, we focus on a specific approach that is targeting astrocytes. Indeed, these non-neuronal brain cells respond to any insult, injury, or disease of the brain, including AD. The study of astrocytes is complicated by the fact that they exert a plethora of homeostatic functions, and their disease-induced changes could be context-, time-, and disease specific. However, this complex but fervent area of research has produced a large amount of data targeting different astrocytic functions using pharmacological approaches. Here, we review the most recent literature findings that have been published in the last five years to stimulate new hypotheses and ideas to work on, highlighting the peculiar ability of palmitoylethanolamide to modulate astrocytes according to their morpho-functional state, which ultimately suggests a possible potential disease-modifying therapeutic approach for AD.


Assuntos
Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Gliose/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Animais , Astrócitos/efeitos dos fármacos , Gliose/tratamento farmacológico , Gliose/etiologia , Humanos , Fármacos Neuroprotetores/uso terapêutico
4.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922372

RESUMO

Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender in NeP onset is worldwide reported, and although the cause is generally attributed to sex hormones, the actual mechanisms and the players involved are still unclear. Glial and immune cells take part in NeP development, and orchestrate the neuroimmune and inflammatory response, releasing pro-inflammatory factors with chemoattractant properties that activate resident immune cells and recruit immune cells from circulation. The neuro-immune crosstalk is a key contributor to pain hypersensitivity following peripheral nervous system injury. Our previous works showed that in spite of the fact that female mice had an earlier analgesic response than males following nerve lesion, the recovery from NeP was never complete, suggesting that this difference could occur in the very early stages after injury. To further investigate gender differences in immune and neuroimmune responses to NeP, we studied the main immune cells and mediators elicited both in plasma and sciatic nerves by peripheral nerve lesion. After injury, we found a different pattern of distribution of immune cell populations showing either a higher infiltration of T cells in nerves from females or a higher infiltration of macrophages in nerves from males. Moreover, in comparison to male mice, the levels of cytokines and chemokines were differently up- and down-regulated in blood and nerve lysates from female mice. Our study provides some novel insights for the understanding of gender-associated differences in the generation and perseveration of NeP as well as for the isolation of specific neurodegenerative mechanisms underlying NeP. The identification of gender-associated inflammatory profiles in neuropathy is of key importance for the development of differential biomarkers and gender-specific personalized medicine.


Assuntos
Gliose/patologia , Hiperalgesia/patologia , Inflamação/patologia , Macrófagos/patologia , Neuralgia/patologia , Traumatismos dos Nervos Periféricos/complicações , Nervo Isquiático/patologia , Animais , Citocinas , Feminino , Gliose/etiologia , Hiperalgesia/etiologia , Inflamação/etiologia , Masculino , Camundongos , Neuralgia/etiologia , Fatores Sexuais
5.
Molecules ; 26(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806413

RESUMO

MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.


Assuntos
Sistema Nervoso Central/patologia , Gliose/patologia , Metionina Sulfóxido Redutases/fisiologia , Plasticidade Neuronal , Selênio/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Gliose/etiologia , Gliose/metabolismo , Humanos , Camundongos , Camundongos Knockout
6.
Exp Neurol ; 341: 113721, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33852877

