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1.
Biomolecules ; 11(8)2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34439922

RESUMO

BACKGROUND: Chronic pain is a major issue affecting more than 50% of the older population and up to 80% of nursing homes residents. Research on pain in the elderly focuses mainly on the development of clinical tools to assess pain in patients with dementia and cognitive impairment or on the efficacy and tolerability of medications. In this review, we searched for evidence of specific pain mechanisms or modifications in pain signals processing either at the cellular level or in the central nervous system. METHODS: Narrative review. RESULTS: Investigation on pain sensitivity led to conflicting results, with some studies indicating a modest decrease in age-related pain sensitivity, while other researchers found a reduced pain threshold for pressure stimuli. Areas of the brain involved in pain perception and analgesia are susceptible to pathological changes such as gliosis and neuronal death and the effectiveness of descending pain inhibitory mechanisms, particularly their endogenous opioid component, also appears to deteriorate with advancing age. Hyperalgesia is more common at older age and recovery from peripheral nerve injury appears to be delayed. In addition, peripheral nociceptors may contribute minimally to pain sensation at either acute or chronic time points in aged populations. CONCLUSIONS: Elderly subjects appear to be more susceptible to prolonged pain development, and medications acting on peripheral sensitization are less efficient. Pathologic changes in the central nervous system are responsible for different pain processing and response to treatment. Specific guidelines focusing on specific pathophysiological changes in the elderly are needed to ensure adequate treatment of chronic pain conditions.


Assuntos
Envelhecimento , Dor Crônica/diagnóstico , Dor Crônica/terapia , Geriatria , Limiar da Dor , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Encéfalo/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Gliose/fisiopatologia , Humanos , Hiperalgesia , Pessoa de Meia-Idade , Neurônios/metabolismo , Manejo da Dor , Medição da Dor , Percepção , Sistema Nervoso Periférico/fisiopatologia , Pressão , Medula Espinal/fisiopatologia , Adulto Jovem
2.
Res Vet Sci ; 138: 39-48, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34091228

RESUMO

Methotrexate (MTX), an antifolate drug, is widely used in chemotherapeutic protocols for metastatic and primary brain tumors and some autoimmune diseases. Its efficacy for brain tumors is limited by the high incidence of central nervous system (CNS) complications. This investigation aimed to observe the morphological effects, including astroglial and microglial responses, following systemic short-term MTX administration in adult rats. Male Wistar rats received 5 or 10 mg/kg/day of MTX by intraperitoneal route for 4 consecutive days (respectively, MTX5 and MTX10 groups) or the same volume of 0.9% saline solution (control group). On the 5th day, brain samples were collected for hematoxylin-eosin and luxol fast blue staining techniques, as well as for immunohistochemical staining for glial fibrillary acidic protein (GFAP) expression in astrocytes and Iba1 (ionized calcium binding adaptor molecule 1) for microglia in the frontal cortex, hippocampus, hypothalamus and molecular/granular layers of the cerebellum. Morphometric analyses were performed using Image Pro-Plus software. Brain levels of the proinflammatory cytokines TNF-α and IL-1ß were determined by ELISA. No signs of neuronal loss or demyelination were observed in all groups. Increased GFAP and Iba1 expression was found in all areas from the MTX groups, although it was slightly higher in the MTX10 group compared to the MTX5. Both TNF-α and IL-1ß levels were decreased in the MTX5 group compared to controls. In the MTX10 group, TNF-α decreased, although IL-1ß was increased relative to controls. MTX administration induced microglial reaction and astrogliosis in several CNS areas. In the MTX5 group, it apparently occurred in the presence of decreased proinflammatory cytokines.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Astrócitos/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/fisiopatologia , Metotrexato/administração & dosagem , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Relação Dose-Resposta a Droga , Gliose/induzido quimicamente , Gliose/patologia , Masculino , Microglia/metabolismo , Microglia/patologia , Ratos , Ratos Wistar
3.
Sci Rep ; 11(1): 12803, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140581

