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1.
J Nippon Med Sch ; 81(3): 148-56, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24998961

RESUMEN

Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by pruritic and eczematous skin lesions and dermatitis that worsens under stressful conditions. However, the relation of these symptoms to an individual's stress sensitivity is not well understood. On the other hand, expression of the translocator protein (18 kDa) (TSPO), formerly known as the peripheral-type benzodiazepine receptor, has been used as a biological marker of trait anxiety and stress sensitivity. The present study was designed to address this issue by examining TSPO in patients with AD. Fifty-two patients with AD (30 male and 22 female) and 163 healthy volunteers (89 male and 74 female) participated in this study. State-Trait Anxiety Inventory (STAI) scores were significantly higher in patients with AD, especially male patients, than in healthy subjects. The expression of platelet TSPO, as determined with a binding assay with [(3)H] PK11195, was also significantly higher in patients with AD, indicating that AD is a stress-responsive disease. In genomic analysis using lymphocytes, a single-nucleotide polymorphism of the human TSPO gene at exon 4 (485G>A), which is presumably associated with an individual's stress sensitivity, showed significantly lower frequencies of G/G and higher frequencies of G/A in patients with AD than in healthy subjects. The severity of AD, as determined with the Scoring of Atopic Dermatitis index, was correlated with TSPO expression in male patients with the G/A phenotype. In conclusion, the present study provides new evidence that variation in the TSPO gene affects susceptibility to AD.


Asunto(s)
Dermatitis Atópica/metabolismo , Dermatitis Atópica/psicología , Receptores de GABA/metabolismo , Estrés Psicológico/fisiopatología , Alelos , Ansiedad/psicología , Dermatitis Atópica/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Isoquinolinas/metabolismo , Masculino , Polimorfismo de Nucleótido Simple , Ensayo de Unión Radioligante , Receptores de GABA/genética , Índice de Severidad de la Enfermedad , Tritio
2.
Psychiatry Clin Neurosci ; 68(1): 1-20, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24372896

RESUMEN

What psychiatric symptoms are caused by central noradrenergic dysfunction? The hypothesis considered in this review is that noradrenergic dysfunction causes the abnormalities in arousal level observed in functional psychoses. In this review, the psychiatric symptoms of noradrenergic dysfunction were inferred pathophysiologically from the neuroscience literature. This inference was examined based on the literature on the biology of psychiatric disorders and psychotropics. Additionally, hypotheses were generated as to the cause of the noradrenergic dysfunction. The central noradrenaline system, like the peripheral system, mediates the alarm reaction during stress. Overactivity of the system increases the arousal level and amplifies the emotional reaction to stress, which could manifest as a cluster of symptoms, such as insomnia, anxiety, irritability, emotional instability and exaggerated fear or aggressiveness (hyperarousal symptoms). Underactivity of the system lowers the arousal level and attenuates the alarm reaction, which could result in hypersomnia and insensitivity to stress (hypoarousal symptoms). Clinical data support the hypothesis that, in functional psychoses, the noradrenergic dysfunction is in fact associated with the arousal symptoms described above. The anti-noradrenergic action of anxiolytics and antipsychotics can explain their sedative effects on the hyperarousal symptoms of these disorders. The results of animal experiments suggest that excessive stress can be a cause of long-term noradrenergic dysfunction.


Asunto(s)
Neuronas Adrenérgicas/patología , Ansiolíticos/farmacología , Antipsicóticos/farmacología , Síntomas Conductuales/fisiopatología , Trastornos Mentales/fisiopatología , Neuronas Adrenérgicas/efectos de los fármacos , Animales , Ansiolíticos/uso terapéutico , Antipsicóticos/uso terapéutico , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/fisiología , Síntomas Conductuales/tratamiento farmacológico , Humanos , Trastornos Mentales/complicaciones , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/psicología , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatología
3.
Brain Res ; 1460: 63-72, 2012 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-22578359

