RESUMO
RATIONALE: Tiagabine is an anticonvulsant drug which may also have sleep-enhancing properties. It acts by inhibiting reuptake at the gamma-aminobutyric acid (GABA) transporter (GAT-1). OBJECTIVES: The aim of the study was to determine whether tiagabine acted as a discriminative stimulus and, if so, whether other GABAergic compounds would generalise to it. MATERIALS AND METHODS: Rats were trained to discriminate tiagabine (30 mg/kg p.o.) from vehicle, and generalisation to drugs that modulate GABA was assessed. RESULTS: Gaboxadol (5-20 mg/kg p.o.), a selective extrasynaptic GABA A agonist, generalised to tiagabine, although the extent of the generalisation was inconclusive. Indiplon (1 mg/kg p.o.), a benzodiazepine-like hypnotic, also partially generalised to tiagabine, although zolpidem and S-zopiclone did not. Baclofen, a GABA B receptor agonist, and gabapentin, which increases synaptic GABA, did not generalise to tiagabine. (+)-Bicuculline (3 mg/kg i.p.), a GABA A receptor antagonist, blocked the tiagabine cue, but the less brain-penetrant salt form, bicuculline methochloride, had no effect. CONCLUSIONS: These data suggest that tiagabine generates a discriminative stimulus in rats, and provides a central GABA-mediated cue, but is distinct from the other GABAergic compounds tested.
Assuntos
Anticonvulsivantes/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , GABAérgicos/farmacologia , Ácidos Nipecóticos/farmacologia , Administração Oral , Aminas/farmacologia , Animais , Compostos Azabicíclicos/farmacologia , Baclofeno/farmacologia , Benzodiazepinas/farmacologia , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Encéfalo/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA/efeitos dos fármacos , Gabapentina , Generalização do Estímulo/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Injeções Intraperitoneais , Isoxazóis/farmacologia , Masculino , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Tiofenos/farmacologia , Tiagabina , Zolpidem , Ácido gama-Aminobutírico/farmacologiaRESUMO
Gaboxadol is a selective extrasynaptic GABA(A) receptor agonist (SEGA) which enhances slow-wave sleep, and may act principally at extrasynaptic GABA(A)alpha4betadelta receptors. Drug discrimination is a very useful approach for exploring in vivo pharmacological similarities and differences between compounds and was therefore used to compare gaboxadol and zolpidem, an established hypnotic drug, against zopiclone, S-zopiclone, indiplon and tiagabine, all of which have been reported to enhance sleep. Gaboxadol generalised to itself, but not to zolpidem, zopiclone, S-zopiclone, R-zopiclone, indiplon or tiagabine. By contrast, zolpidem generalised to itself, zopiclone, S-zopiclone and indiplon, but not to R-zopiclone (the inactive enantiomer of zopiclone), gaboxadol or tiagabine. This suggests that zolpidem, zopiclone, S-zopiclone and indiplon share a discriminative stimulus, which may be mediated by their efficacy at GABA(A)alpha1betagamma receptors. Gaboxadol and tiagabine each have a different discriminative stimulus from all the other drugs tested.
Assuntos
Aprendizagem por Discriminação/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Generalização Psicológica/efeitos dos fármacos , Isoxazóis/farmacologia , Sono/efeitos dos fármacos , Animais , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Interações Medicamentosas , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The objective of this study was to explore the relationship between partially reduced oxygen species and the aging process. Effect of age on antioxidant defenses and prooxidant generation was evaluated by comparing the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, and rates of mitochondrial O-2 and H2O2 generation in the liver, heart, and brain of 3-month and 18-month-old Sprague-Dawley rats. In addition, comparisons of antioxidant defenses and mitochondrial prooxidant generation were made between short-lived insects and the rat tissues. Results indicated that antioxidant enzymes exhibit a mixed pattern of age-related alterations. In each organ of the rat examined, activities of some enzymes were up with age and of others down with age. The overall magnitude of decline in antioxidant defenses observed here and elsewhere in the literature was deemed to be unlikely to be functionally significant. In contrast, the rate of mitochondrial O-2 and H2O2 generation increased in various tissues of the rat. Antioxidant defenses in insects were comparable to tissues in the rat but rates of O-2 and H2O2 generations were notably higher. Results are interpreted to suggest that rates of prooxidant generation may be more crucial than antioxidant levels as possible longevity determinants.