RESUMO

Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease. CD68-positive bone marrow (BM)-derived cells (BMDCs) accumulate in the pathological lesion in the SOD1(G93A) ALS mouse model after BM transplantation (BMT). Therefore, we investigated whether BMDCs can be applied as gene carriers for cell-based gene therapy by employing the accumulation of BMDCs. In ALS mice, YFP reporter signals were observed in 12-14% of white blood cells (WBCs) and in the spinal cord via transplantation of BM after lentiviral vector (LV) infection. After confirmation of gene transduction by LV with the CD68 promoter in 4-7% of WBCs and in the spinal cord of ALS mice, BM cells were infected with LVs expressing glutamate transporter (GLT) 1 that protects neurons from glutamate toxicity, driven by the CD68 promoter, which were transplanted into ALS mice. The treated mice showed improvement of motor behaviors and prolonged survival. Additionally, interleukin (IL)-1ß was significantly suppressed, and IL-4, arginase 1, and FIZZ were significantly increased in the mice. These results suggested that GLT1 expression by BMDCs improved the spinal cord environment. Therefore, our gene therapy strategy may be applied to treat neurodegenerative diseases such as ALS in which BMDCs accumulate in the pathological lesion by BMT.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Células da Medula Óssea/metabolismo , Transportador 2 de Aminoácido Excitatório/genética , Técnicas de Transferência de Genes , Atividade Motora/fisiologia , Esclerose Amiotrófica Lateral/complicações , Animais , Biomarcadores/metabolismo , Transplante de Medula Óssea , Sobrevivência Celular , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Terapia Genética , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Ácido Glutâmico/metabolismo , Lentivirus/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Neurônios Motores/metabolismo , Atrofia Muscular/complicações , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Degeneração Neural/complicações , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Medula Espinal/metabolismo , Superóxido Dismutase-1/metabolismo , Análise de Sobrevida
4.
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
5.
Mol Neurobiol ; 58(6): 2508-2522, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33447969

RESUMO

Lafora disease (LD; OMIM#274780) is a fatal rare neurodegenerative disorder characterized by generalized epileptic seizures and the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), typically in the brain. LD is caused by mutations in two genes EPM2A or EPM2B, which encode respectively laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase. Much remains unknown about the molecular bases of LD and, unfortunately, appropriate treatment is still missing; therefore patients die within 10 years from the onset of the disease. Recently, we have identified neuroinflammation as one of the initial determinants in LD. In this work, we have investigated anti-inflammatory treatments as potential therapies in LD. With this aim, we have performed a preclinical study in an Epm2b-/- mouse model with propranolol, a ß-adrenergic antagonist, and epigallocatechin gallate (EGCG), an antioxidant from green tea extract, both of which displaying additional anti-inflammatory properties. In vivo motor and cognitive behavioral tests and ex vivo histopathological brain analyses were used as parameters to assess the therapeutic potential of propranolol and EGCG. After 2 months of treatment, we observed an improvement not only in attention defects but also in neuronal disorganization, astrogliosis, and microgliosis present in the hippocampus of Epm2b-/- mice. In general, propranolol intervention was more effective than EGCG in preventing the appearance of astrocyte and microglia reactivity. In summary, our results confirm the potential therapeutic effectiveness of the modulators of inflammation as novel treatments in Lafora disease.


Assuntos
Encéfalo/patologia , Inflamação/patologia , Doença de Lafora/patologia , Animais , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Catequina/análogos & derivados , Catequina/farmacologia , Modelos Animais de Doenças , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Glucanos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Corpos de Inclusão/efeitos dos fármacos , Corpos de Inclusão/metabolismo , Inflamação/complicações , Inflamação/fisiopatologia , Doença de Lafora/complicações , Doença de Lafora/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora , Degeneração Neural/complicações , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fenótipo , Propranolol/farmacologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/metabolismo
6.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466831

RESUMO

Aside from the classical motor symptoms, Parkinson's disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson's. In this study, we hypothesized that Parkinson's-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson's, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson's disease pathology. This study implicates the involvement of orexin in early Parkinson's-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson's disease symptomology.