RESUMEN

To elucidate the mechanism of epileptogenesis, seizures were investigated in the EL mouse, which is an excellent model for epilepsy. In these mice, epileptic seizures initiate in the parietal cortex, where markers of GABA-mediated inhibition are reduced compared with the parietal cortex of DDY mice (the parent strain). This is the first report on units of neuronal activity in the parietal cortex of EL and DDY mice (14 each) using an extracellular microelectrode in vivo under moderate pentobarbital anesthesia. The parietal cortex neurons of the EL mice were less active at rest than those of the DDY mice, but they responded more actively to proprioceptive afferent input from muscle stimulation than the DDY neurons. Three types of spontaneous firing were classified in both EL and DDY cortical neurons: periodically firing, Type A; continuously firing, Type B; and random firing, Type C. The proportions of these three types of neurons were almost the same in the EL mice as in the DDY mice. The peak frequency of the periodical cycle of Type A neurons in the EL mice (375 ms) was longer than that of the Type A neurons in the DDY mice (225 ms). Four patterns of responses to stimulation were observed in the parietal cortex neurons. More excitatory patterns were observed in the EL mice than in the DDY mice. The trans-laminar distribution of cells with different response patterns was also different between the EL and DDY mice. These characteristics of parietal cortex neurons may help determine the seizure susceptibility or ictogenesis in EL mice because the mechanisms underlying these patterns could provide the basis for hypersynchronized discharges in epileptic seizures.


Asunto(s)
Neuronas/fisiología , Lóbulo Parietal/citología , Lóbulo Parietal/fisiología , Potenciales de Acción/fisiología , Animales , Animales no Consanguíneos , Modelos Animales de Enfermedad , Epilepsia/fisiopatología , Femenino , Masculino , Ratones , Ratones Mutantes Neurológicos
4.
Epilepsia ; 51 Suppl 3: 131-4, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20618418

RESUMEN

Neurosteroids such as allopregnanolone (THP) act as positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors and have exerted anticonvulsant properties. However, their role in the regulation of epileptogenesis is unclear. It has been shown that circulating levels of THP fluctuate during development and seizure episodes. Furthermore, both chronic administration of THP and its withdrawal transiently increase expression of the alpha4 subunit of the GABAA receptor in the brain. The steroidogenic enzymes, 5-alpha-reductase (5aR) and 3-alpha-hydroxysteroid dehydrogenase (3aHSD) have been identified as well, indicating that various cell types are involved in the biosynthesis of neuroactive steroids in the brain. The purpose of the present study is to examine how GABAA receptor-modulating neurosteroids contribute to the epileptogenesis by using the epileptic mutant EL mouse. Male EL mice and control animals, DDY mice, were used. EL mice show secondary generalized seizures, which initiate primarily at the parietal cortex and generalize through the hippocampus. In the interictal period during development, changes of THP, 5aR, 3aSDH, and GABAA receptor alpha4, gamma2, and delta subunits were investigated by western blotting in the hippocampus. In EL mice, levels of the neurosteroid THP and the steroidogenic enzymes 5aR and 3aSDH significantly increased at 3 weeks of age, and rapidly decreased thereafter (5-10 weeks). The sharp withdrawal was observed before mice experienced frequent seizures. In contrast, GABAA alpha4, gamma2, and delta expressions were upregulated (3-8 weeks). In the brain of EL mice, positive neurosteroids such as THP were withdrawn before mice experienced repetitive seizures, which may likely be a trigger for ictogenesis and epileptogenesis. Furthermore, reorganization of the GABAA receptor subunits may lead to a hypersensitivity of the receptor to neurosteroids. Therefore, GABAA receptor-regulating neurosteroids may be a promising target for the development of novel antiepileptic agents.


Asunto(s)
Epilepsia/tratamiento farmacológico , Neurotransmisores/fisiología , Pregnanolona/análisis , Receptores de GABA-A/fisiología , 3-Hidroxiesteroide Deshidrogenasas/análisis , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/análisis , Factores de Edad , Animales , Modelos Animales de Enfermedad , Electroforesis en Gel de Poliacrilamida , Epilepsia/fisiopatología , Hipocampo/química , Hipocampo/crecimiento & desarrollo , Hipocampo/fisiopatología , Immunoblotting , Masculino , Ratones , Ratones Endogámicos , Neurotransmisores/análisis , Pregnanolona/fisiología , Receptores de GABA-A/análisis
5.
Eur J Pharmacol ; 632(1-3): 14-22, 2010 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-20097194

