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1.
Mil Med ; 175(12): 1030-6, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21265315

RESUMO

UNLABELLED: A 41-year-old male sustained a massive crushing injury to his left posterior thigh and buttock and transection of the sciatic nerve; he underwent an above-knee amputation with fillet flap. He was interviewed 24 months postoperatively to determine his phantom limb experience. At 37 and 42 months, testing for touch-pressure sensitivity of the residual limb and buttock was done with a 1-gram monofilament. RESULTS: (1) He described a typical phantom limb with some unusual features. (2) Stimulation of points on transposed and original skin were located accurately or roughly according to normal anatomy, were mislocated, or felt simultaneously at the point stimulated and another place, i.e., bilocations. It is hypothesized that such mislocations and bilocations represented clinical correlates of cortical somatosensory reorganization. It is not clear why a typical phantom limb could occur when there was only partial deafferentation of the limb. Further studies are recommended.


Assuntos
Traumatismos da Perna/cirurgia , Membro Fantasma/fisiopatologia , Retalhos Cirúrgicos , Adulto , Amputação Cirúrgica , Membros Artificiais , Coito/fisiologia , Defecação/fisiologia , Humanos , Masculino , Pressão , Procedimentos de Cirurgia Plástica , Lesões dos Tecidos Moles/cirurgia , Tato , Micção/fisiologia
2.
Epilepsy Behav ; 16(3): 415-7, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19762285

RESUMO

The inbred Balb/c mouse strain was more sensitive than the outbred NIH Swiss mouse to flurazepam's ability to antagonize electrically precipitated seizures. In prior work, a reduction in flurazepam's antiseizure efficacy was not observed 24h after forcing Balb/c mice to swim for up to 10 min in ambient temperature water. Thus, we wondered if a stress-induced reduction would be observed after forcing mice to swim for up to 10 min in cold (6 degrees C) water, a more severe stress. The current data show that 24 h after exposure to this stress, the ability of flurazepam to raise the threshold voltage for the elicitation of tonic hindlimb extension in the Balb/c mouse strain was reduced. The genetically inbred Balb/c mouse strain is emerging as an interesting animal model in which to study interactions of stress and genetic factors that affect endogenous neurotransmission mediated by l-glutamate and GABA at the NMDA and GABA(A) receptor complexes, respectively.


Assuntos
Ansiolíticos/uso terapêutico , Flurazepam/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/genética , Análise de Variância , Animais , Ansiolíticos/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrochoque/efeitos adversos , Flurazepam/farmacologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Psicológico/etiologia
3.
Psychiatry Res ; 167(1-2): 21-7, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19339054

RESUMO

Cognitive psychology offers tools to localize the memory processes most vulnerable to disruption in schizophrenia and to identify how patients with schizophrenia best remember. In this research, we used the University of Southern California Repeatable Episodic Memory Test (USC-REMT; Parker, E.S., Landau, S.M., Whipple, S.C., Schwartz, B.L., 2004. Aging, recall, and recognition: A study on the sensitivity of the University of Southern California Repeatable Episodic Memory Test (USC-REMT). Journal of Clinical and Experimental Neuropsychology 26(3), 428-440.) to examine how two different recognition memory probes affect memory performance in patients with schizophrenia and matched controls. Patients with schizophrenia studied equivalent word lists and were tested by yes-no recognition and forced-choice recognition following identical encoding and storage conditions. Compared with controls, patients with schizophrenia were particularly impaired when tested by yes-no recognition relative to forced-choice recognition. Patients had greatest deficits on hits in yes-no recognition but did not exhibit elevated false alarms. The data point to the importance of retrieval processes in schizophrenia, and highlight the need for further research on ways to help patients with schizophrenia access what they have learned.