Assuntos
Modelos Animais de Doenças , Metabolismo Energético/genética , Atividade Motora/genética , Neurônios/metabolismo , Orexinas/genética , Doença de Parkinson/genética , alfa-Sinucleína/genética , Animais , Composição Corporal/genética , Gliose/genética , Gliose/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Orexinas/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , alfa-Sinucleína/metabolismo
7.
Neural Plast ; 2020: 8864246, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299401

RESUMO

Astrocytes play a crucial role in neuronal firing activity. Their abnormal state may lead to the pathological transition of neuronal firing patterns and even induce seizures. However, there is still little evidence explaining how the astrocyte network modulates seizures caused by structural abnormalities, such as gliosis. To explore the role of gliosis of the astrocyte network in epileptic seizures, we first established a direct astrocyte feedback neuronal network model on the basis of the hippocampal CA3 neuron-astrocyte model to simulate the condition of gliosis when astrocyte processes swell and the feedback to neurons increases in an abnormal state. We analyzed the firing pattern transitions of the neuronal network when astrocyte feedback starts to change via increases in both astrocyte feedback intensity and the connection probability of astrocytes to neurons in the network. The results show that as the connection probability and astrocyte feedback intensity increase, neuronal firing transforms from a nonepileptic synchronous firing state to an asynchronous firing state, and when astrocyte feedback starts to become abnormal, seizure-like firing becomes more severe and synchronized; meanwhile, the synchronization area continues to expand and eventually transforms into long-term seizure-like synchronous firing. Therefore, our results prove that astrocyte feedback can regulate the firing of the neuronal network, and when the astrocyte network develops gliosis, there will be an increase in the induction rate of epileptic seizures.


Assuntos
Potenciais de Ação/fisiologia , Astrócitos/fisiologia , Comunicação Celular/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Simulação por Computador , Epilepsia/fisiopatologia , Gliose/fisiopatologia , Humanos , Redes Neurais de Computação
8.
Int J Mol Sci ; 21(23)2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33255257

RESUMO

Progressive fetal infection/inflammation is strongly associated with neural injury after preterm birth. We aimed to test the hypotheses that progressively developing fetal inflammation leads to neuroinflammation and impaired white matter development and that the histopathological changes can be detected using high-field diffusion tensor magnetic resonance imaging (MRI). Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive intravenous saline (control; n = 6) or a progressive infusion of lipopolysaccharide (LPS, 200 ng intravenous over 24 h then doubled every 24 h for 5 days to induce fetal inflammation, n = 7). Sheep were killed 10 days after starting the infusions, for histology and high-field diffusion tensor MRI. Progressive LPS infusion was associated with increased circulating interleukin (IL)-6 concentrations and moderate increases in carotid artery perfusion and the frequency of electroencephalogram (EEG) activity (p < 0.05 vs. control). In the periventricular white matter, fractional anisotropy (FA) was increased, and orientation dispersion index (ODI) was reduced (p < 0.05 vs. control for both). Histologically, in the same brain region, LPS infusion increased microglial activation and astrocyte numbers and reduced the total number of oligodendrocytes with no change in myelination or numbers of immature/mature oligodendrocytes. Numbers of astrocytes in the periventricular white matter were correlated with increased FA and reduced ODI signal intensities. Astrocyte coherence was associated with increased FA. Moderate astrogliosis, but not loss of total oligodendrocytes, after progressive fetal inflammation can be detected with high-field diffusion tensor MRI.