RESUMO

Traumatic brain injury (TBI) is often associated with sustained attention and memory deficits. As persisting neuroinflammation and neurodegeneration may contribute to posttraumatic psychomotor dysfunction, we studied the relationship of brain cellular reactions three months after a weight-drop closed head injury in male mice with posttraumatic learning and memory using automated home-cage monitoring of socially housed mice in IntelliCages as well as tests for locomotor activity, anxiety and forepaw fine motor skills. One month after TBI, deficits in place learning and cognitive flexibility in reverse learning were clearly detectable in IntelliCages and these memory deficits correlated with the initial trauma severity on the functional neuroscore. While sucrose preference or its extinction were not influenced by TBI, traumatized mice performed significantly worse in a complex episodic memory learning task. In consecutive locomotor and forepaw skilled use tests, posttraumatic hyperactivity and impairment of contralateral paw use were evident. Analysis of cellular reactions to TBI three months after injury in selected defined regions of interest in the immediate lesion, ipsi- and contralateral frontoparietal cortex and hippocampus revealed a persistent microgliosis and astrogliosis which were accompanied by iron-containing macrophages and myelin degradation in the lesion area as well as with axonal damage in the neighboring cortical regions. Microglial and astroglial reactions in cortex showed a positive correlation with the initial trauma severity and a negative correlation with the spatial and episodic memory indicating a role of brain inflammatory reactions in posttraumatic memory deficits.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Gliose/patologia , Gliose/fisiopatologia , Índice de Gravidade de Doença , Aprendizagem Espacial/fisiologia , Animais , Lesões Encefálicas Traumáticas/complicações , Gliose/etiologia , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
7.
Int J Mol Sci ; 22(4)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672129

RESUMO

Neuroinflammation, typically manifest as microglial activation and astrogliosis accompanied by transcriptomic alterations, represents a common hallmark of various neurodegenerative conditions including prion diseases. Microglia play an overall neuroprotective role in prion disease, whereas reactive astrocytes with aberrant phenotypes propagate prions and contribute to prion-induced neurodegeneration. The existence of heterogeneous subpopulations and dual functions of microglia and astrocytes in prion disease make them potential targets for therapeutic intervention. A variety of neuroinflammation-related molecules are involved in prion pathogenesis. Therapeutics targeting neuroinflammation represents a novel approach to combat prion disease. Deciphering neuroinflammation in prion disease will deepen our understanding of pathogenesis of other neurodegenerative disorders.


Assuntos
Inflamação/patologia , Microglia/patologia , Doenças Priônicas/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Gliose/etiologia , Humanos , Microglia/metabolismo , Fagocitose/fisiologia , Doenças Priônicas/metabolismo , Receptores Toll-Like/metabolismo
8.
Neurochem Res ; 46(4): 755-769, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33389472

RESUMO

Cerebral ischemia leads to reactive astrogliosis and glial scar formation. Glial scarring can impede functional restoration during the recovery phase of stroke. Salidroside has been shown to have neuroprotective effects after ischemic stroke, but its impact on long-term neurological recovery, especially whether it regulates reactive astrogliosis and glial scar formation, is unclear. In this study, male adult C57/BL6 mice were subjected to transient cerebral ischemia injury followed by intravenous salidroside treatment. Primary astrocytes were treated with lipopolysaccharide (LPS) or conditioned medium from cultured primary neurons subjected to oxygen-glucose deprivation (CM-OGD). Salidroside significantly improved long-term functional outcomes following ischemic stroke in the rotarod and corner tests. It also reduced brain glial scar volume and decreased expression of the glial scar marker, glial fibrillary acidic protein (GFAP) and inhibited astrocyte proliferation. In primary astrocyte cultures, salidroside protected astrocytes from CM-OGD injury-induced reactive astroglial proliferation, increasing the percentage of cells in G0/G1 phase and reducing the S populations. The inhibitory effect of salidroside on the cell cycle was related to downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4) mRNA expression and increased p27Kip1 mRNA expression. Similar results were found in the LPS-stimulated injury model in astroglial cultures. Western blot analysis demonstrated that salidroside attenuated the CM-OGD-induced upregulation of phosphorylated Akt and glycogen synthase kinase 3ß (GSK-3ß). Taken together, these results suggested that salidroside can inhibit reactive astrocyte proliferation, ameliorate glial scar formation and improve long-term recovery, probably through its effects on the Akt/GSK-3ß pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Gliose/tratamento farmacológico , Glucosídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fenóis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Proliferação de Células/efeitos dos fármacos , Gliose/etiologia , Gliose/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo
9.
Int J Mol Sci ; 22(3)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33503976

