RESUMO
This study was conducted to evaluate the interaction between dose of estradiol cypionate (ECP) and ovarian status in beef cows on which different weaning/suckling regimens were imposed before fixed-time artificial insemination (FTAI). A total of 8070 estrous cycling and anestrous cows were subjected to three experiments, when calves were weaned early (Experiment 1), anti-suckling nose plates were applied for 9 or 10 days (Experiment 2), or there was continued suckling (Experiment 3). The cows were administered an estradiol/progesterone-based treatment regimen for FTAI and were treated with 0.5 or 1.0 mg of ECP im at the time of progesterone intravaginal device removal. Artificial insemination was performed from 46 to 56 h after the time of ECP treatment. Pregnancy per artificial insemination (P/AI) was affected by dose of ECP differentially in early-weaned and suckled cows. Whereas P/AI percentage was greater in early-weaned cows treated with 0.5 than 1.0 mg ECP (P < 0.05), P/AI percentage was greater for suckled cows treated with 1.0 than 0.5 mg ECP (P < 0.05). Although there were greater P/AI percentages in estrous cycling than anestrous cows (P < 0.05) when there was nose plate weaning and continuation of suckling, there was no difference between estrous cycling and anestrous cows (P = NS) when there was early weaning. Overall results indicate ECP administration affects fertility in a dose-dependent manner, suggesting an interaction between suckling and estrous cycling effects. As more critical the condition was (i.e., suckling anestrous cows), larger dose of estradiol was required.
RESUMO
Mental retardation (MR) is a nonprogressive condition characterized by a significant impairment of intellectual capabilities with deficit of cognitive and adaptive functioning and onset before 18 years. Mental retardation occurs in about 2 to 3% of the general population and it is estimated that 25 to 35% of the cases may be due to genetic causes. Among these "genetic" MR, 25 to 30% are probably due to mutations in a gene on the X chromosome (X-linked mental retardation, XLMR). Given the genetic heterogeneity of XLMR, the availability of a considerable number of patients with accurate phenotypic classification is a crucial factor for research. The X-linked Mental Retardation Italian Network, which has been active since 2003, has collected detailed clinical information and biological samples from a vast number of MR patients. Collected samples and clinical information are inserted within the XLMR bank, a comprehensive molecular and clinical web-based database available at the address http://xlmr.unisi.it. The database is organized in three distinct parts. Part I and II contain several electronic schedules to register information on the family, the phenotypic description, the photographs, and a 20 sec movie of the patient. Part III allows the registration of molecular analyses performed on each case; samples and clinical data are usable via password-restricted access. Clinical and molecular centers interested in joining the network may request a password by simply contacting the Medical Genetics of the University of Siena. The XLMR bank is an innovative biological database that allows the collection of molecular and clinical data, combines descriptive and iconographic resources, and represents a fundamental tool for researchers in the field of mental retardation.
Assuntos
Bases de Dados Factuais , Bases de Dados Genéticas , Deficiência Intelectual Ligada ao Cromossomo X/epidemiologia , Deficiência Intelectual Ligada ao Cromossomo X/genética , Segurança Computacional , Processamento Eletrônico de Dados , Humanos , Itália , Modelos Biológicos , Modelos Moleculares , Linhagem , Controle de QualidadeRESUMO
The enzyme kynurenine aminotransferase (KAT) catalyses the conversion of L-kynurenine to kynurenic acid. A combination of polymerase chain reaction techniques and hybridization screening was used to isolate a cDNA clone encompassing the entire coding region of KAT from rat kidney. Identification of the cDNA as coding for KAT was based both on the comparison of amino acid sequences obtained from purified rat KAT and on the expression of KAT activity in COS-1 cells transfected with the cDNA. RNA blot analysis indicated that KAT mRNA is widely expressed in rat tissues. Cultured cells transfected with the cDNA for KAT also showed glutamine transaminase K activity. Based mainly on sequence data, these results demonstrate that rat kidney KAT is identical with glutamine transaminase K.
