RESUMO
Alcohol addiction is a chronic neuropsychiatric disorder that represents one of the most serious global public health problems. Yet, currently there still lacks an effective pharmacotherapy. Omega-3 polyunsaturated fatty acids (N-3 PUFAs) have exhibited beneficial effects in a variety of neurological disorders, particularly in reversing behavioral deficits and neurotoxicity induced by prenatal alcohol exposure and binge drinking. In the present study, we investigated if fish oil, which is rich in N-3 PUFAs, had beneficial effects on preventing relapse and alleviating withdrawal symptoms after chronic alcohol exposure. Our results demonstrated that fish oil significantly reduced the chronic alcohol exposure-induced aberrant dendritic morphologic changes of the medium-sized spiny neurons in the core and the shell of nucleus accumbens. This inhibited the expression of AMPAR2-lacking AMPARs and their accumulation on the post synaptic membranes of medium-sized spiny neurons and eventually alleviated withdrawal symptoms and alcohol dependence. Our study therefore suggests that N-3 PUFAs are promising for treating withdrawal symptoms and alcohol dependence.
Assuntos
Alcoolismo/patologia , Depressores do Sistema Nervoso Central/farmacologia , Dendritos/efeitos dos fármacos , Etanol/farmacologia , Óleos de Peixe/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Convulsões por Abstinência de Álcool , Animais , Dendritos/patologia , Locomoção/efeitos dos fármacos , Camundongos , Núcleo Accumbens/citologia , Núcleo Accumbens/patologia , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Recidiva , Sinapses/patologiaRESUMO
Cerebral microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the "single cortical microinfarct model" generated via occluding a penetrating arteriole by femtosecond laser ablation and the "multiple diffuse microinfarcts model" induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the microinfarct size. The protective effects of ω-3 PUFAs against microinfarcts were further verified in a multiple diffuse microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia.
Assuntos
Doença de Alzheimer/dietoterapia , Infarto Cerebral/dietoterapia , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Caderinas/genética , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Infarto Cerebral/genética , Infarto Cerebral/metabolismo , Infarto Cerebral/patologia , Modelos Animais de Doenças , Óleos de Peixe/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/administração & dosagem , Proteína Serina-Treonina Quinases de Interação com Receptores/genéticaRESUMO
Currently no effective therapies are available for the treatment of traumatic brain injury (TBI). Early intervention that specifically provides neuroprotection is of most importance which profoundly influences the outcome of TBI. In the present study, we adopted a closed-skull mild TBI model to investigate potential roles of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in protecting against TBI. Using two-photon laser scanning microscopy (2PLSM), parenchymal cell death and reactive oxidative species (ROS) expression were directly observed and recorded after TBI through a thinned skull bone window. Fat-1 mice with high endogenous ω-3 PUFAs significantly inhibited ROS expression and attenuated parenchymal cell death after compression injury during the early injury phase. Elevated generation of glutathione (GSH) and neuroprotectin D1 (NPD1) in the parenchyma of fat-1 mice could be the contributor to the beneficial role of ω-3 PUFAs in TBI. The results of the study suggest that ω-3 PUFAs is an effective neuroprotectant as an early pharmacological intervention for TBI and the information derived from this study may help guide dietary advice for those who are susceptible to repetitive mild TBI.
Assuntos
Lesões Encefálicas Traumáticas/patologia , Encéfalo/patologia , Ácidos Graxos Ômega-3/metabolismo , Animais , Caderinas/metabolismo , Morte Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/metabolismo , Glutationa/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential in a variety of neurological disorders, including ischemic stroke. However, the underlying mechanisms still lack investigation. Here, we report that cultured cortical neurons isolated from fat-1 mice with high endogenous n-3 PUFAs were tolerant to oxygen-glucose deprivation/reperfusion (OGD/R) injury. Fat-1 neurons exhibited significantly attenuated reactive oxygen species (ROS) activation induced by OGD/R injury, upregulated antiapoptotic proteins Bcl-2 and Bcl-xL, and reduced cleaved caspase-3. Exogenous administration of docosahexaenoic acid (DHA), a major component of the n-3 PUFA family, resulted in similar protective effects on cultured cortex neurons. We further verified the protective effects of n-3 PUFAs in vivo, using a mini ischemic model with a reproducible cortical infarct and manifest function deficits by occlusion of the distal branch of the middle cerebral artery with focused femtosecond laser pulses. The Fat-1 animals showed decreased ROS expression and higher level of glutathione in the injured brain, associated with improved functional recovery. We therefore provide evidence that n-3 PUFAs exert their protective effects against ischemic injury both in vitro and in vivo, partly through inhibiting ROS activation.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Córtex Cerebral/patologia , Ácidos Graxos Ômega-3/uso terapêutico , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Isquemia Encefálica/fisiopatologia , Caderinas/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Graxos Ômega-3/farmacologia , Feminino , Glucose/deficiência , Glutationa/metabolismo , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Regulação para Cima/efeitos dos fármacosRESUMO
Transient global cerebral ischemia, one of the consequences of cardiac arrest and cardiovascular surgery, usually leads to delayed death of hippocampal cornu Ammonis1 (CA1) neurons and cognitive deficits. Currently, there are no effective preventions or treatments for this condition. Omega-3 (ω-3) PUFAs have been shown to have therapeutic potential in a variety of neurological disorders. Here, we report that the transgenic mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs, were protected from global cerebral ischemia injury. The results of the study show that the hippocampal CA1 neuronal loss and cognitive deficits induced by global ischemia insult were significantly less severe in fat-1 mice than in WT mice controls. The protection against global cerebral ischemia injury was closely correlated with increased production of resolvin D1, suppressed nuclear factor-kappa B activation, and reduced generation of pro-inflammatory mediators in the hippocampus of fat-1 mice compared with WT mice controls. Our study demonstrates that fat-1 mice with high endogenous ω-3 PUFAs exhibit protective effects on hippocampal CA1 neurons and cognitive functions in a global ischemia injury model.
Assuntos
Isquemia Encefálica/prevenção & controle , Região CA1 Hipocampal/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Neurônios/metabolismo , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Região CA1 Hipocampal/patologia , Caderinas/genética , Caderinas/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/prevenção & controle , Camundongos , Camundongos Mutantes , Neurônios/patologiaRESUMO
OBJECTIVE: To explore the effect of crystal water on deteriming content of baicalin. METHODS: Baicalin samples containing different amount of crystal water were determined by HPLC. RESULTS: The determining results of baicalin were accurate and stable on condition that the samples contain some crystal water or some impurities, and the determining results of baicalin were reduced remarkably on condition that the samples are anhydrous and pure. CONCLUSION: The determining results of baicalin contents were accurate and stable only if the oxygen in 1 place forms hydrogen bond, and the determining results of baicalin contents were reduced remarkably on condition that the oxygen in 1 place forms protonated ether of form positive carbonic.