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1.
J Cereb Blood Flow Metab ; 42(8): 1507-1523, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35048735

RESUMO

Anaplerosis occurs predominately in astroglia through the action of pyruvate carboxylase (PC). The rate of PC (Vpc) has been reported for cerebral cortex (or whole brain) of awake humans and anesthetized rodents, but regional brain rates remain largely unknown and, hence, were subjected to investigation in the current study. Awake male rats were infused with either [2-13C]glucose or [1-13C]glucose (n = 27/30) for 8, 15, 30, 60 or 120 min, followed by rapid euthanasia with focused-beam microwave irradiation to the brain. Blood plasma and extracts of cerebellum, hippocampus, striatum, and cerebral cortex were analyzed by 1H-[13C]-NMR to establish 13C-enrichment time courses for glutamate-C4,C3,C2, glutamine-C4,C3, GABA-C2,C3,C4 and aspartate-C2,C3. Metabolic rates were determined by fitting a three-compartment metabolic model (glutamatergic and GABAergic neurons and astroglia) to the eighteen time courses. Vpc varied by 44% across brain regions, being lowest in the cerebellum (0.087 ± 0.004 µmol/g/min) and highest in striatum (0.125 ± 0.009) with intermediate values in cerebral cortex (0.106 ± 0.005) and hippocampus (0.114 ± 0.005). Vpc constituted 13-19% of the oxidative glucose consumption rate. Combination of cerebral cortical data with literature values revealed a positive correlation between Vpc and the rates of glutamate/glutamine-cycling and oxidative glucose consumption, respectively, consistent with earlier observations.


Assuntos
Ácido Glutâmico , Piruvato Carboxilase , Animais , Encéfalo/metabolismo , Isótopos de Carbono/metabolismo , Glucose/metabolismo , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Masculino , Neurônios/metabolismo , Neurotransmissores/metabolismo , Piruvato Carboxilase/metabolismo , Ratos , Vigília , Ácido gama-Aminobutírico/metabolismo
2.
Curr Pharm Biotechnol ; 21(15): 1632-1644, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32718284

RESUMO

BACKGROUND: Chiral safety, especially chiral drug inversion in vivo, is the top priority of current scientific research. Medicine researchers and pharmacists often ignore that one enantiomer will be converted or partially converted to another enantiomer when it is ingested in vivo. So that, in the context that more than 50% of the listed drugs are chiral drugs, it is necessary and important to pay attention to the inversion of chiral drugs. METHODS: The metabolic and stereoselective pharmacokinetic characteristics of seven chiral drugs with one chiral center in the hydroxy group were reviewed in vivo and in vitro including the possible chiral inversion of each drug enantiomer. These seven drugs include (S)-Mandelic acid, RS-8359, Tramadol, Venlafaxine, Carvedilol, Fluoxetine and Metoprolol. RESULTS: The differences in stereoselective pharmacokinetics could be found for all the seven chiral drugs, since R and S isomers often exhibit different PK and PD properties. However, not every drug has shown the properties of one direction or two direction chiral inversion. For chiral hydroxyl group drugs, the redox enzyme system may be one of the key factors for chiral inversion in vivo. CONCLUSION: In vitro and in vivo chiral inversion is a very complex problem and may occur during every process of ADME. Nowadays, research on chiral metabolism in the liver has the most attention, while neglecting the chiral transformation of other processes. Our review may provide the basis for the drug R&D and the safety of drugs in clinical therapy.