RESUMEN

Amlodipine, a dihydropyridine derivative, has been shown to block not only L-type but also N-type Ca(2+) channels. Aiming to understand the mechanism underlying such a selective blockade by amlodipine, the interaction of amlodipine with N-type channels was investigated using the Xenopus oocyte expression system together with the two-microelectrode voltage-clamp technique and the binding assay for [(3)H]amlodipine. When expressed as the alpha(1B)alpha(2/)delta(1)beta(1a) combination, the N-type channel formed a high affinity binding site for [(3)H]amlodipine (K(d), 3.08nM) and was profoundly blocked by amlodipine (IC(50), 2.7 microM at -60mV). By contrast, R-type (alpha(1E)alpha(2/)delta(1)beta(1a)) channels did not possess a high affinity binding site for [(3)H]amlodipine and their channel activities were not influenced by amlodipine. In comparison of amino acid sequences in the transmembrane regions IIIS5, IIIS6 and IVS6 of the alpha(1) subunit, which are involved in dihydropyridine binding in L-type channels, the two amino acid residues Lys(1287) (corresponding to Met(1295) in alpha1B) and Phe(1699) (corresponding to Leu(1697) in alpha(1B)) were unique in alpha(1E). An amino acid substitution of Lys1287Met in IIIS5 of alpha(1E) conferred a high affinity binding site for amlodipine (K(d), 13.1nM) and a sensitivity to amlodipine (IC(50), 11.3 microM). In N-type channel, reversely, an amino acid substitution of Met1295Lys in IIIS5 of alpha(1B) deprived a high affinity binding site for amlodipine and reduced the channel blockade by amlodipine (IC(50), 29.6 microM). The results indicate that Met(1295) in the region IIIS5 of alpha(1B) is critical for amlodipine to efficiently bind and block the N-type Ca(2+) channel.


Asunto(s)
Amlodipino/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/metabolismo , Dihidropiridinas/farmacología , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Amlodipino/metabolismo , Animales , Sitios de Unión/genética , Canales de Calcio Tipo N/genética , Dihidropiridinas/metabolismo , Relación Dosis-Respuesta a Droga , Electrofisiología , Femenino , Lisina/metabolismo , Microelectrodos , Oocitos/metabolismo , Técnicas de Placa-Clamp , Xenopus
6.
Neurochem Res ; 35(3): 412-7, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19795208

RESUMEN

Several lines of evidence strongly suggest that accumulation of noradrenaline (NA) in the brain may underlie the hyperarousal symptoms experienced in post-traumatic stress disorder. In animal experiments, however, the effect of stress on NA content appears complex; acute stress reduces the level, while chronic stress tends to increase it. To explain this discrepancy, it is necessary to observe the long-term effects of acute stress on NA metabolism in the brain. In this study, rats were exposed to intermittent intense footshock stress for 1 h, and the brain NA content was measured for 7 days after the stress stimulus. Hypothalamic NA content was immediately reduced and recovered within 24 h. However, a significant NA increase was observed 7 days after the footshock. In the cerebral cortex and hippocampus, an increase in NA content was observed 1 day after the stress and lasted for at least 7 days. The fact that the content of 3-methoxy-4-hydroxyphenylglycol, a major NA metabolite, only transiently increased in all these regions possibly reflects NA release. These results indicate that increase in the brain NA content can be induced by acute stress, though its emergence is delayed. Importantly, this suggests that both acute and chronic stress may lead to NA accumulation under the same mechanism.


Asunto(s)
Química Encefálica/fisiología , Norepinefrina/metabolismo , Estrés Psicológico/metabolismo , Enfermedad Aguda , Animales , Corteza Cerebral/metabolismo , Cromatografía Líquida de Alta Presión , Enfermedad Crónica , Modelos Animales de Enfermedad , Electrochoque , Pie/inervación , Pie/fisiología , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Metoxihidroxifenilglicol/metabolismo , Ratas , Ratas Wistar , Espectrometría de Fluorescencia , Trastornos por Estrés Postraumático/metabolismo
7.
Gene Regul Syst Bio ; 2: 267-74, 2008 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-19787089