RESUMO

Müller cells, the major retinal macroglia, are key to maintaining vascular integrity as well as retinal fluid and ion homeostasis. Although platelet derived growth factor (PDGF) receptor expression in Müller glia has been reported earlier, their actual role for Müller cell function and intimate interaction with cells of the retinal neurovascular unit remains unclear. To close this gap of knowledge, Müller cell-specific PDGF receptor alpha (PDGFRα) knockout (KO) mice were generated, characterized, and subjected to a model of choroidal neovascularization (CNV). PDGFRα-deficient Müller cells could not counterbalance hypoosmotic stress as efficiently as their wildtype counterparts. In wildtypes, the PDGFRα ligand PDGF-BB prevented Müller cell swelling induced by the administration of barium ions. This effect could be blocked by the PDGFR family inhibitor AC710. PDGF-BB could not restore the capability of an efficient volume regulation in PDGFRα KO Müller cells. Additionally, PDGFRα KO mice displayed reduced rod and cone-driven light responses. Altogether, these findings suggest that Müller glial PDGFRα is central for retinal functions under physiological conditions. In contrast, Müller cell-specific PDGFRα KO resulted in less vascular leakage and smaller lesion areas in the CNV model. Of note, the effect size was comparable to pharmacological blockade of PDGF signaling alone or in combination with anti-vascular endothelial growth factor (VEGF) therapy-a treatment regimen currently being tested in clinical trials. These data imply that targeting PDGF to treat retinal neovascular diseases may have short-term beneficial effects, but may elicit unwarranted side effects given the putative negative effects on Müller cell homeostatic functions potentially interfering with a long-term positive outcome.


Assuntos
Células Ependimogliais/metabolismo , Homeostase , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Imunofluorescência , Expressão Gênica , Técnicas de Inativação de Genes , Gliose/etiologia , Gliose/metabolismo , Gliose/patologia , Camundongos , Camundongos Knockout , Neuroglia/metabolismo , Especificidade de Órgãos/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Retina/metabolismo , Retina/patologia
10.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440708

RESUMO

Calbindin-D28k (CB), a calcium-binding protein, mediates diverse neuronal functions. In this study, adult gerbils were fed a normal diet (ND) or exposed to intermittent fasting (IF) for three months, and were randomly assigned to sham or ischemia operated groups. Ischemic injury was induced by transient forebrain ischemia for 5 min. Short-term memory was examined via passive avoidance test. CB expression was investigated in the Cornu Ammonis 1 (CA1) region of the hippocampus via western blot analysis and immunohistochemistry. Finally, histological analysis was used to assess neuroprotection and gliosis (microgliosis and astrogliosis) in the CA1 region. Short-term memory did not vary significantly between ischemic gerbils with IF and those exposed to ND. CB expression was increased significantly in the CA1 pyramidal neurons of ischemic gerbils with IF compared with that of gerbils fed ND. However, the CB expression was significantly decreased in ischemic gerbils with IF, similarly to that of ischemic gerbils exposed to ND. The CA1 pyramidal neurons were not protected from ischemic injury in both groups, and gliosis (astrogliosis and microgliosis) was gradually increased with time after ischemia. In addition, immunoglobulin G was leaked into the CA1 parenchyma from blood vessels and gradually increased with time after ischemic insult in both groups. Taken together, our study suggests that IF for three months increases CB expression in hippocampal CA1 pyramidal neurons; however, the CA1 pyramidal neurons are not protected from transient forebrain ischemia. This failure in neuroprotection may be attributed to disruption of the blood-brain barrier, which triggers gliosis after ischemic insults.