Assuntos
Envelhecimento , Antioxidantes , Mitocôndrias/metabolismo , Oxirredutases/metabolismo , Superóxidos/metabolismo , Animais , Drosophila/fisiologia , Radicais Livres , Moscas Domésticas/fisiologia , Peróxido de Hidrogênio/metabolismo , Masculino , Mitocôndrias/enzimologia , Especificidade de Órgãos , Oxigênio/metabolismo , Ratos , Ratos Endogâmicos , Maturidade SexualRESUMO
The objective of this study was to further elucidate the role of oxidative stress in the aging process by determining whether or not the rates of mitochondrial superoxide anion radical and hydrogen peroxide (H2O2) production, the activity of cytochrome c oxidase, and the concentration of protein carbonyls are correlated with the life span potential of different species. A comparison was made among five different species of dipteran flies, namely, Drosophila melanogaster (fruit fly), Musca domestica (house fly), Sarcophaga bullata (flesh fly), Calliphora vicina (blow fly) and Phaenecia sericata (a species of blow flies), which range more than 2-fold in their life span potentials. The average life span potential of these species was found to be inversely correlated with the rates of mitochondrial superoxide and H2O2 production and with the level of protein carbonyls, and to be directly related to the activity of cytochrome c oxidase. The significance of these findings in context of the validity of the oxidative stress hypothesis of aging is discussed. It is inferred that longer life span potential in these insect species is associated with relatively low levels of oxidant generation and oxidative molecular damage. These results accord with our previous findings on different mammalian species.
Assuntos
Dípteros/metabolismo , Peróxido de Hidrogênio/metabolismo , Longevidade , Mitocôndrias/metabolismo , Proteínas/metabolismo , Superóxidos/metabolismo , Animais , Drosophila melanogaster/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Moscas Domésticas/metabolismo , Proteínas/químicaRESUMO
The purpose of this study was to understand the nature of the causes underlying the senescence-related decline in skeletal muscle mass and performance. Protein and lipid oxidative damage to upper hindlimb skeletal muscle mitochondria was compared between mice fed ad libitum and those restricted to 40% fewer calories--a regimen that increases life span by approximately 30-40% and attenuates the senescence-associated decrement in skeletal muscle mass and function. Oxidative damage to mitochondrial proteins, measured as amounts of protein carbonyls and loss of protein sulfhydryl content, and to mitochondrial lipids, determined as concentration of thiobarbituric acid reactive substances, significantly increased with age in the ad libitum-fed (AL) C57BL/6 mice. The rate of superoxide anion radical generation by submitochondrial particles increased whereas the activities of antioxidative enzymes superoxide dismutase, catalase, and glutathione peroxidase in muscle homogenates remained unaltered with age in the AL group. In calorically-restricted (CR) mice there was no age-associated increase in mitochondrial protein or lipid oxidative damage, or in superoxide anion radical generation. Crossover studies, involving the transfer of 18- to 22-month-old mice fed on the AL regimen to the CR regimen, and vice versa, indicated that the mitochondrial oxidative damage could not be reversed by CR or induced by AL feeding within a time frame of 6 weeks. Results of this study indicate that mitochondria in skeletal muscles accumulate significant amounts of oxidative damage during aging. Although such damage is largely irreversible, it can be prevented by restriction of caloric intake.