RESUMEN

PURPOSE: Epileptic mutant EL mice show secondary generalized seizures. Seizure discharges initiate in the parietal cortex and generalize through the hippocampus. We have previously demonstrated an increase in the activity of inducible nitric oxide synthetase (iNOS) as well as a decrease in the activity of superoxide dismutase (SOD) in the hippocampus of EL mice, suggesting that cell toxic free radicals are increased in the brain of EL mice. In parallel with this, neurotrophic factors were significantly increased in the hippocampus of EL mice in earlier developmental stages before exhibiting frequent seizures. These findings were no longer present after frequent seizures, suggesting that these events may trigger ictogenesis. On the other hand, it is reported that limbic seizures rapidly induce cytokines and related inflammatory mediators. It remains to be seen, however, whether cytokines contribute to the transition from interictal to ictal state. The present study was designed to address this issue using EL mice. METHODS: EL mice at the age from 4 to 23 weeks and their control animal, DDY mice at the age of 10 and 20 weeks were used. Seizures were induced in EL mice once every week since 5 weeks. Cytokines, such as interleukin-1 alpha (IL-1a), interleukin 1-beta (IL-1b), IL-6, IL-1 receptor (IL-1r), IL-1 receptor antagonist (IL-ra) and tumor necrosis factor alpha (TNF-a) were examined by Western blotting in the 'focus complex' of brain (namely, in the parietal cortex and hippocampus) of EL mice in the interictal period at different developmental stages. In 15 week old EL mice, which show seizures once a week, these cytokines were similarly determined 5 min, 2 hr, 4 hr, 11 hr, 24 hr, 3 days and 6 days after the last seizure induced. RESULTS: A significant increase in the level of cytokines was observed in the brain of EL mice at any stages during development, compared with the level of cytokines in the brain of control DDY. Cytokines were increased predominantly before experiencing frequent seizures. In EL mice at the age of 15 weeks, the level of cytokines in the hippocampus was highest 6 days after seizures. In the parietal cortex, cytokines were most highly expressed 2 hr after seizures. The results indicate that cytokines were kept up-regulated until next seizures in the hippocampus, whereas they were transiently up-regulated immediately after seizures in the parietal cortex. CONCLUSION: It is concluded that in the brain of EL mice, pro-inflammatory cytokines are increased progressively and periodically in association with the development and the seizure activity, respectively. A periodic increase of cytokines prior to the next seizure episode may play a role in triggering the ictal activity. Namely, alteration of region-specific cytokines may induce ictal activities from the interictal state. It is conceivable that inflammatory cytokines may work together with neuronal factors during epileptogenesis and in the transition from interictal to ictal state.

8.
Epilepsia ; 48 Suppl 5: 119-25, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17910591

RESUMEN

We have recently found that there was DNA fragmentation without cell loss in the hippocampus in EL mice, an epileptic mutant. Neurotrophic factors are also expressed at high levels during the early developmental stages. In the present study, we used EL mice to examine how altered cyclin and the corresponding cyclin dependent kinase (CDK) family are related to cell proliferation during development and during epileptogenesis. Developmental changes of cyclin family and corresponding CDK family (cyclin D/CDK-4, cyclin E/CDK-2, cyclin A/CDK-2, cyclin A/CDK-1, cyclin B/CDK-1) were examined by Western blotting in the hippocampus of EL mice and in nonepileptic control animals (DDY mice). In addition, we attempted to quantify cell proliferation during this period. The developmental changes in cell proliferation were determined by using systemic injections of Bromo-deoxyUridine (BrdU) to label dividing cells. As compared with the control DDY mice, EL mice show an upregulation of cell cycle specific Cyclins/CDKs during early developmental stages suggesting that reentry into the cell cycle is enhanced prior to the onset of seizure activity, possibly due to the abundance of neurotrophic factors. These results show that Cyclins/CDKs are activated during early stages of development in an epileptic animal, before the mouse exhibits seizures. These results suggest that reentry of cells into the cell cycle, with consequent cell proliferation in the hippocampus, contribute to the seizure predispositions of EL mice.