Assuntos
Gliose/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Leucoencefalopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Animais , Gliose/fisiopatologia , Gliose/veterinária , Inflamação/fisiopatologia , Inflamação/veterinária , Leucoencefalopatias/fisiopatologia , Leucoencefalopatias/veterinária , Ovinos , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia
9.
J Vis Exp ; (165)2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33252109

RESUMO

Diverse vascular diseases such as diabetic retinopathy, occlusion of retinal veins or arteries and ocular ischemic syndrome can lead to retinal ischemia. To investigate pathological mechanisms of retinal ischemia, relevant experimental models need to be developed. Anatomically, a main retinal blood supplying vessel is the ophthalmic artery (OpA) and OpA originates from the internal carotid artery of the common carotid artery (CCA). Thus, disruption of CCA could effectively cause retinal ischemia. Here, we established a mouse model of retinal ischemia by transient bilateral common carotid artery occlusion (tBCCAO) to tie the right CCA with 6-0 silk sutures and to occlude the left CCA transiently for 2 seconds via a clamp, and showed that tBCCAO could induce acute retinal ischemia leading to retinal dysfunction. The current method reduces reliance on surgical instruments by only using surgical needles and a clamp, shortens occlusion time to minimize unexpected animal death, which is often seen in mouse models of middle cerebral artery occlusion, and maintains reproducibility of common retinal ischemic findings. The model can be utilized to investigate the pathophysiology of ischemic retinopathies in mice and further can be used for in vivo drug screening.


Assuntos
Arteriopatias Oclusivas/complicações , Artéria Carótida Primitiva/patologia , Isquemia/etiologia , Retina/lesões , Animais , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/fisiopatologia , Círculo Arterial do Cérebro/patologia , Modelos Animais de Doenças , Eletrorretinografia , Gliose/complicações , Gliose/diagnóstico por imagem , Gliose/patologia , Gliose/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isquemia/diagnóstico por imagem , Isquemia/patologia , Isquemia/fisiopatologia , Masculino , Camundongos , Perfusão , Estabilidade Proteica , Reprodutibilidade dos Testes , Retina/diagnóstico por imagem , Retina/patologia , Retina/fisiopatologia , Tomografia de Coerência Óptica
10.
J Chem Neuroanat ; 110: 101855, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33031915

RESUMO

OBJECTIVE(S): Although the available therapeutic agents alleviate the symptoms in patients with temporal lobe epilepsy (TLE), these antiepileptic drugs do not provide adequate control of seizures in 30-40 % of patients. This study was conducted to evaluate anti-epileptic effects of simultaneous inhibition of dipeptidyl peptidase-4 and P2 × 7 purinoceptors in Kainate treated rats. MATERIALS AND METHODS: Brilliant Blue G)BBG(, linagliptin)lin(and lin + BBG were administrated 30 min prior to induction of the intrahippocampal kainate model of epilepsy in male Wistar rats. In the case of valproic acid group, the animals intraperitoneally received valproic acid for 7 consecutive days prior to induction of the model. We carried out histological evaluations, monitoring of behavior, recording of intracranial electroencepholography (IEEG), and determination of astrogliosis and DNA fragmentation using ELISA methods. RESULTS: Our results showed that BBG and lin combination therapy had better effects on decrease in astrogliosis, DNA fragmentation and cognitive disturbances than ones whereas its effects on neuronal survival and seizure severity was similar to only BBG or lin. Likewise, the effects of lin + BBG on decrease in DNA fragmentation and cognitive disturbances were better than valproic acid group. CONCLUSION: Our findings suggest that simultaneous inhibition of dipeptidyl peptidase-4 and P2 × 7 purinoceptors might more efficiently provide protection against progression of the kainate-induced TLE in rats.


Assuntos
Anticonvulsivantes/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Epilepsia/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/administração & dosagem , Fragmentação do DNA/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada , Eletroencefalografia , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Gliose/tratamento farmacológico , Gliose/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Ácido Caínico , Linagliptina/administração & dosagem , Linagliptina/uso terapêutico , Masculino , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Ratos , Ratos Wistar , Corantes de Rosanilina/administração & dosagem , Corantes de Rosanilina/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Resultado do Tratamento
11.
Cells ; 9(10)2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33050187