Assuntos
Calbindina 1/genética , Jejum , Expressão Gênica , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Animais , Calbindina 1/imunologia , Morte Celular/genética , Morte Celular/imunologia , Gerbillinae , Gliose/etiologia , Imunoglobulina G/imunologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia
11.
Int J Mol Sci ; 21(23)2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33291737

RESUMO

Melatonin is of great importance for regulating several eye processes, including pressure homeostasis. Melatonin in combination with agomelatine has been recently reported to reduce intraocular pressure (IOP) with higher efficacy than each compound alone. Here, we used the methylcellulose (MCE) rat model of hypertensive glaucoma, an optic neuropathy characterized by the apoptotic death of retinal ganglion cells (RGCs), to evaluate the hypotensive and neuroprotective efficacy of an eye drop nanomicellar formulation containing melatonin/agomelatine. Eye tissue distribution of melatonin/agomelatine in healthy rats was evaluated by HPLC/MS/MS. In the MCE model, we assessed by tonometry the hypotensive efficacy of melatonin/agomelatine. Neuroprotection was revealed by electroretinography; by levels of inflammatory and apoptotic markers; and by RGC density. The effects of melatonin/agomelatine were compared with those of timolol (a beta blocker with prevalent hypotensive activity) or brimonidine (an alpha 2 adrenergic agonist with potential neuroprotective efficacy), two drugs commonly used to treat glaucoma. Both melatonin and agomelatine penetrate the posterior segment of the eye. In the MCE model, IOP elevation was drastically reduced by melatonin/agomelatine with higher efficacy than that of timolol or brimonidine. Concomitantly, gliosis-related inflammation and the Bax-associated apoptosis were partially prevented, thus leading to RGC survival and recovered retinal dysfunction. We suggest that topical melatoninergic compounds might be beneficial for ocular health.


Assuntos
Anti-Hipertensivos/administração & dosagem , Glaucoma/etiologia , Fármacos Neuroprotetores/administração & dosagem , Acetamidas/farmacologia , Animais , Apoptose , Caspase 3/metabolismo , Modelos Animais de Doenças , Glaucoma/diagnóstico , Glaucoma/tratamento farmacológico , Gliose/etiologia , Melatonina/farmacologia , Ratos , Retina/metabolismo , Transdução de Sinais , Resultado do Tratamento , Proteína X Associada a bcl-2/metabolismo
12.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339379

RESUMO

A systemic inflammatory response induces multiple organ dysfunction and results in poor long-term neurological outcomes in neonatal sepsis. However, there is no effective therapy for treating or preventing neonatal sepsis besides antibiotics and supportive care. Therefore, a novel strategy to improve neonatal sepsis-related morbidity and mortality is desirable. Recently, we reported that prophylactic therapy with human amniotic stem cells (hAFSCs) improved survival in a rat model of lipopolysaccharide (LPS)-induced neonatal sepsis through immunomodulation. Besides improving the mortality, increasing survival without major morbidities is an important goal of neonatal intensive care for neonatal sepsis. This study investigated long-term neurological outcomes in neonatal sepsis survivors treated with hAFSCs using the LPS-induced neonatal sepsis model in rats. We found that prophylactic therapy with hAFSCs improved spatial awareness and memory-based behavior in neonatal sepsis survivors at adolescence in rats. The treatment suppressed acute reactive gliosis and subsequently reduced astrogliosis in the hippocampal region over a long period of assessment. To the best of our knowledge, this is the first report that proves the concept that hAFSC treatment improves cognitive impairment in neonatal sepsis survivors. We demonstrate the efficacy of hAFSC therapy in improving the mortality and morbidity associated with neonatal sepsis.