Asunto(s)
Ciclo Celular/fisiología , Proliferación Celular , Fragmentación del ADN , Hipocampo/fisiopatología , Convulsiones/genética , Convulsiones/fisiopatología , Animales , Apoptosis/genética , Apoptosis/fisiología , Western Blotting , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/fisiología , Bromodesoxiuridina , Proteína Quinasa CDC2/fisiología , Ciclo Celular/genética , Ciclinas/fisiología , Modelos Animales de Enfermedad , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatología , Expresión Génica/genética , Expresión Génica/fisiología , Predisposición Genética a la Enfermedad/genética , Ratones , Ratones Endogámicos , Ratones Mutantes , Modelos Genéticos , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/fisiología
9.
Am J Med Genet B Neuropsychiatr Genet ; 141B(3): 222-6, 2006 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-16511838

RESUMEN

Panic disorder (PD) is the repeated sudden occurrence of panic attacks, episodes characterized by psychological symptoms. Peripheral benzodiazepine receptor (PBR) is closely associated with personality traits for anxiety tolerance, and that it holds promise as a biological marker of stressful conditions. We have performed association analyses using the polymorphism to determine the PBR in PD. We screened the subjects for sequence variations within the 5' region, the coding region (exons 2-4), and the 3' noncoding region. One novel missense variant in exon 4, derived from the nucleotide transition in codon 162 (CGT --> CAT:485G > A) resulting in an arginine-to-histidine (Arg --> His) change, was detected in these subjects. The 485G > polymorphism of the PBR gene was analyzed in 91 PD patients and 178 controls. The genotypic and allelic analyses of the 485G > A revealed significant differences between the panic patients and the comparison subjects (P = 0.021 and 0.014, respectively). The present study provides new and important evidence that variation in the PBR gene influences susceptibility to PD.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Mutación , Trastorno de Pánico/genética , Receptores de GABA-A/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Polimorfismo de Nucleótido Simple
10.
Epilepsia ; 46 Suppl 5: 10-6, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15987247

RESUMEN

PURPOSE: We recently observed inducible nitric oxide synthetase (iNOS) expression and decreased Cu, Zn-superoxide dismutase (Cu, Zn-SOD) activities in the hippocampus of epileptic mutant EL mice at the age of 30 weeks. In addition, the immediate early gene (IEG) c-fos is unusually expressed in the interictal period, suggesting activation of protein cascades associated with the epileptogenesis. Furthermore, DNA fragmentation has been detected preferentially in the hippocampus CA1 and the parietal cortex of EL mouse brain. It remains to be seen, however, how these abnormalities are related to the DNA fragmentation, and whether neuronal cell loss is involved. The present study was designed to address these issues. METHODS: NOS isoenzymes, pro- (Bax) and antiapoptotic factors (Bcl-2, Bcl-XL), and neurotrophic factors (brain-derived neurotrophic factor, BDNF; neurotrophin-3, NT-3; fibroblast growth factor-2, FGF-2) were determined by immunoblotting in the EL mouse brain at various developmental stages. Hematoxylin-eosin staining was applied to the formalin-fixed brains to examine the cell loss in the tissue. IEG expression in the interictal period was analyzed by in situ hybridization by using the 35S x-ray emulsion method. RESULTS: nNOS was the major component of NOS in the hippocampus of either EL or control DDY mice. In EL mice, however, iNOS was detectable at the age of 10 weeks, at which the animals usually experience the first seizures. eNOS, which appears in DDY brain, could scarcely be identified. Even in the interictal period, EL mice expressed c-fos continuously, preferentially in the parietal cortex and hippocampal CA1. In DDY mice, very low steady-state levels of Bcl-2 and Bax remained constant throughout development. In EL mice, these Bcl-2 and Bax levels were increased even before experiencing frequent seizures. BDNF in EL mice markedly increased temporarily during ictogenesis and epileptogenesis in their early periods. Unexpectedly, no cell loss was found in the hippocampus. CONCLUSIONS: DNA fragmentation without cell loss found in EL mouse brains appears to result from initial activation and later inactivation of the apoptotic process. Neurotrophic factors may play a role in the ictogenesis and the epileptogenesis during the early development. These gene expressions closely related to the periods critical for ictogenesis and epileptogenesis may be of particular importance in the development of antiepileptic drugs (AEDs) with novel mechanisms.