RESUMO

Cobalamin deficiency affects human physiology with sequelae ranging from mild fatigue to severe neuropsychiatric abnormalities. The cellular and molecular aspects of the nervous system disorders associated with hypovitaminosis B12 remain largely unknown. Growing evidence indicates that astrogliosis is an underlying component of a wide range of neuropathologies. Previously, we developed an in vitro model of cobalamin deficiency in normal human astrocytes (NHA) by culturing the cells with c-lactam of hydroxycobalamin (c-lactam OH-Cbl). We revealed a non-apoptotic activation of caspases (3/7, 8, 9) in cobalamin-deficient NHA, which may suggest astrogliosis. The aim of the current study was to experimentally verify this hypothesis. We indicated an increase in the cellular expression of two astrogliosis markers: glial fibrillary acidic protein and vimentin in cobalamin-deficient NHA using Western blot analysis and immunocytochemistry with confocal laser scanning microscopy. In the next step of the study, we revealed c-lactam OH-Cbl as a potential non-toxic vitamin B12 antagonist in an in vivo model using zebrafish embryos. We believe that the presented results will contribute to a better understanding of the cellular mechanism underlying neurologic pathology due to cobalamin deficiency and will serve as a foundation for further studies.


Assuntos
Gliose/metabolismo , Deficiência de Vitamina B 12/metabolismo , Animais , Astrócitos/metabolismo , Biomarcadores , Proteína Glial Fibrilar Ácida/análise , Gliose/complicações , Gliose/fisiopatologia , Humanos , Modelos Biológicos , Modelos Teóricos , Vimentina/análise , Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/patologia , Peixe-Zebra
12.
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
13.
Sci Rep ; 10(1): 12319, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704088

RESUMO

Molecular hydrogen (H2) protect neurons against reactive oxygen species and ameliorates early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study investigated the effect of H2 on delayed brain injury (DBI) using the rat SAH + unilateral common carotid artery occlusion (UCCAO) model with the endovascular perforation method. 1.3% H2 gas (1.3% hydrogen premixed with 30% oxygen and balanced nitrogen) inhalation was performed on days 0 and 1, starting from anesthesia induction and continuing for 2 h on day 0, and starting from anesthesia induction and continuing for 30 min on day 1. EBI was assessed on the basis of brain edema, expression of S100 calcium-binding protein B (S100B), and phosphorylation of C-Jun N-terminal kinase on day 2, and neurological deficits on day 3. Reactive astrogliosis and severity of cerebral vasospasm (CV) were assessed on days 3 and 7. DBI was assessed on the basis of neurological deficits and neuronal cell death on day 7. EBI, reactive astrogliosis, and DBI were ameliorated in the H2 group compared with the control group. CV showed no significant improvement between the control and H2 groups. This study demonstrated that H2 gas inhalation ameliorated DBI by reducing EBI without improving CV in the rat SAH + UCCAO model.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Hidrogênio/administração & dosagem , Hidrogênio/uso terapêutico , Hemorragia Subaracnóidea/complicações , Administração por Inalação , Animais , Pressão Sanguínea , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/complicações , Edema Encefálico/fisiopatologia , Lesões Encefálicas/fisiopatologia , Morte Celular , Artérias Cerebrais/patologia , Artérias Cerebrais/fisiopatologia , Circulação Cerebrovascular , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Pressão Intracraniana , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Neurônios/patologia , Fosforilação , Ratos Sprague-Dawley , Proteínas S100/metabolismo , Hemorragia Subaracnóidea/fisiopatologia , Fatores de Tempo , Vasoespasmo Intracraniano/patologia , Vasoespasmo Intracraniano/fisiopatologia , Água , Perda de Peso
14.
Cell Rep ; 31(12): 107776, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32579912

RESUMO

Glaucoma is a neurodegenerative disease that features the death of retinal ganglion cells (RGCs) in the retina, often as a result of prolonged increases in intraocular pressure. We show that preventing the formation of neuroinflammatory reactive astrocytes prevents the death of RGCs normally seen in a mouse model of glaucoma. Furthermore, we show that these spared RGCs are electrophysiologically functional and thus still have potential value for the function and regeneration of the retina. Finally, we demonstrate that the death of RGCs depends on a combination of both an injury to the neurons and the presence of reactive astrocytes, suggesting a model that may explain why reactive astrocytes are toxic only in some circumstances. Altogether, these findings highlight reactive astrocytes as drivers of RGC death in a chronic neurodegenerative disease of the eye.