Assuntos
Disfunção Cognitiva/prevenção & controle , Gliose/prevenção & controle , Transplante de Células-Tronco Mesenquimais/métodos , Sepse Neonatal/complicações , Líquido Amniótico/citologia , Animais , Células Cultivadas , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Gliose/etiologia , Gliose/terapia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Int J Mol Sci ; 21(20)2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33050466

RESUMO

Amyloid-beta oligomers (AßO) have been proposed as the most potent neurotoxic and inflammation inducers in Alzheimer's disease (AD). AßO contribute to AD pathogenesis by impairing the production of several cytokines and inflammation-related signaling pathways, such as the Janus kinases/signal transducer of transcription factor-3 (JAK/STAT3) pathway. STAT3 modulates glial activation, indirectly regulates Aß deposition, and induces cognitive decline in AD transgenic models. However, in vivo studies using an AßO microinjection rat model have not yet explored STAT3 role. The main purpose of this study was to elucidate if a single microinjection of AßO could promote an increased expression of STAT3 in glial cells favoring neuroinflammation and neurodegeneration. We designed a model of intrahippocampal microinjection and assessed glial activation, cytokines production, STAT3 expression, and neurodegeneration in time. Our results showed robust expression of STAT3 in glial cells (mainly in astrocytes) and neurons, correlating with neuronal death in response to AßO administration. A STAT3 inhibition assay conducted in rat primary hippocampal cultures, suggested that the induction of the transcription factor by AßO in astrocytes leads them to an activation state that may favor neuronal death. Notwithstanding, pharmacological inhibition of the JAK2/STAT3 pathway should be focused on astrocytes because it is also essential in neurons survival. Overall, these findings strongly suggest the participation of STAT3 in the development of neurodegeneration.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Gliose/etiologia , Gliose/metabolismo , Neurônios/metabolismo , Fator de Transcrição STAT3/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Astrócitos/patologia , Biomarcadores , Morte Celular , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imunofluorescência , Gliose/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Imuno-Histoquímica , Agregados Proteicos , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Multimerização Proteica , Ratos , Fator de Transcrição STAT3/genética
14.
Nat Commun ; 11(1): 4524, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913280

RESUMO

Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.


Assuntos
Lesões Encefálicas/fisiopatologia , Gliose/fisiopatologia , Sistema Glinfático/fisiologia , Meninges/fisiopatologia , Animais , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Gliose/etiologia , Gliose/patologia , Gliose/prevenção & controle , Sistema Glinfático/patologia , Humanos , Masculino , Meninges/patologia , Camundongos , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/uso terapêutico
15.
Mar Drugs ; 18(8)2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32708004

RESUMO

Neurodegenerative diseases are age-related disorders caused by progressive neuronal death in different regions of the nervous system. Neuroinflammation, modulated by glial cells, is a crucial event during the neurodegenerative process; consequently, there is an urgency to find new therapeutic products with anti-glioinflammatory properties. Five new furanocembranolides (1-5), along with leptolide, were isolated from two different extracts of Leptogorgia sp., and compound 6 was obtained from chemical transformation of leptolide. Their structures were determined based on spectroscopic evidence. These seven furanocembranolides were screened in vitro by measuring their ability to modulate interleukin-1ß (IL-1ß) production by microglial BV2 cells after LPS (lipopolysaccharide) stimulation. Leptolide and compounds 3, 4 and 6 exhibited clear anti-inflammatory effects on microglial cells, while compound 2 presented a pro-inflammatory outcome. The in vitro results prompted us to assess anti-glioinflammatory effects of leptolide in vivo in a high-fat diet-induced obese mouse model. Interestingly, leptolide treatment ameliorated both microgliosis and astrogliosis in this animal model. Taken together, our results reveal a promising direct biological effect of furanocembranolides on microglial cells as bioactive anti-inflammatory molecules. Among them, leptolide provides us a feasible therapeutic approach to treat neuroinflammation concomitant with metabolic impairment.