Assuntos
Transtornos Cognitivos/diagnóstico , Rememoração Mental , Reconhecimento Psicológico , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Adulto , Escalas de Graduação Psiquiátrica Breve , Comportamento de Escolha , Transtornos Cognitivos/psicologia , Aprendizagem por Discriminação , Feminino , Humanos , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/psicologia , Testes Neuropsicológicos
4.
Eur Neuropsychopharmacol ; 18(4): 299-302, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17804205

RESUMO

Guanosine, a purine nucleotide, promotes the reuptake of l-glutamate by astrocytes; astrocytic reuptake of glutamate is a major mechanism of its synaptic inactivation. The current experiments showed that guanosine reduced the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor "open-channel" blocker, to raise the threshold voltage for electrically-precipitated tonic hindlimb extension in unstressed intact mice. This modulatory effect may be due to guanosine's removal of glutamate from the synaptic cleft, resulting in a reduced proportion of NMDA receptor-associated ion channels in the open configuration. The modulatory effect of guanosine on MK-801's ability to disrupt rotorod performance in unstressed mice or antagonize electrically-precipitated seizures in stressed mice was not seen. The inability to demonstrate modulation in the rotorod paradigm may reflect the sensitivity of this measure of motor incoordination to MK-801's disruptive effects. Whereas failure to see this effect in our incremental electroconvulsive shock paradigm in stressed mice may be due to the fact that stress and guanosine act in the same direction to reduce MK-801's antiseizure efficacy. Given the phencyclidine model of schizophrenia and its pharmacological actions as a noncompetitive NMDA receptor "open-channel" blocker and guanosine's antagonistic effect on MK-801's antiseizure efficacy in unstressed mice, the current data support development of guanine-based purines for the treatment of at least some aspects of schizophrenia.


Assuntos
Guanosina/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Temperatura Baixa/efeitos adversos , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Eletrochoque , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Equilíbrio Postural/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/fisiopatologia , Estresse Psicológico/fisiopatologia , Natação/psicologia
5.
Eur Neuropsychopharmacol ; 18(8): 565-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18164185

RESUMO

Twenty-four hours after mice are exposed to a single session of forced swimming in cold water, the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically precipitated seizures is reduced. Conceivably, this reduction in MK-801's antiseizure efficacy reflects a stress-induced alteration in NMDA receptor-mediated neurotransmission due to changes in gene expression 24 h after a single stress. Recently, epigenetic interventional strategies impacting expression of genes whose regulation is controlled by the acetylation status of histone proteins in the nucleosome, an octomeric complex of histone proteins and promoter regions of double-stranded DNA, have been tested in preclinical models of various neuropsychiatric disorders, including Huntington disease and major depression. These strategies have been studied extensively in cancer biology. In the current investigation, the severity of the stress-induced reduction of MK-801's ability to raise the threshold voltage for the elicitation of tonic hindlimb extension was reduced when sodium butyrate (1.5 g/kg, ip) was administered around the time of stress. Prior research showed that this dose of sodium butyrate reliably increased the acetylation status of H3 and H4 histone proteins in the hippocampus and cerebral cortex of mice. Thus, the attenuation of the stress-induced reduction of MK-801's antiseizure efficacy may be due to the increased acetylation of histone proteins in the nucleosomal core and promotion of gene expression. These data encourage development of epigenetic strategies to prevent some of the deleterious consequences of stress.


Assuntos
Butiratos/uso terapêutico , Maleato de Dizocilpina/efeitos adversos , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Fármacos Neuroprotetores/efeitos adversos , Estresse Psicológico/tratamento farmacológico , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Eletrochoque/efeitos adversos , Masculino , Camundongos , Estresse Psicológico/fisiopatologia
6.
Eur Neuropsychopharmacol ; 18(11): 814-9, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18674888

