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1.
Neuroscience ; 431: 103-114, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068082

RESUMO

Focal cerebral infarction leads to autophagic activation, which contributes to secondary neuronal damage in the ipsilateral thalamus. Although Nogo-A deactivation enhances neuronal plasticity, its role in autophagic activation in the thalamus after ischemic stroke remains unclear. This study aimed to investigate the potential roles of Nogo-A/Nogo-66 receptor 1 (NgR1) in autophagic activation in the ipsilateral thalamus after cerebral infarction. Focal neocortical infarction was established using the middle cerebral artery occlusion (MCAO) method. Secondary damage in the ipsilateral thalamus was assessed by Nissl staining and immunostaining. The expression of Nogo-A, NgR1, Rho-A and Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as well as autophagic flux were evaluated by immunofluorescence and immunoblotting. The roles of Nogo-A-NgR1 signaling in autophagic activation were determined by intraventricular delivery of an NgR1 antagonist peptide, NEP1-40, at 24 h after MCAO. The results showed that Nogo-A and NgR1 overexpression temporally coincided with marked increases in the levels of Beclin1, LC3-II and sequestosome 1 (SQSTM1)/p62 in the ipsilateral thalamus at seven and fourteen days after MCAO. In contrast, NEP1-40 treatment significantly reduced the expression of Rho-A and ROCK1 which was accompanied by marked reductions of LC3-II conversion as well as the levels of Beclin1 and SQSTM1/p62. Furthermore, NEP1-40 treatment significantly reduced neuronal loss and gliosis in the ipsilateral thalamus, and accelerated somatosensory recovery at the observed time-points after MCAO. These results suggest that blockade of Nogo-A-NgR1 signaling inhibits autophagic activation, attenuates secondary neuronal damage in the ipsilateral thalamus, and promotes functional recovery after focal cerebral cortical infarction.


Assuntos
Neurônios , Tálamo , Animais , Infarto da Artéria Cerebral Média/tratamento farmacológico , Proteínas Nogo , Receptor Nogo 1 , Ratos , Ratos Sprague-Dawley
2.
Brain Pathol ; 30(1): 165-178, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278793

RESUMO

Conflicting evidence exists regarding whether focal cerebral infarction contributes to cerebral amyloid-ß (Aß) deposition, as observed in Alzheimer's disease. In this study, we aimed to evaluate the presence of Aß deposits in the ipsilateral thalamus and hippocampus 12 months post-stroke in non-human primates, whose brains are structurally and functionally similar to that of humans. Four young male cynomolgus monkeys were subjected to unilateral permanent middle cerebral artery occlusion (MCAO), and another four sham-operated monkeys served as controls. All monkeys underwent magnetic resonance imaging examination on post-operative day 7 to assess the location and size of the infarction. The numbers of neurons, astrocytes, microglia and the Aß load in the non-affected thalamus and hippocampus ipsilaterally remote from infarct foci were examined immunohistochemically at sacrifice 12 months after operation. Thioflavin S and Congo Red stainings were used to identify amyloid deposits. Multiple Aß antibodies recognizing both the N-terminal and C-terminal epitopes of Aß peptides were used to avoid antibody cross-reactivity. Aß levels in cerebrospinal fluid (CSF) and plasma were examined using enzyme-linked immunosorbent assay. The initial infarct was restricted to the left temporal, parietal, insular cortex and the subcortical white matter, while the thalamus and hippocampus remained intact. Of note, there were fewer neurons and more glia in the ipsilateral thalamus and hippocampus in the MCAO group at 12 months post-stroke compared to the control group (all P < 0.05). However, there was no sign of extracellular Aß plaques in the thalamus or hippocampus. No statistically significant difference was found in CSF or plasma levels of Aß40 , Aß42 or the Aß40 /Aß42 ratio between the two groups (P > 0.05). These results suggest that significant secondary neuronal loss and reactive gliosis occur in the non-affected thalamus and hippocampus without Aß deposits in the late period after MCAO in non-human primates.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , Placa Amiloide/patologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/fisiologia , Animais , Isquemia Encefálica/patologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Hipocampo/patologia , Infarto da Artéria Cerebral Média/patologia , Macaca fascicularis , Masculino , Neuroglia/patologia , Lobo Temporal/metabolismo , Tálamo/patologia
3.
Stroke ; 48(12): 3366-3374, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29146879