Assuntos
Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Diterpenos/farmacologia , Furanos/farmacologia , Gliose/tratamento farmacológico , Resistência à Insulina , Microglia/efeitos dos fármacos , Obesidade/complicações , Animais , Antozoários/química , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Encéfalo/metabolismo , Encéfalo/patologia , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Linhagem Celular , Dieta Hiperlipídica , Diterpenos/química , Diterpenos/isolamento & purificação , Furanos/química , Furanos/isolamento & purificação , Gliose/etiologia , Gliose/metabolismo , Gliose/patologia , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Estrutura Molecular , Obesidade/metabolismo , Relação Estrutura-Atividade
16.
Int J Radiat Oncol Biol Phys ; 108(3): 745-757, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470502

RESUMO

PURPOSE: Improved efficacy of anticancer therapy and a growing pool of survivors give rise to a question about their quality of life and return to premorbid status. Radiation is effective in brain metastasis eradication, although the optimal approach and long-term effects on brain function are largely unknown. We studied the effects of radiosurgery on brain function. METHODS AND MATERIALS: Adult C57BL/6J mice with or without brain metastases (rat 9L gliosarcoma) were treated with cone beam single-arc stereotactic radiosurgery (SRS; 40 Gy). Tumor growth was monitored using bioluminescence, whereas longitudinal magnetic resonance imaging, behavioral studies, and histologic analysis were performed to evaluate brain response to the treatment for up to 18 months. RESULTS: Stereotactic radiosurgery (SRS) resulted in 9L metastases eradication within 4 weeks with subsequent long-term survival of all treated animals, whereas all nontreated animals succumbed to the brain tumor. Behavioral impairment, as measured with a recognition memory test, was observed earlier in mice subjected to radiosurgery of tumors (6 weeks) in comparison to SRS of healthy brain tissue (10 weeks). Notably, the deficit resolved by 18 weeks only in mice not bearing a tumor, whereas tumor eradication was complicated by the persistent cognitive deficits. In addition, the results of magnetic resonance imaging were unremarkable in both groups, and histopathology revealed changes. SRS-induced tumor eradication triggered long-lasting and exacerbated neuroinflammatory response. No demyelination, neuronal loss, or hemorrhage was detected in any of the groups. CONCLUSIONS: Tumor disintegration by SRS leads to exacerbated neuroinflammation and persistent cognitive deficits; therefore, methods aiming at reducing inflammation after tumor eradication or other therapeutic methods should be sought.


Assuntos
Neoplasias Encefálicas/radioterapia , Encéfalo/efeitos da radiação , Disfunção Cognitiva/etiologia , Gliossarcoma/radioterapia , Radiocirurgia/efeitos adversos , Animais , Atenção/efeitos da radiação , Comportamento , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Disfunção Cognitiva/diagnóstico por imagem , Encefalite/diagnóstico por imagem , Encefalite/etiologia , Encefalite/patologia , Gliossarcoma/mortalidade , Gliossarcoma/patologia , Gliossarcoma/secundário , Gliose/etiologia , Medições Luminescentes , Ativação de Macrófagos , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias/métodos , Radiocirurgia/métodos , Dosagem Radioterapêutica , Reconhecimento Psicológico
17.
J Neurosci ; 40(11): 2371-2380, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047056