Assuntos
Liases , Transaminases/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Clonagem Molecular , DNA Complementar , Rim/enzimologia , Dados de Sequência Molecular , RatosRESUMO
Kynureninase [E.C.3.7.1.3.] is one of the enzymes involved in the biosynthesis of NAD cofactors from tryptophan through the kynurenine pathway. By tryptic and CNBr digestion of purified rat liver kynureninase, we obtained about 28% of the amino acid sequence of the enzyme. The rat kynureninase cDNA, isolated by means of reverse-transcribed polymerase chain reaction and hybridization screening, codes for a polypeptide of 464 amino acids. Northern blot analysis revealed the synthesis of a 2.0 kb rat kynureninase mRNA. A cDNA encoding human liver kynureninase was also isolated. The deduced amino acid sequence is 85% identical to that of the rat protein. COS-1 cells were transfected with both cDNAs. The Km values of the rat enzyme, for L-kynurenine and DL-3-hydroxykynurenine, were 440 +/- 20 microM and 32 +/- 5 microM and of the human enzyme 440 /- 20 microM and 49 +/- 6 microM, respectively. Interestingly, COS-1 cells transfected with the cDNA coding for rat kynureninase also display cysteine-conjugate beta-lyase activity.
Assuntos
Liases de Carbono-Enxofre , Hidrolases/genética , Fígado/enzimologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Células COS , Clonagem Molecular , Expressão Gênica/genética , Humanos , Hidrolases/química , Hidrolases/metabolismo , Cinética , Cinurenina/análogos & derivados , Cinurenina/metabolismo , Liases/metabolismo , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Alinhamento de Sequência , Análise de Sequência , Transfecção/genéticaRESUMO
Competing enzymatic mechanisms degrade the tryptophan metabolite L-kynurenine to kynurenate, an inhibitory and neuroprotective compound, and to the neurotoxins 3-hydroxykynurenine and quinolinate. Kynurenine 3-hydroxylase inhibitors such as PNU 156561 shift metabolism towards enhanced kynurenate production, and this effect may underlie the recently discovered anticonvulsant and neuroprotective efficacy of these drugs. Using electrophysiological and neurotoxicological endpoints, we now used PNU 156561 as a tool to examine the functional interplay of kynurenate, 3-hydroxykynurenine and quinolinate in the rat hippocampus in vivo. First, population spike amplitude in area CA1 and the extent of quinolinate-induced excitotoxic neurodegeneration were studied in animals receiving acute or prolonged intravenous infusions of L-kynurenine, PNU 156561, (L-kynurenine+PNU 156561) or kynurenate. Only the latter two treatments, but not L-kynurenine or PNU 156561 alone, caused substantial inhibition of evoked responses in area CA1, and only prolonged (3h) infusion of (L-kynurenine+PNU 156561) or kynurenate was neuroprotective. Biochemical analyses in separate animals revealed that the levels of kynurenate attained in both blood and brain (hippocampus) were essentially identical in rats receiving extended infusions of L-kynurenine alone or (L-kynurenine+PNU 156561) (4 and 7microM, respectively, after an infusion of 90 or 180min). However, addition of the kynurenine 3-hydroxylase inhibitor resulted in a significant decrement in the formation of 3-hydroxykynurenine and quinolinate in both blood and brain. These data suggest that the ratio between kynurenate and 3-hydroxykynurenine and/or quinolinate in the brain is a critical determinant of neuronal excitability and viability. The anticonvulsant and neuroprotective potency of kynurenine 3-hydroxylase inhibitors may therefore be due to the drugs' dual action on both branches of the kynurenine pathway of tryptophan degradation.
Assuntos
Butiratos/farmacologia , Hipocampo/fisiologia , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Fármacos Neuroprotetores/farmacologia , Ácido 3-Hidroxiantranílico/metabolismo , Animais , Barreira Hematoencefálica , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Ácido Cinurênico/farmacologia , Cinurenina/análogos & derivados , Cinurenina/farmacologia , Quinurenina 3-Mono-Oxigenase , Masculino , Oxigenases de Função Mista/antagonistas & inibidores , Neurotoxinas/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ácido Quinolínico/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Biochemical events underlying neurotensin action at the pituitary were investigated in primary culture of anterior pituitary cells prelabeled with [3H]inositol. Incubation with the tridecapeptide produced a dose-dependent increase in the content of total [3H]inositol phosphates. The time-course showed that the effect was rapid and significant within 1 min. Fractionation of [3H]inositol phosphates revealed that inositol triphosphate (IP3) and inositol diphosphate (IP2) increased earlier than inositol monophosphate (IP1). Structure/activity correlation studies demonstrated the specificity of neurotensin effect, showing that acetylneurotensin(8-13) displayed an action similar to the natural peptide, while neurotensin(1-6) hexapeptide did not exhibit any effect. The neurotensin analog [D-Trp11]-neurotensin antagonized in a concentration-dependent manner the effect of neurotensin both on prolactin release and on [3H]inositol phosphate production. The loss of prelabeled phosphoinositides was also investigated. Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) and phosphatidylinositol-4-phosphate (PtdIns-4-P) decreased significantly within 15 s, while a slight decline in phosphatidylinositol (PtdIns) level appeared only 1 min after neurotensin addition. These results suggest that neurotensin action at the pituitary is mediated by the early hydrolysis of polyphosphoinositides, leading to the production of 1,2-diacylglycerol and inositol phosphates which may initiate intracellular processes responsible for hormonal release.