Assuntos
Envelhecimento , Ingestão de Energia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Fatores Etários , Animais , Peso Corporal , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Compostos de Sulfidrila/análise , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
The effect of aging on the release of H2O2 by mitochondria was studied in the housefly in order to elucidate the causes of previously observed age-related increase in the level of oxidative stress. Intact flight muscle mitochondria of the housefly, supplemented with alpha-glycerophosphate, produce 1-2 nmol H2O2/min per mg protein, even in the absence of respiratory inhibitors. The rate of H2O2 secretion progressively increases approximately 2-fold during aging of the fly. Neither uncoupling of oxidative phosphorylation nor mechanical damage to mitochondria during the isolation procedure appear to be responsible for the age-related increase in H2O2 production. Activities of NADH-ferricyanide reductase, succinate-ubiquinone reductase, and NADH-, succinate- and alpha-glycerophosphate-cytochrome c reductases, were approximately 2-fold higher in mitochondria from the old than those from the young flies. However, the concentration of enzymatically reducible ubiquinone remained unchanged with age. Infliction of damage by exposure of mitochondria to free radical-generating systems in vitro caused an increase in the rate of H2O2 generation. Glutaraldehyde, an intermolecular crosslinking agent, induced an increase in the rate of H2O2 generation by mitochondria. Results of this study demonstrate that aging in the housefly is associated with an increase in the rate of H2O2 generation by mitochondria probably due, at least in part, to self-inflicted damage by mitochondria. Intermolecular cross-linking in the inner mitochondrial membrane can contribute towards the increased H2O2 generation.
Assuntos
Envelhecimento/metabolismo , Peróxido de Hidrogênio/metabolismo , Animais , Radicais Livres , Glutaral/farmacologia , Moscas Domésticas/metabolismo , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Fosforilação Oxidativa , Partículas Submitocôndricas/efeitos dos fármacos , Partículas Submitocôndricas/metabolismoRESUMO
The objective of this study was to determine if aging in the gerbil, Meriones unguiculatus, is associated with elevation in the level of oxidative stress. Studies were conducted on the brain, heart, kidney, liver and testis of young (3-6 months), adult (15 months), and old (23-25 months) animals. Oxidative damage to proteins, measured as the concentration of protein carbonyls and loss of activity of glucose-6-phosphate dehydrogenase, and to DNA, measured as the concentration of 8-hydroxydeoxyguanosine, increased with age of the animals. There was no appreciable age-related change in the activity of alkaline proteases, which preferentially degrade oxidized protein. Rates of mitochondrial superoxide anion radical and hydrogen peroxide generation also increased with age, most notably in the heart. Antioxidative defenses, measured as activities of superoxide dismutase, catalase and glutathione peroxidase and concentration of glutathione, did not exhibit a uniform pattern of age-related changes. However, when the antioxidative potential of the tissue homogenates was measured as their susceptibility to undergo protein oxidation, in response to experimentally-induced oxidative stress, using X-irradiation, tissues of the old animals were significantly more vulnerable than those of the young animals. Results of this study are interpreted to indicate: (i) that the level of molecular oxidative damage to DNA and proteins increases with age, and (ii) that the increased oxidative damage is due to both an an elevation in the rates of oxidant generation and an increase in the susceptibility of tissues to oxidative damage.
Assuntos
Envelhecimento/fisiologia , Gerbillinae/fisiologia , Estresse Oxidativo/fisiologia , Animais , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Longevidade , Masculino , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Especificidade da Espécie , Superóxido Dismutase/metabolismo , Superóxidos/metabolismoRESUMO
The general objective of this study was to examine the relationship between oxygen free radicals and the aging process. The rate of superoxide anion radical (O2.-) generation was measured in liver sub-mitochondrial particles from mouse, rat, rabbit, pig and cow, and in flight muscle sub-mitochondrial particles from the housefly. The rate of O2.- generation was determined as superoxide dismutase inhibitable reduction of ferricytochrome c in the presence of antimycin A and KCN. O2.- generation was inversely related to maximum species life span potential (MLSP) (r = -0.92). A 24-fold difference in the rate of O2.- production was observed between the cow and the fly while a 6-fold difference existed among the mammals. The results are interpreted to indicate that under identical conditions, mitochondria from organisms with low MLSP have a relatively greater propensity to generate O2.-. This may be suggestive of innate differences in the molecular organization of the inner mitochondrial membrane among different species.
