RESUMEN
Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20-100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-alpha/beta activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.
Asunto(s)
Adenosina/metabolismo , Hipocampo/metabolismo , Potenciación a Largo Plazo/fisiología , Aprendizaje por Laberinto/fisiología , Morfina/administración & dosificación , Receptor de Adenosina A1/metabolismo , Adenosina/toxicidad , Agonistas del Receptor de Adenosina A1 , Animales , Esquema de Medicación , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Morfina/toxicidad , Conducta Espacial/efectos de los fármacos , Conducta Espacial/fisiologíaRESUMEN
To further investigate pathogenesis and pathogenic process of type 2 diabetes mellitus (T2DM), we compared the urinary metabolic profiling of Zucker obese and Goto-kakizaki (GK) rats by NMR-based metabonomics. Principal component analysis (PCA) on urine samples of both models rats indicates markedly elevated levels of creatine/creatinine, dimethylamine, and acetoacetate, with concomitantly declined levels of citrate, 2-ketoglurarate, lactate, hippurate, and succinate compared with control rats, respectively. Simultaneously, compared with Zucker obese rats, the GK rats show decreased levels of trimethylamine, acetate, and choline, as well as increased levels of creatine/creatinine, acetoacetate, alanine, citrate, 2-ketoglutarate, succinate, lactate, and hippurate. This study demonstrates metabolic similarities between the two stages of T2DM, including reduced tricarboxylic acid (TCA) cycle and increased ketone bodies production. In addition, compared with Zucker obese rats, the GK rats have enhanced concentration of energy metabolites, which indicates energy metabolic changes produced in hyperglycemia stage more than in insulin resistance stage.
Asunto(s)
Biomarcadores/orina , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/orina , Modelos Animales de Enfermedad , Resistencia a la Insulina/fisiología , Metabolómica , Ácidos Acíclicos/orina , Animales , Creatina/orina , Diabetes Mellitus Tipo 2/genética , Dimetilaminas/orina , Hipuratos/orina , Hiperglucemia/fisiopatología , Hiperglucemia/orina , Cuerpos Cetónicos/biosíntesis , Cuerpos Cetónicos/orina , Espectroscopía de Resonancia Magnética , Masculino , Análisis Multivariante , Obesidad/metabolismo , Obesidad/fisiopatología , Ratas , Ratas Wistar , Ratas Zucker , Especificidad de la Especie , Taurina/orinaRESUMEN
Supratentorial focal ischemia may reduce cerebral blood volume and cerebellar glucose metabolic rate contralateral to the region of ischemia. The present study investigated the effects of middle cerebral artery occlusion (MCAO) on cerebral metabolism in the ischemic cerebral hemisphere and the nonischemic cerebellum in rats 1, 3, 9 and 24 h following ischemia using ex vivo proton nuclear magnetic resonance (1H NMR) spectroscopy. The results demonstrated that focal ischemia induced increases in the levels of lactate and alanine, and a decrease in succinate, as early as 1 h following ischemia in the left cerebral hemisphere and the right cerebellum. A continuous increase in lactate levels and decrease in creatine levels were detected in both cerebral areas 3 and 24 h postMCAO. The most obvious difference between the two cerebral areas was that there was no statistically significant difference in Nacetyl aspartate (NAA) levels in the right cerebellum at all time points; however, the amino acid levels of NAA in the left cerebral hemisphere were markedly decreased 3, 9 and 24 h postMCAO. In addition, an obvious increase in glutamine was observed in the right and left cerebellum at 3, 9 and 24 h postMCAO. Furthermore, the present study demonstrated that γaminobutyric acid levels were decreased at 1 h in the left and right cerebellum and were evidently increased at 24 h in the right cerebellum postMCAO. In conclusion, supratentorial ischemia has been indicated to affect the activities of the nonischemic contralateral cerebellum. Therefore, these results suggested that an NMRbased metabonomic approach may be used as a potential means to elucidate cerebral and cerebellar metabolism following MCAO, which may help improve understanding regarding cerebral infarction at a molecular level. Ex vivo 1H NMR analysis may be useful for the assessment of clinical biopsies.
Asunto(s)
Isquemia Encefálica/metabolismo , Cerebelo/metabolismo , Metabolismo Energético , Animales , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Cerebelo/patología , Infarto de la Arteria Cerebral Media , Masculino , Metabolómica/métodos , Espectroscopía de Protones por Resonancia Magnética , RatasRESUMEN
Phytoestrogen is the bioactive substance from plant, with structure is very simliar to that of estrogen. Phytoestrogen is mainly comprises of isoflavone, lignan and coumarin. Epidemiological restrarch shows that the increasing the uptake phytoestrogen of can reduce the morbidities of breast and other cancers. In this paper, the food source, characteristic and relevant researches both in vitro and in vivo were reviewed, and its mechanisms of intervening breast cancer were also discussed.
Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Fitoestrógenos/farmacología , Plantas Medicinales , Animales , Antioxidantes/farmacología , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Cumarinas/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , Femenino , Humanos , Isoflavonas/farmacología , Lignanos/farmacología , Fitoestrógenos/aislamiento & purificación , Plantas Medicinales/química , Proteínas Tirosina Quinasas/metabolismoRESUMEN
Increasing evidence has shown that the brain is a site of diabetic end-organ damage. This study investigates cerebral metabolism and the interactions between astrocytes and neurons at different stages of diabetes to identify the potential pathogenesis of diabetic encephalopathy. [1-(13)C]glucose or [2-(13)C]acetate is infused into 1- and 15-week diabetic rats, the brain extracts of which are analyzed by using (1)H and (13)C magnetic resonance spectroscopy. The (13)C-labeling pattern and enrichment of cerebral metabolites are also investigated. The increased (13)C incorporation in the glutamine, glutamate, and γ-aminobutyric acid carbons from [2-(13)C]acetate suggests that the astrocytic mitochondrial metabolism is enhanced in 1-week diabetic rats. By contrast, the decreased labeling from [1-(13)C]glucose reflected that the neuronal mitochondrial metabolism is impaired. As diabetes developed to 15 weeks, glutamine and glutamate concentrations significantly decreased. The increased labeling of glutamine C4 but unchanged labeling of glutamate C4 from [2-(13)C]acetate suggests decreased astrocyte supply to the neurons. In addition, the enhanced pyruvate recycling pathway manifested by the increased lactate C2 enrichment in 1-week diabetic rats is weakened in 15-week diabetic rats. Our study demonstrates the overall metabolism disturbances, changes in specific metabolic pathways, and interaction between astrocytes and neurons during the onset and development of diabetes. These results contribute to the mechanistic understanding of diabetes pathogenesis and evolution.
Asunto(s)
Acetatos/metabolismo , Astrocitos/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucosa/metabolismo , Imagen por Resonancia Magnética , Neuronas/metabolismo , Animales , Encéfalo/metabolismo , Isótopos de Carbono , Ácido Glutámico/metabolismo , Imagen por Resonancia Magnética/métodos , Masculino , Ratas Sprague-DawleyRESUMEN
The brain of a human neonate is more vulnerable to hypoglycemia than that of pediatric and adult patients. Repetitive and profound hypoglycemia during the neonatal period (RPHN) causes brain damage and leads to severe neurologic sequelae. Ex vivo high-resolution (1)H nuclear magnetic resonance (NMR) spectroscopy was carried out in the present study to detect metabolite alterations in newborn and adolescent rats and investigate the effects of RPHN on their occipital cortex and hippocampus. Results showed that RPHN induces significant changes in a number of cerebral metabolites, and such changes are region-specific. Among the 16 metabolites detected by ex vivo (1)H NMR, RPHN significantly increased the levels of creatine, glutamate, glutamine, γ-aminobutyric acid, and aspartate, as well as other metabolites, including succine, taurine, and myo-inositol, in the occipital cortex of neonatal rats compared with the control. By contrast, changes in these neurochemicals were not significant in the hippocampus of neonatal rats. When the rats had developed into adolescence, the changes above were maintained and the levels of other metabolites, including lactate, N-acetyl aspartate, alanine, choline, glycine, acetate, and ascorbate, increased in the occipital cortex. By contrast, most of these metabolites were reduced in the hippocampus. These metabolic changes suggest that complementary mechanisms exist between these two brain areas. RPHN appears to affect occipital cortex and hippocampal activities, neurotransmitter transition, energy metabolism, and other metabolic equilibria in newborn rats; these effects are further aggravated when the newborn rats develop into adolescence. Changes in the metabolism of neurotransmitter system may be an adaptive measure of the central nervous system in response to RPHN.
Asunto(s)
Hipocampo/metabolismo , Hipoglucemia/metabolismo , Hipoglucemia/patología , Espectroscopía de Resonancia Magnética , Lóbulo Occipital/metabolismo , Protones , Animales , Animales Recién Nacidos , Análisis Discriminante , Hipocampo/patología , Humanos , Análisis de los Mínimos Cuadrados , Metaboloma , Lóbulo Occipital/patología , Análisis de Componente Principal , Ratas , Ratas WistarRESUMEN
Dependence and impairment of learning and memory are two well-established features caused by abused drugs such as opioids. The hippocampus is an important region associated with both drug dependence and learning and memory. However, the molecular events in hippocampus following exposure to abused drugs such as opioids are not well understood. Here we examined the effect of chronic morphine treatment on hippocampal protein expression by proteomic analyses. We found that chronic exposure of mice to morphine for 10 days produced robust morphine withdrawal jumping and memory impairment, and also resulted in a significant downregulation of hippocampal protein levels of three metabolic enzymes, including Fe-S protein 1 of NADH dehydrogenase, dihydrolipoamide acetyltransferase or E2 component of the pyruvate dehydrogenase complex and lactate dehydrogenase 2. Further real-time quantitative PCR analyses confirmed that the levels of the corresponding mRNAs were also remarkably reduced. Consistent with these findings, lower ATP levels and an impaired ability to convert glucose into ATP were also observed in the hippocampus of chronically treated mice. Opioid antagonist naltrexone administrated concomitantly with morphine significantly suppressed morphine withdrawal jumping and reversed the downregulation of these proteins. Acute exposure to morphine also produced robust morphine withdrawal jumping and significant memory impairment, but failed to decrease the expression of these three proteins. Intrahippocampal injection of D-glucose before morphine administration significantly enhanced ATP levels and suppressed morphine withdrawal jumping and memory impairment in acute morphine-treated but not in chronic morphine-treated mice. Intraperitoneal injection of high dose of D-glucose shows a similar effect on morphine-induced withdrawal jumping as the central treatment. Taken together, our results suggest that reduced expression of the three metabolic enzymes in the hippocampus as a result of chronic morphine treatment contributes to the development of drug-induced symptoms such as morphine withdrawal jumping and memory impairment.