Assuntos
Neurotensina/farmacologia , Fosfatidilinositóis/metabolismo , Adeno-Hipófise/efeitos dos fármacos , Prolactina/metabolismo , Animais , Células Cultivadas , Cromatografia em Camada Fina , Feminino , Fosfatos de Inositol/metabolismo , Fosfatos de Fosfatidilinositol , Adeno-Hipófise/citologia , Adeno-Hipófise/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Quinolinic acid (QUIN) is an endogenous neurotoxin which originates from the kynurenine pathway of tryptophan metabolism. An increase of brain QUIN level occurs in several degenerative and inflammatory disorders, but the cellular source of QUIN is still a matter of controversy. In the present study, the gerbil model of transient global ischemia was used to investigate the time course and the cellular localization of QUIN immunoreactivity. Neurodegeneration was evident in the subiculum and in the CA1 area of the hippocampus 4, 7 and 14 days after ischemia. QUIN positive cells, with microglia-like morphology, appeared in the subiculum and in the CA1, 4 days after ischemia. At 7 days post-ischemia they extended to the whole CA1, disappearing at 14 days. Neither neurodegeneration nor QUIN positive cells could be detected in ischemic gerbils sacrificed at 1 and 2 days after ischemia and in sham-operated animals. These findings suggest that microglia-like cells infiltrating the degenerating areas of the hippocampus represent the major source of QUIN following transient ischemia in the gerbil. Thus, in situ production of QUIN in vulnerable brain regions may contribute to the pathophysiological mechanisms of delayed brain injury.
Assuntos
Hipocampo/metabolismo , Ataque Isquêmico Transitório/metabolismo , Ácido Quinolínico/metabolismo , Animais , Especificidade de Anticorpos , Gerbillinae , Hipocampo/patologia , Imuno-Histoquímica , Ataque Isquêmico Transitório/patologia , Masculino , Ácido Quinolínico/imunologia , Coelhos , Fatores de TempoRESUMO
We have investigated the age-dependent profile of two groups of NMDAR1 mRNA isoforms, the NR1(0)XX and the NR1(1)XX, which are characterized by the absence and the presence, respectively, of an N-terminal positioned 21 amino acid insert. mRNAs of the two spliced variants were investigated at different ages in discrete rat brain areas by means of the reverse transcription-polymerase chain reaction. The existence of regional variations was confirmed as well as a region-specific pattern of NR1(0)XX/1XX ratio and its age-dependent changes. At 6 months, the ratio was > 3 in prosencephalic structures and < 1 in metencephalic regions. The greatest age-related changes were found in the cerebellum that switched from a maximal ratio of 5.1 +/- 0.4 at day 6 through a progressive decay down to the value of 0.3 +/- 0.04 at 24 months. Age-dependent changes of the different NR1 spliced variant mRNAs are relevant to understand possible regulatory mechanisms of the pharmacological properties and functions of different NMDAR subtypes.
Assuntos
Química Encefálica , Encéfalo/crescimento & desenvolvimento , RNA Mensageiro/análise , Receptores de N-Metil-D-Aspartato/genética , Fatores Etários , Animais , Sequência de Bases , Encéfalo/metabolismo , Córtex Cerebelar/química , Córtex Cerebral/química , Regulação da Expressão Gênica , Hipocampo/química , Hipotálamo/química , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Ponte/química , RNA Mensageiro/genética , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/biossíntese , Receptores de N-Metil-D-Aspartato/classificaçãoRESUMO
The excitotoxic brain metabolite quinolinic acid (QUIN) has been hypothetically linked to the pathogenesis of seizure disorders and other neurodegenerative events affecting the hippocampal formation. Its biosynthetic enzyme, 3-hydroxyanthranilic acid oxygenase (3-HAO) and its catabolic enzyme, quinolinic acid phosphoribosyltransferase (QPRT), can be used as markers for the cellular localization of the brain's QUIN system. Measured between 2 days and 2 months following intrahippocampal ibotenic acid injections, the activities of both enzymes increased at the lesion site due to the synthesis of new enzyme protein. The time course of the increase in 3-HAO activity coincided with that of the known astrocytic proliferation following excitotoxic insults. It is less obvious if the elevation in QPRT activity, too, is related to an increase in the number of reactive glial cells. No changes in the activity of hippocampal 3-HAO or QPRT were noted 7 or 60 days after cholinergic deafferentation by fornix-fimbria transection nor were any changes observed in the contralateral hippocampus at any time-point following the ibotenate lesion. These data raise the possibility that a feed-forward mechanism, resulting in ever increasing amounts of QUIN in the brain, may be operant in situations of progressive hippocampal nerve cell loss.