Assuntos
Astrócitos/patologia , Neurônios/patologia , Neurotoxinas/toxicidade , Retina/lesões , Retina/patologia , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Morte Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Complemento C1q/metabolismo , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Modelos Animais de Doenças , Glaucoma/complicações , Glaucoma/patologia , Glaucoma/fisiopatologia , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Interleucina-1/metabolismo , Pressão Intraocular , Camundongos Knockout , Microesferas , Neurônios/efeitos dos fármacos , Retina/efeitos dos fármacos , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Fator de Necrose Tumoral alfa/metabolismo
15.
Brain Res Bull ; 162: 208-217, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32599126

RESUMO

Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by inflammatory processes in the central nervous system (CNS). Decades of research led to discovery of several disease-modifying therapeutics strategies with moderate success. Experimental autoimmune encephalomyelitis (EAE) is currently the most commonly used experimental model for MS and for studying various therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation technique with multiple beneficial effects on healthy as well as CNS with pathology. However, the molecular and cellular mechanisms of rTMS on acute EAE are scarce. Our study demonstrated beneficial effects of theta-burst stimulation (TBS), an experimental paradigm of rTMS, on disease course of acute EAE. TBS treatment attenuated reactive gliosis, restored myelin sheet and down-regulated expression of vimentin in EAE rats. These effects were reflected through reduced clinical parameters, shorter duration of illness and days spent in paralysis. Based on our research, rTMS deserves further considerations for its neuroprotective effect on EAE, and is an excellent candidate for further research and points that it could be used for more than for simple symptomatic therapy.


Assuntos
Encefalomielite Autoimune Experimental/fisiopatologia , Encefalomielite Autoimune Experimental/terapia , Gliose/prevenção & controle , Gliose/fisiopatologia , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana/métodos , Animais , Feminino , Ratos , Substância Branca/fisiopatologia
16.
Neurol India ; 68(2): 270-273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32415002

RESUMO

The posterior quadratic epilepsy (PQE) is a form of a multilobar epilepsy, involving the temporal-parietal and occipital lobes. Basically, epilepsies with localized networks to the posterior temporal, posterior parietal, and occipital lobes can benefit from this type of surgery. Gliosis due to perinatal insult and cortical dysplasis and angiomas in Sturge Weber syndrome involving the PQ have often been cited in the literature as the etiology for PQE. However, before considering surgery, it is important to localize the epileptogenic focus through a complete pre operative work up involving; EEG (Electro-Encephalo-Graphy), video EEG, single photon emission computed tomography (SPECT), positron emission tomography (PET), and magneto encephalography (MEG). Historically, these pathologies were dealt with multi-lobar resections, which were associated with high morbidity and mortality, owing to blood loss, especially in young children, hydrocephalus, and hemosiderosis. Based on the theory of networks involved in epileptogenesis, the concept of disconnection in epilepsy surgery was introduced. Delalande and colleagues, described the technique of hemispheric disconnection (functional hemispherectomy) for pathologies like: hemimegalencephaly, rasmussens encephalitis involving the entire hemisphere. The technique has evolved with time, moving towards minimally invasive endoscopic vertical hemispherotomy, described by Chandra and colleagues.[1],[2] The posterior quadrant disconnection (PQD) evolved as a tailored disconnection on similar lines as hemispherotomy, for managing refractory epilepsy arising from the posterior quadrant.[3] The technique and principles involved in the PQD surgery are similar to the those of peri-insular hemispherotomy and has been described in the literature by few authors.[3],[4],[5],[6] The technique of performing PQD will be described here in a step-wise fashion with illustrations supplemented by a surgical video.