Asunto(s)
Encéfalo/metabolismo , Epilepsia/metabolismo , Ratones Mutantes Neurológicos/fisiología , Óxido Nítrico Sintasa/metabolismo , Animales , Apoptosis/genética , Apoptosis/fisiología , Encéfalo/enzimología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fragmentación del ADN/genética , Fragmentación del ADN/fisiología , Modelos Animales de Enfermedad , Epilepsia/genética , Expresión Génica , Genes Inmediatos-Precoces/genética , Genes Inmediatos-Precoces/fisiología , Genes bcl-2/genética , Genes bcl-2/fisiología , Genes fos/genética , Genes fos/fisiología , Hipocampo/metabolismo , Hibridación in Situ , Isoenzimas/metabolismo , Ratones , Ratones Endogámicos , Plasticidad Neuronal/genética , Óxido Nítrico Sintasa de Tipo II , Lóbulo Parietal/metabolismo , Ácido gamma-Aminobutírico/metabolismo
12.
Ann N Y Acad Sci ; 1025: 135-9, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15542710

RESUMEN

Piracetam and structurally related nootropics are known to potentiate the anticonvulsant effects of antiepileptic drugs. It remains to be seen, however, whether these nootropics inhibit proconvulsant actions of many toxic agents including Ro 5-4864, a specific agonist for peripheral-type benzodiazepine receptors (PBR). The present study was designed to address this issue using EL mice, an animal model of epilepsy. In behavioral pharmacological experiments, EL mice were highly susceptible to convulsions induced by Ro 5-4864 (i.p.) in comparison with nonepileptic DDY mice. Nefiracetam administered orally to EL mice inhibited spontaneous seizures. In DDY mice, convulsions induced by Ro 5-4864 were prevented by nefiracetam when administered by i.v. injection. Aniracetam (i.v.) was partially effective, but piracetam and oxiracetam were ineffective as anticonvulsants. Binding assay for brain tissues revealed a higher density of mitochondrial PBR in EL mice compared with DDY mice. Binding of the PBR ligands Ro 5-4864 to either EL or DDY mouse brain was inhibited by micromolar concentrations of these nootropic agents in the sequence of nefiracetam > aniracetam >> oxiracetam, piracetam. This rank order is identical to potency as anticonvulsants. These data suggest that nefiracetam may prevent toxic effects of PBR agonists through interacting with PBR.


Asunto(s)
Convulsivantes/antagonistas & inhibidores , Epilepsia/genética , Epilepsia/prevención & control , Nootrópicos/farmacología , Pirrolidinonas/farmacología , Animales , Benzodiazepinonas/antagonistas & inhibidores , Benzodiazepinonas/metabolismo , Benzodiazepinonas/toxicidad , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Convulsivantes/metabolismo , Convulsivantes/toxicidad , Relación Dosis-Respuesta a Droga , Epilepsia/inducido químicamente , Masculino , Ratones , Ratones Mutantes Neurológicos , Nootrópicos/metabolismo , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Pirrolidinonas/metabolismo , Receptores de GABA/metabolismo
13.
Ann N Y Acad Sci ; 1025: 389-97, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15542741

RESUMEN

It has recently been reported that nefiracetam, a nootropic agent, is capable of attenuating the development of morphine dependence and tolerance in mice. The mechanism of this antimorphine action is not clear. The present study was designed to address this issue using Xenopus oocytes expressing delta-opioid receptors, G proteins (G(i3alpha) or G(o1alpha)), and N-type (alpha1B) Ca2+ channels. Membrane currents through Ca2+ channels were recorded from the oocytes under voltage-clamp conditions. The Ca2+ channel currents were reduced reversibly by 40-60% in the presence of 1 microM leucine-enkephalin (Leu-Enk). The Leu-Enk-induced current inhibition was recovered promptly by nefiracetam (1 microM), while control currents in the absence of Leu-Enk were not influenced by nefiracetam. A binding assay revealed that 3H-nefiracetam preferentially bound to the membrane fraction of oocytes expressing G(i3alpha). When delta-opioid receptors were coexpressed, the binding was significantly increased. However, an additional expression of alpha1B Ca2+ channels decreased the binding. The results suggest that nefiracetam preferentially binds to G(i3alpha) associated with delta-opioid receptors, thereby inhibiting the association of G proteins with Ca2+ channels. In conclusion, nefiracetam negatively regulates the inhibitory pathway of opioid receptor-G protein-Ca2+ channel.