Assuntos
Hipocampo/metabolismo , Degeneração Neural , Piridinas/metabolismo , Ácidos Quinolínicos/metabolismo , Animais , Hipocampo/enzimologia , Masculino , Oxirredutases/metabolismo , Pentosiltransferases/metabolismo , Ácido Quinolínico , Ratos , Ratos EndogâmicosRESUMO
By testing the effect of spermine on N-methyl-D-aspartate (NMDA)-evoked [3H]noradrenaline release in rat hippocampal slices, we revealed a presynaptic spermine-sensitive NMDA receptor most probably localized on noradrenergic terminals. Spermine (1 mM), per se totally inactive, was able to reverse the tetrodotoxin-induced blockade of the NMDA effect, restoring tritium efflux to approximately 50% of the NMDA-evoked release measured in the absence of tetrodotoxin. This effect was partially antagonized by D(-)-2-amino-7-phosphonoheptanoic acid. Our results may help to elucidate the role that spermine exerts on excitatory amino acids receptors.
Assuntos
Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Espermina/farmacologia , Tetrodotoxina/farmacologia , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Masculino , Norepinefrina/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Kynurenic acid is an endogenous excitatory amino-acid receptor antagonist with neuroprotective and anticonvulsant properties. We demonstrate here that systemic administration of the new and potent kynurenine 3-hydroxylase inhibitor (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a dose-dependent elevation in endogenous kynurenine and kynurenic acid levels in rat brain tissue. In hippocampal microdialysates, peak increases of 10- and 80-fold above basal kynurenic acid concentrations, respectively, were obtained after a single oral or intraperitoneal administration of 400 mg/kg FCE 28833A. After intraperitoneal treatment with FCE 28833A, extracellular brain kynurenic acid levels remained significantly elevated for at least 22 h, rendering this compound a far more effective enhancer of kynurenic acid levels than the previously described kynurenine 3-hydroxylase blocker m-nitrobenzoylalanine. FCE 28833A and similar molecules may have therapeutic value in diseases which are linked to a hyperfunction of excitatory amino-acid receptors.
Assuntos
Encéfalo/efeitos dos fármacos , Butiratos/farmacologia , Ácido Cinurênico/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Repeated but not single injections of estradiol benzoate significantly reduced nigral glutamic acid decarboxylase (GAD, EC 4.1.1.15). A single injection of the catecholestrogen 2-hydroxyestradiol produced similar results. Tolerance developed to the latter effect, as reflected by the lack of nigral GAD activity changes in rats repeatedly injected with 2-hydroxyestradiol. Repeated injection of the antiestrogen tamoxifen not only failed to antagonize the action of estradiol benzoate but itself reduced nigral GAD activity. Hypophysectomy, which itself decreased nigral GAD activity prevented the lowering effects of either repeated estradiol benzoate administration or single 2-hydroxyestradiol injection on the enzymatic activity.
Assuntos
Estrogênios de Catecol/farmacologia , Estrogênios/farmacologia , Glutamato Descarboxilase/metabolismo , Substância Negra/enzimologia , Animais , Estradiol/análogos & derivados , Estradiol/farmacologia , Hipofisectomia , Masculino , Ratos , Ratos EndogâmicosRESUMO
The temporal sequence of electrophysiological and biochemical correlates of epilepsy induced by systemic injection of kainic acid (15 mg/kg i.p.) was investigated in male rats. A significant decrease in the hippocampal concentration of glutamate and aspartate was observed 20 min after the injection. These decreases preceded both electrographic and behavioral manifestations of epilepsy, thus suggesting a causal relationship between acidic amino acid changes and the genesis of kainate-induced hyperactivity. About 30-45 min after kainate injection, a decrease in glutamate, aspartate, glycine and taurine and no change in GABA concentration were observed. Bioelectrical activity, recorded in the regio inferior (CA3) of the hippocampus or in the fascia dentata revealed the presence of high frequency bursts separated by a long-lasting depression of discharge. About 55-75 min after the injection, the number of spikes in each burst increased and the duration and frequency of interictal pauses decreased. This stage was characterized by a decrease in glutamate and aspartate, restoration to normal of glutamine, glycine and taurine and a decrease in GABA.