Assuntos
Ácidos Mandélicos/farmacocinética , Nitrilas/farmacocinética , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Pirimidinas/farmacocinética , Álcool Desidrogenase/metabolismo , Animais , Humanos , Fígado/enzimologia , Ácidos Mandélicos/química , Estrutura Molecular , Nitrilas/química , Pirimidinas/química , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-Atividade
3.
J Neurochem ; 127(3): 353-64, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24033360

RESUMO

Most ingested ethanol is metabolized in the liver to acetaldehyde and then to acetate, which can be oxidized by the brain. This project assessed whether chronic exposure to alcohol can increase cerebral oxidation of acetate. Through metabolism, acetate may contribute to long-term adaptation to drinking. Two groups of adult male Sprague-Dawley rats were studied, one treated with ethanol vapor and the other given room air. After 3 weeks the rats received an intravenous infusion of [2-(13) C]ethanol via a lateral tail vein for 2 h. As the liver converts ethanol to [2-(13) C]acetate, some of the acetate enters the brain. Through oxidation the (13) C is incorporated into the metabolic intermediate α-ketoglutarate, which is converted to glutamate (Glu), glutamine (Gln), and GABA. These were observed by magnetic resonance spectroscopy and found to be (13) C-labeled primarily through the consumption of ethanol-derived acetate. Brain Gln, Glu, and, GABA (13) C enrichments, normalized to (13) C-acetate enrichments in the plasma, were higher in the chronically treated rats than in the ethanol-naïve rats, suggesting increased cerebral uptake and oxidation of circulating acetate. Chronic ethanol exposure increased incorporation of systemically derived acetate into brain Gln, Glu, and GABA, key neurochemicals linked to brain energy metabolism and neurotransmission. The liver converts ethanol to acetate, which may contribute to long-term adaptation to drinking. Astroglia oxidize acetate and generate neurochemicals, while neurons and glia may also oxidize ethanol. When (13) C-ethanol is administered intravenously, (13) C-glutamine, glutamate, and GABA, normalized to (13) C-acetate, were higher in chronic ethanol-exposed rats than in control rats, suggesting that ethanol exposure increases cerebral oxidation of circulating acetate.


Assuntos
Química Encefálica/fisiologia , Depressores do Sistema Nervoso Central/farmacocinética , Etanol/farmacocinética , Ácido 3-Hidroxibutírico/metabolismo , Acetatos/metabolismo , Administração por Inalação , Animais , Biotransformação , Depressores do Sistema Nervoso Central/administração & dosagem , Ingestão de Energia , Etanol/administração & dosagem , Glucose/metabolismo , Ácido Láctico/metabolismo , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Micro-Ondas , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Fixação de Tecidos
4.
Proc Natl Acad Sci U S A ; 110(35): 14444-9, 2013 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-23940368

RESUMO

It has been reported that chronic and acute alcohol exposure decreases cerebral glucose metabolism and increases acetate oxidation. However, it remains unknown how much ethanol the living brain can oxidize directly and whether such a process would be affected by alcohol exposure. The questions have implications for reward, oxidative damage, and long-term adaptation to drinking. One group of adult male Sprague-Dawley rats was treated with ethanol vapor and the other given room air. After 3 wk the rats received i.v. [2-(13)C]ethanol and [1, 2-(13)C2]acetate for 2 h, and then the brain was fixed, removed, and divided into neocortex and subcortical tissues for measurement of (13)C isotopic labeling of glutamate and glutamine by magnetic resonance spectroscopy. Ethanol oxidation was seen to occur both in the cortex and the subcortex. In ethanol-naïve rats, cortical oxidation of ethanol occurred at rates of 0.017 ± 0.002 µmol/min/g in astroglia and 0.014 ± 0.003 µmol/min/g in neurons, and chronic alcohol exposure increased the astroglial ethanol oxidation to 0.028 ± 0.002 µmol/min/g (P = 0.001) with an insignificant effect on neuronal ethanol oxidation. Compared with published rates of overall oxidative metabolism in astroglia and neurons, ethanol provided 12.3 ± 1.4% of cortical astroglial oxidation in ethanol-naïve rats and 20.2 ± 1.5% in ethanol-treated rats. For cortical astroglia and neurons combined, the ethanol oxidation for naïve and treated rats was 3.2 ± 0.3% and 3.8 ± 0.2% of total oxidation, respectively. (13)C labeling from subcortical oxidation of ethanol was similar to that seen in cortex but was not affected by chronic ethanol exposure.