Asunto(s)
Canales de Calcio/metabolismo , Proteínas de Unión al GTP/metabolismo , Nootrópicos/metabolismo , Pirrolidinonas/metabolismo , Receptores Opioides/metabolismo , Animales , Femenino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Nootrópicos/farmacología , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Pirrolidinonas/farmacología , Xenopus
14.
J Alzheimers Dis ; 6(4): 435-42; discussion 443-9, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15345814

RESUMEN

Alpha-synuclein is a major constituent of pathological intracellular inclusion bodies, a common feature of several neurodegenerative diseases. Two missense mutations in the alpha-synuclein gene have been identified in confirmed autosomal-dominant familial Parkinson's disease, which segregate with the illness. However, the physiological function of alpha-synuclein remains unknown. After biochemical investigations we have revealed tubulin to be an alpha-synuclein associated/binding protein. Here, we show that alpha-synuclein induces polymerization of purified tubulin into microtubules. Mutant forms of alpha-synuclein lose this potential. The binding site of alpha-synuclein to tubulin is identified, and co-localization of alpha-synuclein with microtubules is shown in cultured cells. To our knowledge, this is the first demonstration of microtubule-polymerizing activity of alpha-synuclein. Now we can see a striking resemblance between alpha-synuclein and tau: both have the same physiological function and pathological features, making abnormal structures in diseased brains known as synucleinopathies and tauopathies. The discovery of a physiological role for alpha-synuclein may provide a new dimension in researches into the mechanisms of alpha-synuclein-associated neurodegenerative diseases.


Asunto(s)
Proteínas Asociadas a Microtúbulos/fisiología , Proteínas del Tejido Nervioso/fisiología , Oxidorreductasas de Alcohol , Animales , Sitios de Unión , Encéfalo/metabolismo , Encéfalo/patología , Células COS/metabolismo , Cartilla de ADN/genética , Proteínas de Unión al ADN/metabolismo , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Espacio Intracelular/metabolismo , Espacio Intracelular/patología , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación Missense/genética , Proteínas del Tejido Nervioso/genética , Fosfoproteínas/metabolismo , Mutación Puntual/genética , Reacción en Cadena de la Polimerasa , Porcinos , Sinucleínas , Transfección/métodos , alfa-Sinucleína , Proteínas tau/metabolismo
16.
J Alzheimers Dis ; 5(2): 139-48, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12719631

RESUMEN

Alpha-synuclein is a neuronal protein originally identified in Alzheimer's disease (AD) amyloid plaques in 1993 and named non-Abeta component precursor (NACP) [92]. Later, the discovery of two missense mutations (G88C and G209A), which resulted in Ala30Pro (A30P) and Ala53Thr (A53T) substitutions, of the alpha-synuclein gene in certain autosomal-dominant early onset familial Parkinson's disease (PD) has greatly promoted the understanding of the role of alpha-synuclein in the pathogenesis of neurodegenerative diseases, such as PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) [5,6,51,75]. At present, it is widely accepted that alpha-synuclein may play a central role in several neurodegenerative disorders because of the presence of insoluble alpha-synuclein as the major fibrillar component of inclusion bodies. From the cloning of the human alpha-synuclein cDNA in 1993 to the present, alpha-synuclein has been carefully documented in many aspects. In this article, we review the progress of studies on alpha-synuclein and its role in alpha-synuclein-related neurodegenerative diseases.


Asunto(s)
Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/farmacología , Enfermedades Neurodegenerativas/fisiopatología , Animales , Clonación Molecular , ADN Complementario , Modelos Animales de Enfermedad , Drosophila , Humanos , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Fosfoproteínas , Sinucleínas , alfa-Sinucleína
17.
Psychopharmacology (Berl) ; 162(3): 301-3, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12122488