RESUMO

BACKGROUND AND PURPOSE: Focal cortical infarction causes neuronal apoptosis in the ipsilateral nonischemic thalamus and hippocampus, which is potentially associated with poststroke cognitive deficits. TSPO (translocator protein) is critical in regulating mitochondrial apoptosis pathways. We examined the effects of the novel TSPO ligand 2-(2-chlorophenyl) quinazolin-4-yl dimethylcarbamate (2-Cl-MGV-1) on poststroke cognitive deficits, neuronal mitochondrial apoptosis, and secondary damage in the ipsilateral thalamus and hippocampus after cortical infarction. METHODS: One hundred fourteen hypertensive rats underwent successful distal middle cerebral artery occlusion (n=76) or sham procedures (n=38). 2-Cl-MGV-1 or dimethyl sulfoxide as vehicle was administrated 2 hours after distal middle cerebral artery occlusion and then for 6 or 13 days (n=19 per group). Spatial learning and memory were tested using the Morris water maze. Secondary degeneration and mitochondrial apoptosis in the thalamus and hippocampus were assessed using Nissl staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling, JC-1 staining, and immunoblotting 7 and 14 days after surgery. RESULTS: Infarct volumes did not significantly differ between the vehicle and 2-Cl-MGV-1 groups. There were more neurons and fewer glia in the ipsilateral thalamus and hippocampus in the vehicle groups than in the sham-operated group 7 and 14 days post-distal middle cerebral artery occlusion. 2-Cl-MGV-1 significantly ameliorated spatial cognitive impairment and decreased neuronal death and glial activation when compared with vehicle treatment (P<0.05). The collapse of mitochondrial transmembrane potential and cytoplasmic release of apoptosis-inducing factors and cytochrome c was prevented within the thalamus. Caspase cleavage and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling+ or Nissl atrophic cells were reduced within the thalamus and hippocampus. This was accompanied by upregulation of B-cell lymphoma 2 and downregulation of Bax (P<0.05). CONCLUSIONS: 2-Cl-MGV-1 reduces neuronal apoptosis via mitochondrial-dependent pathways and attenuates secondary damage in the nonischemic thalamus and hippocampus, potentially contributing to ameliorated cognitive deficits after cortical infarction.


Assuntos
Apoptose/efeitos dos fármacos , Carbamatos/uso terapêutico , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/psicologia , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/psicologia , Hipocampo/patologia , Fármacos Neuroprotetores/uso terapêutico , Quinazolinas/uso terapêutico , Tálamo/patologia , Animais , Infarto Cerebral/patologia , Disfunção Cognitiva/etiologia , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Memória/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neurônios/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Receptores de GABA/biossíntese , Receptores de GABA/genética , Tálamo/efeitos dos fármacos
4.
Clin Exp Pharmacol Physiol ; 43(12): 1216-1224, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27558464

RESUMO

Focal cerebral cortical infarction causes secondary neurodegeneration in the remote regions, such as the ventroposterior nucleus of the thalamus. Retrograde degeneration of thalamocortical fibers is considered as the principle mechanism, but the exact molecular events remain to be elucidated. This study aimed to investigate whether unfolded protein response (UPR) is activated in thalamic neurons following distal middle cerebral artery occlusion (MCAO) in stroke-prone renovascular hypertensive rats. Immunostaining and immunoblotting were performed to evaluate the expression of Grp78 and its downstream effectors in the thalamus at 3, 7 and 14 days after MCAO. Secondary thalamic degeneration was assessed with Nissl staining and NeuN immunostaining. Neuronal death was not apparent at 3 days post-ischaemia but was evident in the thalamus at 7 and 14 days after MCAO. Grp78 level was reduced in the ipsilateral thalamus at 3 and 7 days after MCAO. In parallel, phosphorylated eIF2α and ATF4 levels were elevated, indicating the activation of UPR. In contrast, ATF6α and CHOP levels were not changed. These results suggest that UPR is activated before neuronal death in the ipsilateral thalamus after MCAO and may represent a key early event in the secondary thalamic degeneration.


Assuntos
Infarto Cerebral/metabolismo , Hipertensão/metabolismo , Tálamo/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Animais , Infarto Cerebral/patologia , Hipertensão/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Tálamo/patologia
5.
Med Oncol ; 26(2): 157-60, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18846437

RESUMO

Platinum-based chemotherapy regimens are often recommended for patients with unresectable thymic carcinoma. In more than 60 cases, however, the systemic chemotherapy provides little benefit. In this report, we described a case of advanced KIT- and VEGF-positive thymic carcinoma with liver and lung metastasis. The patient, a 46-year-old man, exhibited a resistance to cisplatin-based chemotherapy, but responded to the treatment with sorafenib, a molecular target-based therapy. After 4 months of sorafenib therapy, his lung and liver metastases as well as the mediastinal tumor shrank dramatically. Moreover, the tumors showed stable disease for at least 9 months. To the best of our knowledge, it is the first report about a response of advanced thymic carcinoma to sorafenib. The preliminary study suggested that molecular target-based therapy could be an alternative treatment to those chemotherapy-refractory patients.


Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma/tratamento farmacológico , Cisplatino/uso terapêutico , Piridinas/uso terapêutico , Neoplasias do Timo/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/diagnóstico por imagem , Carcinoma/patologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Sorafenibe , Neoplasias do Timo/diagnóstico por imagem , Neoplasias do Timo/patologia , Tomografia Computadorizada por Raios X
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