Assuntos
Encéfalo/metabolismo , Etanol/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Animais , Ácido Glutâmico/metabolismo , Glicina/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley
5.
J Neurochem ; 113(6): 1447-58, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20345764

RESUMO

As one of the most widespread drugs of abuse, nicotine has long been known to impact the brain, particularly with respect to addiction. However, the regional effects of nicotine on the concentrations and kinetics of amino acid neurotransmitters and some energetically related neurochemicals have been little studied. In this investigation, acute effects of nicotine were measured by (1)H-observed/(13)C-edited nuclear magnetic resonance spectroscopy method in extracts obtained from nicotine-naïve, freely moving rats given 0.7 mg/kg nicotine or saline, with [1-(13)C] glucose to track metabolism. Nicotine was observed to exert significant effects on the concentrations of N-acetylaspartate and GABA, particularly in the striatum. Nicotine decreased brain glucose oxidation, glutamate-glutamine neurotransmitter cycling, and GABA synthesis regionally, including in the parietal and occipital cortices and the striatum. The olfactory bulb showed kinetics that differed markedly from those observed in the rest of the brain. Independently of nicotine, the concentration of glutamate was found to be correlated significantly with levels of N-acetylaspartate and GABA, suggesting a potential interplay of energetics and excitatory and inhibitory neurotransmission. In summary, the study revealed that the neurochemicals were most affected in the cortex and striatum of the rat brain after acute nicotine treatment.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Vigília , Aminoácidos/metabolismo , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/citologia , Isótopos/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Masculino , Modelos Biológicos , Plasma/efeitos dos fármacos , Plasma/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
6.
NMR Biomed ; 20(3): 375-82, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17451176

RESUMO

Heterogeneous spatiotemporal patterns of C57B/L6 murine brain maturation during the first 7 weeks after birth (i.e. P15 to P45) were assessed in vivo by diffusion tensor imaging (DTI) at 9.4 T. Maps of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were used to assess developmental changes. Because directionally encoded color (DEC) maps provide an efficient and straightforward way to visualize anisotropy direction, they were used to highlight the orientation-dominant anisotropic tissues. In the corpus callosum, the increases in FA (approximately 0.4 to approximately 0.6 from P15 to P45) were primarily dominant in the medial-lateral direction, whereas the ADC decreased slightly (approximately 0.8 x 10(-3) to approximately 0.5 x 10(-3) mm(2)/s from P15 to P45). Similar increases in FA (approximately 0.3 to approximately 0.4 from P15 to P45) and decreases in ADC (approximately 0.8 x 10(-3) to approximately 0.5 x 10(-3) mm(2)/s from P15 to P45) were found in the cingulate, but these anisotropic changes were dominant in the anterior-posterior direction. In the caudate putamen, there were significant FA increases (approximately 0.1 to approximately 0.2 from P15 to P45) dominant in the dorsal-ventral and anterior-posterior directions, whereas the ADC increased rapidly early in development (approximately 0.3 x 10(-3) to approximately 0.7 x 10(-3) mm(2)/s from P15 to P17). There were no significant changes in tissue anisotropy in the somatosensory regions (whisker, forelimb), but the ADC decreased slightly (approximately 0.7 x 10(-3) to approximately 0.5 x 10(-3) mm(2)/s from P15 to P45). Although the major differences in DEC values were mainly observed in white matter pathways, other cortical and subcortical regions showed some potential morphological changes that were consistent with classical histological findings. In summary, these results show that high-resolution DTI at high magnetic fields allows detection and quantification of brain structures throughout normal development in C57B/L6 mice in vivo.


Assuntos
Encéfalo/crescimento & desenvolvimento , Imageamento por Ressonância Magnética/métodos , Animais , Anisotropia , Mapeamento Encefálico , Núcleo Caudado/crescimento & desenvolvimento , Corpo Caloso/crescimento & desenvolvimento , Difusão , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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