RESUMEN

RATIONALE: Anxiety is the one of the main symptoms of psychiatric disorders. Psychosocial stressors have been shown to be related to the onset of anxious episodes. Peripheral-type benzodiazepine receptors (PBR) are involved in regulating stress responses. The sensitivity of PBR to acute or chronic stress has been demonstrated in various situations. The State-Trait Anxiety Inventory (STAI) is one of the longest standing and most frequently used measures of anxiety. The development, evaluation, and use of biological markers with anxious conditions in psychiatry are extremely important. OBJECTIVES: The aims of this survey are to see whether PBR can be used in screening the degrees of anxiety which occur when normal persons are placed in the stressful conditions. METHODS: Twenty-four healthy volunteers (14 men, 10 women; mean age 46 years) participated in this study. We administered the STAI to all the volunteers. The binding of the radioactive PBR antagonist [(3)H]PK 11195 to platelet membranes was determined for these volunteers. RESULTS: The mean STAI scores were 40.3+/-8.0 for trait anxiety and 39.0+/-8.9 for state anxiety. B(max) of the platelet PBR binding was 2845+/-2109 fmol/mg protein. Pearson correlational analyses revealed that B(max) values were significantly and positively correlated with scores for trait anxiety but not significantly correlated with scores for state anxiety. CONCLUSIONS: PBR on platelets are correlated with trait anxiety scales of the STAI in healthy normal subjects. It is therefore suggested that the density of platelet PBR is highly associated with these personality traits for anxiety tolerance. PBR density in platelet could also be used as a promising biological marker of stressful conditions.


Asunto(s)
Ansiedad/psicología , Plaquetas/metabolismo , Receptores de GABA-A/metabolismo , Adulto , Ansiedad/sangre , Unión Competitiva , Femenino , Humanos , Isoquinolinas/metabolismo , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Receptores de GABA-A/deficiencia , Índice de Severidad de la Enfermedad , Tritio
18.
Epilepsia ; 43 Suppl 5: 130-5, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12121307

RESUMEN

PURPOSE: In EL mice, ictogenesis is established at age approximately 10 weeks, whereas epileptogenesis is induced through an experience of repetitive seizures during development. An "abnormal neural plasticity" has been suggested to be involved in these pathologic processes. It also is known that two isoforms of nitric oxide (NO) synthetase (nNOS and eNOS) are essential for the long-term potentiation (LTP), a plastic response of neurons. It appears, therefore, that these NO synthetases might play a major role in the establishment of abnormal neural plasticity. The purpose of the present study was to investigate ictogenesis and epileptogenesis by observing alterations of NO synthetases as well as immediate early gene (IEG) expressions and gamma-aminobutyric acid (GABA) distributions in the brain during development and with respect to seizure history. METHODS: IEG (c-fos and zif) expression in EL mice were analyzed by in situ hybridization with 35S. Distribution of GABA concentrations and glutamic acid decarboxylase (GAD) activities in the parietal cortex of EL mice was quantitatively determined using ultramicroenzymatic chemistry (Lowry, 1978). Three isoforms of NOS were assayed by immunoblotting analysis for hippocampal tissues of EL mice and their control animals, DDY mice. DNA fragmentation was detected with the TUNEL method. RESULTS: In EL mouse brains, IEG expression was related to the seizure history, seizure threshold, and age. Even in the interictal period, the animals expressed IEG continuously when their seizure thresholds were very low. Among various IEG expression sites in the brain, hippocampal CA1 was the most remarkable. These IEG expression sites were almost identical to the brain regions of EL mice where GABA concentrations and GAD activities were altered. Unexpectedly, the eNOS content of EL was very small, although eNOS appears to be responsible for NO that mediates an increase in local cerebral blood flow during focal seizures. nNOS, iNOS, and to a lesser extent, eNOS were essential to establish both ictogenicity and epileptogenicity. DNA fragmentation was observed in the hippocampus of EL mice in the interictal period. CONCLUSIONS: Continuous IEG expression and abnormal GABAergic function are involved in the epileptogenesis of EL mice. Transiently expressed IEG, on the other hand, is associated with the ictogenesis. It is conceivable that an excess amount of iNOS (and subsequent increase in harmful antimicrobial NO) and a lesser amount of eNOS (and subsequent decrease in NO or endothelium-derived relaxing factor, EDRF) may work together to contribute to a focus complex and ictogenesis. Drugs that suppress iNOS and/or potentiate eNOS may be promising candidates for a new type of antiepileptic agent.


Asunto(s)
Epilepsia/genética , Ratones Mutantes Neurológicos/fisiología , Convulsiones/genética , Animales , Fragmentación del ADN , Expresión Génica , Genes Inmediatos-Precoces , Ratones , Óxido Nítrico Sintasa/metabolismo , Ácido gamma-Aminobutírico/metabolismo
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