Assuntos
Superóxidos/metabolismo , Animais , Ânions , Bovinos , Radicais Livres , Moscas Domésticas , Camundongos , Mitocôndrias Hepáticas/metabolismo , Coelhos , Ratos , Especificidade da Espécie , SuínosRESUMO
The general objective of this investigation was to examine the relationship between oxygen free radicals and the aging process. Comparisons of antioxidant defenses were made in six different mammalian species, namely, mouse, rat, guinea pig, rabbit, pig and cow, which range from 3.5 to 30 years in their maximum life span potential (MLSP). Activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase, and concentration of glutathione were measured in the liver, the heart, and the brain. SOD and catalase activities were positively correlated whereas glutathione concentration was negatively correlated with MLSP. Glutathione peroxidase activity exhibited a variable pattern: being positively correlated with MLSP in the brain and negatively correlated in the liver and the heart. In each organ, MLSP was correlated with relatively high levels of one or two of the above antioxidants and low levels of the other antioxidants, indicating the possibility of a compensatory balance among various components of the antioxidant system. No obvious pattern of a relationship was detectable between the overall level of antioxidant defenses and MLSP among the mammalian species examined. The implications of this finding concerning the role of oxidative stress in the aging process and the free radical hypothesis of aging are discussed.
Assuntos
Envelhecimento/metabolismo , Antioxidantes/metabolismo , Longevidade/fisiologia , Animais , Encéfalo/metabolismo , Catalase/metabolismo , Bovinos , Radicais Livres , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Cobaias , Fígado/metabolismo , Camundongos , Miocárdio/metabolismo , Especificidade de Órgãos/fisiologia , Coelhos , Ratos , Ratos Endogâmicos , Especificidade da Espécie , Superóxido Dismutase/metabolismo , SuínosRESUMO
Several 5-HT(1D/1B) receptor agonists are now entering the marketplace as treatments for migraine. This paper describes the development of selective h5-HT(1D) receptor agonists as potential antimigraine agents which may produce fewer side effects. A series of 3-[3-(piperidin-1-yl)propyl]indoles has been synthesized which has led to the identification of 80 (L-772,405), a high-affinity h5-HT(1D) receptor full agonist having 170-fold selectivity for h5-HT(1D) receptors over h5-HT(1B) receptors. L-772,405 also shows very good selectivity over a range of other serotonin and nonserotonin receptors and has excellent bioavailability following subcutaneous administration in rats. It therefore constitutes a valuable tool to delineate the role of h5-HT(1D) receptors in migraine. Molecular modeling and physical properties have been utilized to postulate the binding conformation of these compounds in the receptor cavity.
Assuntos
Indóis/síntese química , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Triazóis/síntese química , Animais , Disponibilidade Biológica , Células CHO , Simulação por Computador , Cricetinae , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Indóis/metabolismo , Indóis/farmacocinética , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1D de Serotonina , Receptores de Serotonina/genética , Proteínas Recombinantes/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacocinética , Relação Estrutura-Atividade , Transfecção , Triazóis/metabolismo , Triazóis/farmacocinéticaRESUMO
The design, synthesis, and biological evaluation of a novel series of 3-[2-(pyrrolidin-1-yl)ethyl]indoles with excellent selectivity for h5-HT1D (formerly 5-HT1Dalpha) receptors over h5-HT1B (formerly 5-HT1Dbeta) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT1D and h5-HT1B receptors. The differential expression of h5-HT1D and h5-HT1B receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT1D subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having 9-fold selectivity for h5-HT1D over h5-HT1B receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT1D receptor and 100-fold selectivity with respect to h5-HT1B receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT1D subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPgammaS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT1D and h5-HT1B receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT1D receptor domain which is absent for the h5-HT1B receptor. The compounds described herein will be important tools to delineate the role of h5-HT1D receptors in migraine.