Assuntos
Epilepsia Resistente a Medicamentos/cirurgia , Gliose/cirurgia , Procedimentos Neurocirúrgicos/métodos , Lobo Occipital/cirurgia , Lobo Parietal/cirurgia , Lobo Temporal/cirurgia , Adolescente , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia , Feminino , Neuroimagem Funcional , Gliose/diagnóstico por imagem , Gliose/fisiopatologia , Humanos , Monitorização Neurofisiológica Intraoperatória , Imageamento por Ressonância Magnética , Neuronavegação , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/fisiopatologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiopatologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiopatologia
17.
Oxid Med Cell Longev ; 2020: 3050971, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32454936

RESUMO

Introduction: Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-ß (Aß) peptide and hyperphosphorylated tau protein. Accumulating evidence has revealed that the slow progressive deterioration of AD is associated with oxidative stress and chronic inflammation in the brain. Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2), which acts through the Nrf2/ARE pathway, is a key regulator of the antioxidant and anti-inflammatory response. Although recent data show a link between Nrf2 and AD-related cognitive decline, the mechanism is still unknown. Thus, we explored how Nrf2 protects brain cells against the oxidative stress and inflammation of AD in a mouse model of AD (APP/PS1 transgenic (AT) mice) with genetic removal of Nrf2. Methods: The spatial learning and memory abilities of 12-month-old transgenic mice were evaluated using a Morris water maze test. Hippocampal levels of Nrf2, Aß, and p-tauS404 and of astrocytes and microglia were determined by immunostaining. Inflammatory cytokines were determined by ELISA and quantitative real-time polymerase chain reaction (qRT-PCR). Oxidative stress was measured by 8-hydroxydeoxyguanosine immunohistochemistry, and the antioxidant response was determined by qRT-PCR. Results: The spatial learning and memory abilities of AT mice were impaired after Nrf2 deletion. Aß and p-tauS404 accumulation was increased in the hippocampus of AT/Nrf2-KO mice. Astroglial and microglial activation was exacerbated, followed by upregulation of the proinflammatory cytokines IL-1ß, IL-6, and TNF-α. Conclusion: Our present results show that Nrf2 deficiency aggravates AD-like pathology in AT mice. This phenotype was associated with increased levels of oxidative and proinflammatory markers, which suggests that the Nrf2 pathway may be a promising therapeutic target for AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Inflamação/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Presenilina-1/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Hipocampo/patologia , Memória , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/deficiência , Fosforilação , Aprendizagem Espacial , Proteínas tau/metabolismo
18.
Invest Ophthalmol Vis Sci ; 61(3): 47, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32232352

RESUMO

Purpose: To analyze the role of microglial and Müller cells in the formation of rings of photoreceptor degeneration caused by phototoxicity. Methods: Two-month-old Sprague-Dawley rats were exposed to light and processed 1, 2, or 3 months later. Retinas were dissected as whole-mounts, immunodetected for microglial cells, Müller cells, and S- and L/M-cones and analyzed using fluorescence, thunder imaging, and confocal microscopy. Cone populations were automatically counted and isodensity maps constructed to document cone topography. Results: Phototoxicity causes a significant progressive loss of S- and L/M-cones of up to 68% and 44%, respectively, at 3 months after light exposure (ALE). One month ALE, we observed rings of cone degeneration in the photosensitive area of the superior retina. Two and 3 months ALE, these rings had extended to the central and inferior retina. Within the rings of cone degeneration, there were degenerating cones, often activated microglial cells, and numerous radially oriented processes of Müller cells that showed increased expression of intermediate filaments. Between 1 and 3 months ALE, the rings coalesced, and at the same time the microglial cells resumed a mosaic-like distribution, and there was a decrease of Müller cell gliosis at the areas devoid of cones. Conclusions: Light-induced photoreceptor degeneration proceeds with rings of cone degeneration, as observed in inherited retinal degenerations in which cone death is secondary to rod degeneration. The spatiotemporal relationship of cone death microglial cell activation and Müller cell gliosis within the rings of cone degeneration suggests that, although both glial cells are involved in the formation of the rings, they may have coordinated actions and, while microglial cells may be more involved in photoreceptor phagocytosis, Müller cells may be more involved in cone and microglial cell migration, retinal remodeling and glial seal formation.