RESUMO

Chronic electroencephalography (EEG) is a widely used tool for monitoring cortical electrical activity in experimental animals. Although chronic implants allow for high-quality, long-term recordings in preclinical studies, the electrodes are foreign objects and might therefore be expected to induce a local inflammatory response. We here analyzed the effects of chronic cranial electrode implantation on glymphatic fluid transport and in provoking structural changes in the meninges and cerebral cortex of male and female mice. Immunohistochemical analysis of brain tissue and dura revealed reactive gliosis in the cortex underlying the electrodes and extensive meningeal lymphangiogenesis in the surrounding dura. Meningeal lymphangiogenesis was also evident in mice prepared with the commonly used chronic cranial window. Glymphatic influx of a CSF tracer was significantly enhanced at 30 d postsurgery in both awake and ketamine-xylazine anesthetized mice with electrodes, supporting the concept that glymphatic influx and intracranial lymphatic drainage are interconnected. Altogether, the experimental results provide clear evidence that chronic implantation of EEG electrodes is associated with significant changes in the brain's fluid transport system. Future studies involving EEG recordings and chronic cranial windows must consider the physiological consequences of cranial implants, which include glial scarring, meningeal lymphangiogenesis, and increased glymphatic activity.SIGNIFICANCE STATEMENT This study shows that implantation of extradural electrodes provokes meningeal lymphangiogenesis, enhanced glymphatic influx of CSF, and reactive gliosis. The analysis based on CSF tracer injection in combination with immunohistochemistry showed that chronically implanted electroencephalography electrodes were surrounded by lymphatic sprouts originating from lymphatic vasculature along the dural sinuses and the middle meningeal artery. Likewise, chronic cranial windows provoked lymphatic sprouting. Tracer influx assessed in coronal slices was increased in agreement with previous reports identifying a close association between glymphatic activity and the meningeal lymphatic vasculature. Lymphangiogenesis in the meninges and altered glymphatic fluid transport after electrode implantation have not previously been described and adds new insights to the foreign body response of the CNS.


Assuntos
Dura-Máter/metabolismo , Eletrodos Implantados/efeitos adversos , Reação a Corpo Estranho/etiologia , Gliose/etiologia , Sistema Glinfático/fisiologia , Linfangiogênese , Animais , Astrócitos/fisiologia , Córtex Cerebral/patologia , Líquido Cefalorraquidiano/fisiologia , Dura-Máter/patologia , Eletroencefalografia/instrumentação , Feminino , Reação a Corpo Estranho/metabolismo , Gliose/metabolismo , Gliose/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/fisiologia , Técnica de Janela Cutânea , Fases do Sono/fisiologia
18.
Horm Behav ; 120: 104690, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31954709

RESUMO

Changes to neonatal nutrition result in long-lasting impairments in energy balance, which may be described as metabolic programing. Astrocytes, which are interconnected by gap junctions, have emerged as important players in the hypothalamic control of food intake. In order to study the effects of nutritional programming on glial morphology and protein expression, cross-fostered male Wistar rats at postnatal day 3 were assigned to three groups based on litter size: small litter (3 pups per dam, SL), normal litter (10 pups per dam, NL), and large litter (16 pups per dam, LL). Rats from the SL group exhibited higher body weight throughout the study and hyperphagia after weaning. LL animals exhibited hyperphagia, high energy efficiency and catch-up of body weight after weaning. Both the SL and LL groups at postnatal day 60 (PN60) exhibited increased levels of plasma leptin, the Lee index (as an index of obesity), adiposity content, immunoreactivity toward T-cell protein tyrosine phosphatase (TCPTP), and glial fibrillary acidic protein (GFAP) in the arcuate nucleus (ARC) of the hypothalamus. Astrocyte morphology was altered in the ARC of SL and LL animals, and this effect occurred in parallel with a reduction in immunoreactivity toward connexin 30 (CX30). The data obtained demonstrate that both neonatal over- and underfeeding promote not only alterations in the metabolic status but also morphological changes in glial cells in parallel with increasing TCPTP and changes in connexin expression.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Conexinas/genética , Gliose/etiologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Adiposidade/fisiologia , Animais , Animais Recém-Nascidos , Conexinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Gliose/genética , Gliose/metabolismo , Hiperfagia/complicações , Hiperfagia/genética , Hiperfagia/metabolismo , Hiperfagia/patologia , Hipotálamo/metabolismo , Tamanho da Ninhada de Vivíparos/fisiologia , Masculino , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Gravidez , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Ratos , Ratos Wistar , Fatores Sexuais , Fatores de Tempo
19.
Horm Behav ; 120: 104675, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31923417