Assuntos
Indóis/síntese química , Oxazóis/síntese química , Pirrolidinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Modelos Moleculares , Oxazóis/química , Oxazóis/metabolismo , Oxazóis/farmacologia , Pirrolidinas/química , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT1B de Serotonina , Receptor 5-HT1D de Serotonina , Receptores de Serotonina/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3, 5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK1 IC50 = 5.3 nM) and sulfonyl (39) (hNK1 IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/síntese química , Pirrolidinas/síntese química , Tiazóis/síntese química , Animais , Células CHO , Permeabilidade Capilar/efeitos dos fármacos , Cricetinae , Diterpenos/toxicidade , Esôfago/irrigação sanguínea , Esôfago/efeitos dos fármacos , Cobaias , Fosfatos de Inositol/metabolismo , Masculino , Piperidinas/farmacocinética , Piperidinas/farmacologia , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ensaio Radioligante , Receptores da Neurocinina-1/biossíntese , Relação Estrutura-Atividade , Tiazóis/farmacocinéticaRESUMO
After the requirement of pseudocycle formation in the ureas 3 and 7 for hD(4) binding and selectivity was confirmed, structural hybridization with the known hD(4) ligand 2 led to the design and identification of the lead 4-(2-oxo-1, 3-dihydroimidazol-2-yl)piperidine 8. Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD(4) over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective "four-step/one-pot" procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1, 3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or 5-position of the 1, 3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD(4) over hD(2) and hD(3). Greater selectivity (>1000-fold) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD(4) over the other dopamine subtypes, but only 32 has >1000-fold selectivity over all the key counterscreens we tested against. Compound 32 is an antagonist at hD(4) and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D(4) receptor.
Assuntos
Antagonistas de Dopamina/síntese química , Imidazóis/síntese química , Canais Iônicos/efeitos dos fármacos , Piperidinas/síntese química , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Ligação Competitiva , Células CHO , Linhagem Celular , Cricetinae , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Relação Estrutura-AtividadeRESUMO
It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.
Assuntos
Compostos de Flúor/síntese química , Indóis/síntese química , Piperidinas/síntese química , Receptores de Serotonina/metabolismo , Administração Oral , Animais , Células CHO , Cricetinae , Compostos de Flúor/química , Compostos de Flúor/metabolismo , Compostos de Flúor/farmacocinética , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacocinética , Ligantes , Masculino , Modelos Moleculares , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1B de Serotonina , Receptor 5-HT1D de Serotonina , Relação Estrutura-AtividadeRESUMO
The purpose of this study was to understand the nature of the biochemical and physiological variations between genetically different lines of Drosophila melanogaster. Selection for early or delayed reproduction has given rise to lines with substantial and heritable differences in longevity. The hypotheses tested were that either: (i) a compensatory slowing of metabolism, (ii) increased antioxidative enzyme activities, or (iii) elevated resistance to stressful conditions underlie these differences in longevity. The metabolic rate, metabolic potential (i.e. total amount of oxygen consumed during average lifespan) and speed of walking were all greater in long-lived than in short-lived flies, but there was no enhancement of antioxidant defenses. In fact, catalase activity was significantly lower in the long-lived flies. Long life was largely maintained under heat stress and starvation conditions, and was maintained to a lesser extent upon exposure to paraquat, a superoxide radical generator. In contrast, the 'short-lived' flies had a longer lifespan under cold stress and hyperoxia, also an inducer of radical generation. These results contradict the first two hypotheses and suggest that alleles underlying either long or short life are linked with enhanced resistance to specific kinds of stress, which may account for the preservation of these alleles in the parental population.
Assuntos
Antioxidantes/metabolismo , Drosophila melanogaster/fisiologia , Animais , Cruzamentos Genéticos , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Feminino , Temperatura Alta , Longevidade , Masculino , Microclima , Especificidade da Espécie , Estresse FisiológicoRESUMO
The age-associated increase in oxidative damage in ad libitum-fed mice is attenuated in mice fed calorically restricted (CR) diets. The objective of this study was to determine if this effect results from a slowing of age-related accumulation of oxidative damage, or from a reversible decrease of oxidative damage by caloric restriction. To address these possibilities, crossover studies were conducted in C57BL/6 mice aged 15 to 22 months that had been maintained, after 4 months of age, on ad libitum (AL) or a 60% of AL caloric regimen. One half of the mice in these groups were switched to the opposite regimen of caloric intake for periods up to 6 weeks, and protein oxidative damage (measured as carbonyl concentration and loss of sulfhydryl content) was measured in homogenates of brain and heart. In AL-fed mice, the protein carbonyl content increased with age, whereas the sulfhydryl content decreased. Old mice maintained continuously under CR had reduced levels of protein oxidative damage when compared with the old mice fed AL. The effects of chronic CR on the carbonyl content of the whole brain and the sulfhydryl content of the heart were fully reversible within 3-6 weeks following reinstatement of AL feeding. The effect of chronic CR on the sulfhydryl content of the brain cortex was only partially reversible. The introduction of CR for 6 weeks in the old mice resulted in a reduction of protein oxidative damage (as indicated by whole brain carbonyl content and cortex sulfhydryl), although this effect was not equivalent to that of CR from 4 months of age. The introduction of CR did not affect the sulfhydryl content of the heart. Overall, the current findings indicate that changes in the level of caloric intake may reversibly affect the concentration of oxidized proteins and sufhydryl content. In addition, chronic restriction of caloric intake also retards the age-associated accumulation of oxidative damage. The magnitude of the reversible and chronic effects appears to be dependent upon the tissue examined and the nature of the oxidative alteration.
