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1.
J Integr Neurosci ; 16(4): 385-400, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28891528

RESUMO

Alzheimer's Disease (AD) is one of the commonest neural degeneration in aging population, and has become a global health challenge. 2-(2-benzofuranyl)-2-imidazoline (2-BFI) was reported to effectively improved the damage of patients with neuropathological disorders. In the present study, we investigated the effect of 2-BFI on the improvement of antioxidative, inflammation, and apoptosis in AD rats. Sprague-Dawley rats (2 months old, n=40) were used in this study and after injection of Aß1-42 into hippocampal CA1 (Cornu Ammonis) region, the rats were given high, moderate and low dose of 2-BFI though intraperitoneal (i.p.) injection. Then spatial memory and navigation ability were analyzed by Morrize Water Maze. For the molecular testing, chemical colorimetry, ELISA and immunoblotting were performed to measure the activities of antioxidative enzymes, the abundance of immune cytokines and expression of apoptotic proteins, respectively. Hematoxylin and Eosin staining was used to analyze the pathological changes. We observed that 2-BFI significantly ameliorated the learning and memory abilities in rat models with AD by dosage treatment, as demonstrated by the shorten learning latency and greater times of travel across the platform quadrant. Additionally, reactive oxygen species (ROS) and malondialdehyde (MDA), were decreased after treatment of 2-BFI with dosage dependency, while the activities of superoxidase dismutase (SOD) and (GPX) Glutathione peroxidase were in turn enhanced, suggesting that 2-BFI could protect the antioxidative enzymes and reduce the oxidative stress in the hippocampus. Moreover, the expression of inflammatory factors including TNF-a and IL-1ß were decreased after 2-BFI treatment. Additionally, the neuronal apoptosis was also attenuated, as shown by Western blot results. Taken together, the cognitive impairment in AD rats could be significantly improved by 2-BFI in a dose-dependent manner through suppressing oxidants accumulation, inhibiting of inflammatory response, as well as enhancing the neural viability.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Imidazóis/farmacologia , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/patologia , Inflamação/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Nootrópicos/farmacologia , Estresse Oxidativo/fisiologia , Fragmentos de Peptídeos , Distribuição Aleatória , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Navegação Espacial/efeitos dos fármacos , Navegação Espacial/fisiologia
2.
Brain Res ; 1361: 86-92, 2010 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-20840843

RESUMO

Stroke is the third leading cause of death and disability in North America and is becoming the most frequent cause of death in the rapid developing China. Protecting neurons in order to minimize brain damage represents an effective approach towards stroke therapeutics. Our recent study demonstrated that 2-(-2-benzofuranyl)-2-imidazoline (2-BFI), a ligand for imidazoline I(2) receptors, is potently neuroprotective against stroke, possibly through transiently antagonizing NMDA receptor activities. In this study, we further investigated the characteristics and mechanisms of 2-BFI-mediated neuroprotection using a rat stroke model of transient occlusion of the middle cerebral artery. Here, we show that 2-BFI was most effective at the dose of 3mg/kg in vivo, with significantly reduced brain infarct size and improved neurological deficits. Lower doses of 2-BFI at 1.5mg/kg, or higher dose of 2-BFI at 6 mg/kg, were either not effective, or toxic to the brain, respectively. Treating stroke rats with 3mg/kg 2-BFI significantly reduced the number of TUNEL positive cells and preserved the integrity of subcellular structures such as nuclear membranes and mitochondria as shown under the electron microscope, confirming neuroprotection. Most interestingly, 2-BFI-treated brains exhibited significant expression of Bcl-2, a gene with a known function in neuroprotection. Taken together, these studies not only demonstrated that 2-BFI at 3mg/kg was effective in neuroprotection, but also, for the first time, showed that 2-BFI provided neuroprotection through up-regulating the neuroprotective gene Bcl-2. 2-BFI can be further developed as a therapeutic drug for stroke treatment.


Assuntos
Benzofuranos/farmacologia , Encéfalo/metabolismo , Imidazóis/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Ataque Isquêmico Transitório/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Benzofuranos/administração & dosagem , Benzofuranos/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/ultraestrutura , Morte Celular/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Receptores de Imidazolinas/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Microscopia Eletrônica , Atividade Motora/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Caminhada
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