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Metabolismo do sistema nervoso Profº Alex Barbosa dos Santos Tipos celulares do sistema nervoso Composição celular do SNC: 90% - células gliais Macroglia (astrócitos e oligodendrócitos) Microglia – 20% das células gliais Neurônios e células ependimárias Células do tecido nervoso central. (Fonte: ttp://www.rienstraclinic.com/newsletter/2006/images/jul_image001.png). Tipos celulares do sistema nervoso Transporte através da BHE http://www.nature.com/nrn/journal/v7/n1/fig_tab/nrn1824_F3.html A schematic diagram of the endothelial cells that form the blood–brain barrier (BBB) and their associations with the perivascular endfeet of astrocytes. The main routes for molecular traffic across the BBB are shown. a | Normally, the tight junctions severely restrict penetration of water-soluble compounds, including polar drugs. b | However, the large surface area of the lipid membranes of the endothelium offers an effective diffusive route for lipid-soluble agents. c | The endothelium contains transport proteins (carriers) for glucose, amino acids, purine bases, nucleosides, choline and other substances. Some transporters are energy-dependent (for example, P-glycoprotein) and act as efflux transporters. AZT, azidothymidine. d | Certain proteins, such as insulin and transferrin, are taken up by specific receptor-mediated endocytosis and transcytosis. e | Native plasma proteins such as albumin are poorly transported, but cationization can increase their uptake by adsorptive-mediated endocytosis and transcytosis. Drug delivery across the brain endothelium depends on making use of pathwaysb–e; most CNS drugs enter via route b. Modified, with permission, from Ref. 8 © (1996) Elsevier Science. 4 Ausência de GLUT 1 na BHE Síndrome de De Vivo – falta de substrato energético decorrente da metabolização da glicose no SNC. Sinais clínicos: retardo no desenvolvimento e complicações motora complexa. Tratamento: introdução de dieta cetogênica. Por quê? Síntese de corpos cetônicos (acetoacetato, β- hidroxibutirato) que são facilmente transportados para o SNC. Transporte através da BHE http://www.funpecrp.com.br/gmr/year2006/vol1-5/gmr0182_full_text.htm Transporte através da BHE LARGE NEUTRAL AMINO ACID SUPPLEMENTATION Phe, as well as other large neutral amino acids (LNAAs: asparagine, cysteine, glutamine, histidine, isoleucine, leucine, methionine, serine, threonine, tyrosine, tryptophan, and valine), are transported across the blood-brain barrier by means of L-type amino acid carrier. High Phe levels, such as those usually seen in PKU patients, reduce the brain uptake of other LNAAs (Figure 1; Pietz et al., 1999; Koch et al., 2003; Kanai and Endou, 2003). Some LNAAs such as tyrosine and tryptophan are precursors of neurotransmitters, and it has been suggested that impaired neurotransmitter synthesis would be an additional factor contributing to the cognitive dysfunction observed in PKU (Pietz et al., 1999; Surtees and Blau, 2000; Weglage et al., 2002; Koch et al., 2003; Matalon et al., 2003). 6 Categorias estruturais dos neurotransmissores Neurotransmissores contendo nitrogênio glutamato, ácido -aminobutiríco (GABA), glicina, acetilcolina, dopamina, noradrenalina, adrenalina, serotonina, histamina, aspartato e NO. Neuropeptídeos Ex: endorfinas, GH, TSH, insulina, glucagon etc. Características gerais dos neurotransmissores A síntese ocorre no neurônio Deve existir no corpúsculo nervoso terminal pré-sináptico A sua libertação na fenda sináptica provoca uma alteração do potencial pós-sináptico Quando administrado a sua ação deve produzir os mesmos efeitos Deve haver um processo natural de desativação http://learn.genetics.utah.edu/content/addiction/drugs/mouse.html Ação de neurotransmissores Síntese de neurotransmissores catecolaminérgicos Transport of catecholamines into storage vesicles. This is a secondary active transport based on the generation of a proton gradient across the vesicular membrane. NT positively charged neurotransmitter (catecholamine); DBH dopamine –hydroxylase; VMAT2 vesicle membrane transporter 2; V-ATPase vesicular ATPase. Armazenamento e liberação de catecolaminas http://dc437.4shared.com/doc/A5DfwpmN/preview.html Término da ação de neurotransmissores Ácido 3 –metóxi-4-hidromandélico (ácido vanilmandélico, VMA) Methylation and oxidation may occur