Assuntos
Aminoácidos/metabolismo , Epilepsia/induzido quimicamente , Hipocampo/fisiologia , Ácido Caínico/farmacologia , Pirrolidinas/farmacologia , Animais , Eletrofisiologia , Hipocampo/metabolismo , Masculino , Ratos , Ratos Endogâmicos , Fatores de Tempo , Ácido gama-Aminobutírico/metabolismoRESUMO
Striatal microdialysis was performed in awake rats in an attempt to produce extracellular quinolinic acid (QUIN) from its putative bioprecursors L-tryptophan, L-kynurenine and 3-hydroxyanthranilic acid (3HANA). Test compounds were included in the microperfusion solution. QUIN concentrations in the dialysate remained below the assay sensitivity (i.e. less than 20 nM) under baseline conditions or after extensive perfusion with 1 mM L-tryptophan or L-kynurenine. 3HANA (10-300 microM) caused dose-dependent increases in extracellular QUIN, which attained steady-state concentrations after 4 h. The initial rate of QUIN production was significantly increased in the ibotenate-lesioned striatum, suggesting a pivotal role of astroglia in the deposition of brain QUIN.
Assuntos
Corpo Estriado/metabolismo , Espaço Extracelular/metabolismo , Piridinas/metabolismo , Ácidos Quinolínicos/metabolismo , Ácido 3-Hidroxiantranílico/metabolismo , Animais , Ácido Ibotênico , Ácido Cinurênico/metabolismo , Masculino , Ácido Quinolínico , Ratos , Ratos Endogâmicos , Triptofano/metabolismoRESUMO
Kynurenic acid (KYNA) production from its bioprecursor L-kynurenine (KYN) was assessed in vivo by intrastriatal microdialysis in freely moving rats. In the absence of KYN, the extracellular concentration of KYNA was below the limit of assay sensitivity (i.e. less than 8 pmol/30 microliters). In the presence of KYN (50-2000 microM), KYNA concentration in the dialysate increased continuously to reach steady-state levels after 2h of perfusion. Introduction of the unspecific transaminase inhibitor aminooxyacetic acid (AOAA) through the dialysis probe caused a progressive decrease of extracellular KYNA, which reached dose-dependent minimal levels within 2 h. One mM AOAA caused an almost complete depletion of KYNA in the dialysate. These data demonstrate that extracellular KYNA can be assessed by microdialysis and that AOAA can be used as a tool to examine the neurobiology of KYNA in awake, freely moving animals.
Assuntos
Ácido Amino-Oxiacético/farmacologia , Corpo Estriado/metabolismo , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Diálise/métodos , Relação Dose-Resposta a Droga , Cinética , Masculino , Ratos , Ratos EndogâmicosRESUMO
In vitro and in vivo techniques were used to examine the production and subsequent fate of the endogenous excitotoxin quinolinic acid (QUIN) following administration of its bioprecursor L-kynurenine (KYN). Incubation of liver slices in the presence of 10-1000 microM KYN resulted in a dose- and time-dependent release of QUIN into the incubation medium. Less than 15% of total QUIN produced was recovered from the tissue. In vivo experiments, performed with a microdialysis probe inserted in the jugular vein of anesthetized rats, showed that injection of KYN (20-600 mg/kg, i.v.) causes rapid and dose-dependent increases in the serum level of QUIN. Peak QUIN concentrations in serum dialysates were reached 75 minutes following KYN administration. Longer lasting increases were detected following the administration of pyrazinamide (20 mg/kg, i.p.), an indirectly acting stimulator of QUIN biosynthesis in the periphery. The data demonstrate the feasibility of assessing the mechanisms of QUIN production and disposition in experimental paradigms which can be expected to allow insights into the function and possible dysfunction of QUIN in the brain.