Assuntos
Células Ependimogliais/fisiologia , Luz/efeitos adversos , Microglia/fisiologia , Lesões Experimentais por Radiação/fisiopatologia , Retina/efeitos da radiação , Células Fotorreceptoras Retinianas Cones/patologia , Degeneração Retiniana/fisiopatologia , Animais , Opsinas dos Cones/metabolismo , Gliose/fisiopatologia , Microscopia Confocal , Microscopia de Fluorescência , Lesões Experimentais por Radiação/etiologia , Ratos , Ratos Sprague-Dawley , Células Fotorreceptoras Retinianas Cones/metabolismo , Degeneração Retiniana/etiologia
19.
Cells ; 9(4)2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244316

RESUMO

Enteric glial cells (EGCs) influence nitric oxide (NO)- and adenosine diphosphate (ADP)- mediated signaling in the enteric nervous system (ENS). Since Toll-like receptor 4 (TLR4) participates to EGC homoeostasis, this study aimed to evaluate the possible involvement of EGCs in the alterations of the inhibitory neurotransmission in TLR4-/- mice. Ileal segments from male TLR4-/- and wild-type (WT) C57BL/6J mice were incubated with the gliotoxin fluoroacetate (FA). Alterations in ENS morphology and neurochemical coding were investigated by immunohistochemistry whereas neuromuscular responses were determined by recording non-adrenergic non-cholinergic (NANC) relaxations in isometrically suspended isolated ileal preparations. TLR4-/- ileal segments showed increased iNOS immunoreactivity associated with enhanced NANC relaxation, mediated by iNOS-derived NO and sensitive to P2Y1 inhibition. Treatment with FA diminished iNOS immunoreactivity and partially abolished NO- and ADP- mediated relaxation in the TLR4-/- mouse ileum, with no changes of P2Y1 and connexin-43 immunofluorescence distribution in the ENS. After FA treatment, S100ß and GFAP immunoreactivity in TLR4-/- myenteric plexus was reduced to levels comparable to those observed in WT. Our findings show the involvement of EGCs in the alterations of ENS architecture and in the increased purinergic and nitrergic-mediated relaxation, determining gut dysmotility in TLR4-/- mice.


Assuntos
Sistema Nervoso Entérico/fisiopatologia , Intestino Delgado/fisiopatologia , Neuroglia/metabolismo , Junção Neuromuscular/fisiopatologia , Receptor 4 Toll-Like/deficiência , Animais , Sistema Nervoso Entérico/efeitos dos fármacos , Fluoracetatos/farmacologia , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Íleo/efeitos dos fármacos , Íleo/patologia , Íleo/fisiopatologia , Intestino Delgado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neuroglia/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Fenótipo , Receptores Purinérgicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
20.
J Neurotrauma ; 37(5): 681-691, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32031052

RESUMO

Reactive astrocytes have traditionally been viewed as a significant contributor to secondary neuronal damage and repair inhibition after central nervous system (CNS) injury attributed, in large part, to their roles in glial scarring. However, more recent transcriptional evidence has uncovered the vast diversity in reactive astrocyte identity and functions that comprises both neuroprotective and -toxic characteristics. Additionally, the capacity of reactive astrocytes to shift between these activation states demonstrates a high level of environment-dependent plasticity that drives the interplay between neuroprotection and -toxicity after CNS injury. These recent findings have spawned a new field of research that seeks to identify and categorize the function of these discrete subpopulations in the context of neurotrauma, as well as identify their regulators. Therefore, this review will discuss the major and most recent advances in this field of research, with a primary emphasis on neuroprotection. This review will also discuss the major pitfalls present in the field, with a particular focus on model species and their impact on the development of novel therapies.


Assuntos
Astrócitos/fisiologia , Lesões Encefálicas/fisiopatologia , Neuroproteção/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Gliose/fisiopatologia , Humanos
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