in any order. Methylated and oxidized derivatives of norepinephrine and epinephrine are produced, and 3-methoxy-4-hydroxymandelic acid is the final product. These compounds are excreted in the urine. MAO monoamine oxidase; COMT catechol O-methyltransferase; SAM S-adenosylmethionine; SAH S-adenosylhomocysteine. Inativação de catecolaminas Metabolismo da Serotonina http://neuroquimicaclinica.blogspot.com.br/2010/08/neurotransmisor-de-la-semana.html Metabolismo da Acetil-colina Metabolismo da Histamina http://www.ierfh.org/br.txt/Nootropicos2009.html AÇÃO DOS NOOTRÓPICOS Vigilância estimulada Vigilância calma Ação dos nootrópicos Metabolismo do glutamato e GABA http://neuromed91.blogspot.com.br/2010/08/gaba-e-glicina.html Compartmentalization of glucose metabolism (metabolic compartmentation) between astrocytes and neurons (not all intermediates are shown). One molecule of glucose can be glycolytically converted into two molecules of pyruvate in both neurons and astrocytes. In astrocytes, pyruvate is also formed from glycogen by glycogenolysis. In both cases, pyruvate production is via intermediates such as glucose-6-phosphate (glucose-6-P). Under anaerobic conditions, pyruvate is quantitatively converted to lactate, and in the brain some lactate is formed even under aerobic conditions. The main metabolic fate of pyruvate is entry into the tricarboxylic acid (TCA) cycle. In neurons, pyruvate enters the TCA cycle exclusively via acetyl coenzyme A (acetyl CoA), formed by oxidative decarboxylation, which is catalyzed by the pyruvate dehydrogenase complex (PDH). Acetyl CoA is metabolized in the TCA cycle after condensation with oxaloacetate (OAA) to form citrate, which is subsequently converted to oxaloacetate during one turn of the cycle generating a substantial amount of ATP without net formation of any TCA cycle intermediate. This does not mean that this process cannot give rise to labeling of glutamate if, for example, [1-14C]glucose is used as the substrate. However, such labeling is due to bidirectional transamination between aketoglutarate (a-KG) and glutamate, which does not change the content of either metabolite. In astrocytes, pyruvate can enter the TCA cycle both via acetyl CoA and via carboxylation mediated by pyruvate carboxylase (PC). The latter reaction generates a new molecule of oxaloacetate, which condenses with acetyl CoA to produce a new molecule of citrate, from which a-ketoglutarate, the immediate precursor of glutamate (and thus also a precursor of GABA), is formed. Although a-ketoglutarate as such might travel from astrocytes to neurons, in the mammalian brain it appears to be mainly or exclusively converted in astrocytes via glutamate to glutamine. This is transported in the glutamate–glutamine cycle (lower rectangle) to neurons, where it is hydrolyzed to form transmitter glutamate by phosphate-activated glutaminase (PAG). Released transmitter glutamate is also predominantly accumulated in astrocytes, where approximately two-thirds are converted by glutamine synthetase (GS) into glutamine, which after return to neurons in the glutamate–glutamine cycle can be reused as a precursor for transmitter glutamate; the remaining one-third is reconverted to a-ketoglutarate, metabolized in the TCA cycle to malate and decarboxylated by malic enzyme (ME) to pyruvate, predominantly although probably not exclusively in astrocytes (indicated by broken arrows in both cell types). Inhibition of astrocyte-specific processes by methionine sulfoximine (MSO; a relatively specific inhibitor of glutamine synthetase) or by fluoroacetate or fluorocitrate (F-Ac; specific inhibitors of the astrocytic TCA cycle) is indicated by breaks in the arrows. 20 TRENDS in Neurosciences Vol.27 No.12 December 2004 Metabolismo do gllutamato e GABA Referências DEVLIN TM - Manual de Bioquímica com Correlações Clínicas. 2a ed. 2007, Ed. Edgard Blucher, São Paulo. Bioquímica Médica Básica de Marks. 2ª ed. Porto Alegre, Artmed, 2007. VOET D e VOET J - Bioquímica. 3ª ed., São Paulo, Artmed, 2006. NELSON DL., COX MM. Princípios de bioquímica de Lehninger, 5 ed. 2011, Artmed: Porto Alegre. Sites para estudo: http://neurotransunb.blogspot.com.br/search/label/Neurotransmissores http://www.ierfh.org/br.txt/Nootropicos2009.html http://neuroquimicaclinica.blogspot.com.br/
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