RESUMO

Consumption of a high fat diet (HFD) increases circulating free fatty acids, which can enter the brain and promote a state of microgliosis, as defined by a change in microglia number and/or morphology. Most studies investigating diet-induced microgliosis have been conducted in male rodents despite well-documented sex differences in the neural control of food intake and neuroimmune signaling. This highlights the need to investigate how sex hormones may modulate the behavioral and cellular response to HFD consumption. Estradiol is of particular interest since it exerts a potent anorexigenic effect and has both anti-inflammatory and neuroprotective effects in the brain. As such, the aim of the current study was to investigate whether estradiol attenuates the development of HFD-induced microgliosis in female rats. Estradiol- and vehicle-treated ovariectomized rats were fed either a low-fat chow diet or a 60% HFD for 4 days, after which they were perfused and brain sections were processed via immunohistochemistry for microglia-specific Iba1 protein. Four days of HFD consumption promoted microgliosis, as measured via an increase in the number of microglia in the arcuate nucleus (ARC) of the hypothalamus and nucleus of the solitary tract (NTS), and a decrease in microglial branching in the ARC, NTS, lateral hypothalamus (LH), and ventromedial hypothalamus. Estradiol replacement attenuated the HFD-induced changes in microglia accumulation and morphology in the ARC, LH, and NTS. We conclude that estradiol has protective effects against HFD-induced microgliosis in a region-specific manner in hypothalamic and hindbrain areas implicated in the neural control of food intake.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Estradiol/farmacologia , Gliose/prevenção & controle , Microglia/efeitos dos fármacos , Ovariectomia/efeitos adversos , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/patologia , Encefalopatias/etiologia , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Contagem de Células , Tamanho Celular/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Estradiol/deficiência , Feminino , Gliose/etiologia , Gliose/patologia , Hipotálamo/metabolismo , Hipotálamo/patologia , Microglia/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/patologia
20.
Mol Neurobiol ; 57(5): 2194-2205, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31974940

RESUMO

Hypoxic-ischemic (HI) brain injury remains an important cause of brain damage in neonates with potential life-long consequences. Caffeine, which is a competitive inhibitor of adenosine receptors, is commonly used as treatment for preterm apnoea in clinical settings. In the current study, we investigated the effects of caffeine given at 0 h, 6 h, 12 h or 24 h after HI in P10 mouse pups. Open field and rotarod behavioural tests were performed 2 weeks after injury, and brain morphology was then evaluated. Gene expression and immunohistological analyses were assessed in mice 1- and 5-day post-HI. A single dose of caffeine directly after HI resulted in a reduction of the lesion in the grey and white matter, judged by immunostaining of MAP2 and MBP, respectively, compared to PBS-treated controls. In addition, the number of amoeboid microglia and apoptotic cells, the area covered by astrogliosis, and the expression of pro-inflammatory cytokines were significantly decreased. Behavioural assessment after 2 weeks showed increased open-field activity after HI, and this was normalised if caffeine was administered immediately after the injury. Later administrations of caffeine did not change the outcomes when compared to the vehicle group. In conclusion, caffeine only yielded neuroprotection and immunomodulation in a neonatal model of brain hypoxia ischaemia if administered immediately after injury.


Assuntos
Cafeína/administração & dosagem , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Antagonistas de Receptores Purinérgicos P1/administração & dosagem , Animais , Lesões Encefálicas/patologia , Cafeína/farmacologia , Cafeína/uso terapêutico , Fragmentação do DNA/efeitos dos fármacos , Doenças Desmielinizantes/prevenção & controle , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Comportamento Exploratório , Feminino , Gliose/etiologia , Gliose/prevenção & controle , Hipóxia-Isquemia Encefálica/metabolismo , Inflamação/genética , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neuroglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Antagonistas de Receptores Purinérgicos P1/farmacologia , Antagonistas de Receptores Purinérgicos P1/uso terapêutico , Distribuição Aleatória , Teste de Desempenho do Rota-Rod , Método Simples-Cego , Organismos Livres de Patógenos Específicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...