Assuntos
Cinurenina/farmacologia , Piridinas/biossíntese , Ácidos Quinolínicos/biossíntese , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Masculino , Ácido Quinolínico , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
GRF, a specific stimulator of GH release, increased in a concentration- and time-dependent manner pituitary [3H]-arachidonate levels in vitro. This effect was antagonized by 100 nM somatostatin. Exogenous arachidonate also stimulated GH release in vitro. Quinacrine, a phospholipase A2 inhibitor, reduced both basal and GRF-stimulated free arachidonate levels as well as GH release. The cyclooxygenase inhibitor indomethacin was ineffective, while BW755c, which also inhibits the lipoxygenase pathway, produced a further increase in the levels of the fatty acid stimulated by GRF and potently reduced GH release. These results provide additional evidence for the involvement of arachidonate metabolism in the hormone-releasing effect of GRF at the somatotroph.
Assuntos
Ácidos Araquidônicos/análise , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Fragmentos de Peptídeos/farmacologia , Hipófise/efeitos dos fármacos , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina , Animais , Ácido Araquidônico , Inibidores de Ciclo-Oxigenase , Relação Dose-Resposta a Droga , Hormônio Liberador de Hormônio do Crescimento/antagonistas & inibidores , Indometacina/farmacologia , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase , Masculino , Fragmentos de Peptídeos/antagonistas & inibidores , Hipófise/análise , Pirazóis/farmacologia , Quinacrina/farmacologia , Ratos , Ratos Endogâmicos , Somatostatina/farmacologiaRESUMO
The evidence for an involvement of QUIN in human seizure disorders is clearly circumstantial. Importantly, QUIN is not a classical neurotransmitter and may thus play only a negligible or no role at all in normal brain function (Foster et al., 1984). We have yet to understand if and how such a possibly inert metabolite may turn into a pathogen. Several crucial questions remain to be addressed before a case can be made for a 'quinolinic acid hypothesis' of temporal lobe epilepsy. Among the most prominent ones figure the extracellular concentration of QUIN in the human brain under normal and pathological ('epileptic') conditions, the relationship between QUIN metabolism in the brain and its extracellular concentration and, a related issue, the regulation of cerebral QUIN metabolism (i.e., turnover). It is of equal importance to assess if NMDA-receptors, particularly those in the hippocampus and other parts of the limbic system, can exert a modulatory function upon brain QUIN. Unquestionably, future experiments with selective NMDA-antagonists will prove useful for the elucidation of such possible (feedback) interactions.
Assuntos
Encéfalo/metabolismo , Convulsivantes , Epilepsia/fisiopatologia , Piridinas/fisiologia , Ácidos Quinolínicos/fisiologia , Receptores de Neurotransmissores/fisiologia , Vias Aferentes/fisiologia , Animais , Mapeamento Encefálico , Fibras Colinérgicas/fisiologia , Ácido Caínico/farmacologia , Ligantes , Oxirredutases/metabolismo , Pentosiltransferases/metabolismo , Ácido Quinolínico , Receptores de N-Metil-D-AspartatoRESUMO
A series of pyrrolo[3,2-c]quinoline derivatives were synthesised and evaluated as inhibitors of selected enzymes of the kynurenine pathway. 7-Chloro-3-methyl-1H-pyrrolo[3,2-c]quinoline-4-carboxylic acid (7a) was found to be a relatively potent and selective inhibitor of kynurenine-3-hydroxylase (KYN-3-OHase). A molecular modelling study showed a good superimposition of 7a with PNU-156561 and kynurenine the natural substrate of KYN-3-OHase.
Assuntos
Inibidores Enzimáticos/síntese química , Oxigenases de Função Mista/antagonistas & inibidores , Pirróis/síntese química , Quinolinas/síntese química , Animais , Inibidores Enzimáticos/farmacologia , Quinurenina 3-Mono-Oxigenase , Fígado/enzimologia , Estrutura Molecular , Pirróis/farmacologia , Quinolinas/farmacologia , RatosRESUMO
Exploratory and descriptive study with the following objectives: to identify the nursing students' feelings related to the undergraduate course and their perception towards the nursing profession. After the four-year course, 57.4% of students perceived nursing in a positive way as a profession for the future, valued, recognised, compensating even with some limitations. However, 25% of students still perceived nursing as a mechanical, manual and sacrificed profession, with a limited scientific vision and with a gap between theory and practice and as a consequence a lower recognition by the society. If current trends are maintained, the nurse's value would be much greater in the next decades within the Brazilian society according to 61% of respondents.