Assuntos
Envelhecimento/metabolismo , Ingestão de Energia , Proteínas/metabolismo , Animais , Peso Corporal , Encéfalo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Oxirredução , Compostos de Sulfidrila/análiseRESUMO
Isolated sphenoid sinusitis (ISS) is a rare entity. ISS accounts for about 1-2% of all sinus infections. Isolated sphenoid sinus involvement may include mucoceles, pyoceles and isolated mycotic infections. We report a case of isolated sphenoid pyocele in a 35 year-old female who presented in August 2007 with frontal and occipital headache, post nasal discharge and bilateral nasal obstruction for 6 years. CT scan showed isolated right sphenoid sinusitis. Diagnostic nasal endoscopy showed a streak of post nasal discharge on right side above the torus tubaris confirming right sphenoiditis. A cyst in the nasopharynx was incidentally detected which was confirmed by fluid aspiration to be Thornwaldt's cyst (TC). TCs have reported prevalence of 0.2-5% and though most are asymptomatic their location renders them vulnerable to infection. Sphenoidotomy was done and the cyst in the nasopharynx was removed and marsupialised. Postoperative course was uneventful.
Assuntos
Indóis/síntese química , Absorção Intestinal , Piperidinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Administração Oral , Animais , Células CHO , Cricetinae , Humanos , Indóis/administração & dosagem , Indóis/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Receptor 5-HT1D de Serotonina , Receptores de Serotonina/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacologiaAssuntos
Encéfalo/metabolismo , Colesterol/metabolismo , Fabaceae , Fígado/metabolismo , Plantas Medicinais , Animais , Colesterol/sangue , RatosRESUMO
The pharmacokinetics of L-838417, a GABAA receptor subtype selective benzodiazepine site agonist, were studied in rats and mice after single oral (p.o.), intraperitoneal (i.p.) and intravenous (i.v.) doses. In both species L-838417 was well absorbed following i.p. administration and whilst in rats p.o. bioavailability was good (41%), in mice it was negligible (<1%), precluding this as a route of administration for mouse behavioural studies. Despite having a similar volume of distribution (ca 1.4 l/kg) in rats and mice, L-838417 was cleared at twice liver blood flow in mice (161 ml/min/kg) and moderately cleared in rats (24 ml/min/kg), potentially explaining the poor oral bioavailability in mice. Finally, as a pharmacodynamic readout the benzodiazepine binding site occupancy was determined in rats (0.3-3 mg/kg, p.o.) and mice (1-30 mg/kg, i.p.) using a [3H]Ro 15-1788 in vivo binding assay. Although the resulting dose-occupancy relationship for both species demonstrated a dose-dependent increase in receptor occupancy, appreciable variability was observed at low dose levels, potentially making interpretation of behavioural responses difficult. In contrast, a clear relationship between plasma and brain concentrations and receptor occupancy were determined suggesting the observed dose-occupancy variability is a consequence of the pharmacokinetic properties of L-838417. The plasma and brain concentrations required to occupy 50% of the benzodiazepine binding sites were similar in both rats (28 ng/ml and 33 ng/ml g, respectively) and mice (63 ng/ml and 53 ng/ml g, respectively), with a non-linear concentration response observed with increasing doses of L-838417. These studies demonstrate the importance of utilizing pharmacokinetic/receptor occupancy data when interpreting pharmacodynamic responses at a given dose.