RESUMO

The genetically-inbred Balb/c mouse strain shows heightened sensitivity to the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to raise the threshold voltage necessary to precipitate tonic hindlimb extension and elicit irregular episodes of intense jumping behavior (referred to as "popping"), relative to other inbred mouse strains and the outbred NIH Swiss mouse. Moreover, an allosteric modulatory effect of sarcosine, a glycine reuptake inhibitor, on MK-801's antagonism of electrically precipitated seizures was detected 24 h after Balb/c mice were forced to swim in cold water for up to 10 min; this was not observed in unstressed Balb/c mice or stressed or unstressed NIH Swiss mice. Phencyclidine (PCP), a noncompetitive NMDA receptor antagonist that binds to the same hydrophobic channel domain as MK-801, precipitates a schizophreniform psychosis in susceptible individuals that shares descriptive similarities with schizophrenia. This observation has led to the hypothesis that NMDA receptor hypofunction (NRH) is involved in the pathophysiology of schizophrenia and the testing of pharmacotherapeutic strategies to facilitate NMDA receptor-mediated neurotransmission in patients with this disorder (e.g., glycine reuptake inhibitors). The heightened behavioral sensitivity of the Balb/c mouse to MK-801 suggests that this mouse strain may be a useful model to study "psychosis-proneness" and screen for positive allosteric modulators of NMDA receptor-mediated neurotransmission. Conceivably, strain differences in the pharmacology of the NMDA receptor are due to differences in the relative expression of individual NMDA receptor subunits to each other (i.e., combinatorial regulation). The current study compared the normal protein expression patterns of six of the eight identified splice variant isoforms of the NR1 NMDA receptor subunit, and NR2A and NR2B subunits in the hippocampus and cerebral cortex of Balb/c and NIH Swiss mice. The heightened behavioral sensitivity of the Balb/c genetically-inbred mouse strain to MK-801, compared to the outbred NIH Swiss mouse strain, does not appear to result from relative alterations of expression of these NMDA receptor protein subunits that were examined.


Assuntos
Comportamento Animal/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Animais , Western Blotting , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Densitometria , Eletroforese em Gel Bidimensional , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fenciclidina/farmacologia , Receptores de N-Metil-D-Aspartato/biossíntese , Especificidade da Espécie
7.
Eur Neuropsychopharmacol ; 18(2): 147-51, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17656074

RESUMO

The regionally selective reduction of expression of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) in schizophrenia underlies impaired sensory inhibition, a possible endophenotype of the disorder. This ligand-gated ion channel receptor has been proposed as a pharmacotherapeutic target in schizophrenia. The current study examined the effect of CDP-choline alone and the combination of CDP-choline and galantamine, administered acutely and once-daily for five consecutive days, in an animal model of NMDA receptor hypofunction that is relevant to schizophrenia. The results support the allosteric modulatory influence of galantamine on CDP-choline; however, individual doses of CDP-choline and galantamine must be carefully titrated in order to achieve optimal levels of alpha7 nAChR "agonism" that may be necessary for the desired therapeutic effect.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Citidina Difosfato Colina/uso terapêutico , Galantamina/uso terapêutico , Nootrópicos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Interações Medicamentosas , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos
8.
CNS Spectr ; 13(5): 393-403, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18496477

RESUMO

Pain, spasticity, tremor, spasms, poor sleep quality, and bladder and bowel dysfunction, among other symptoms, contribute significantly to the disability and impaired quality of life of many patients with multiple sclerosis (MS). Motor symptoms referable to the basal ganglia, especially paroxysmal dystonia, occur rarely and contribute to the experience of distress. A substantial percentage of patients with MS report subjective benefit from what is often illicit abuse of extracts of the Cannabis sativa plant; the main cannabinoids include delta-9-tetrahydrocannabinol (delta9-THC) and cannabidiol. Clinical trials of cannabis plant extracts and synthetic delta9-THC provide support for therapeutic benefit on at least some patient self-report measures. An illustrative case is presented of a 52-year-old woman with MS, paroxysmal dystonia, complex vocal tics, and marijuana dependence. The patient was started on an empirical trial of dronabinol, an encapsulated form of synthetic delta9-THC that is usually prescribed as an adjunctive medication for patients undergoing cancer chemotherapy. The patient reported a dramatic reduction of craving and illicit use; she did not experience the "high" on the prescribed medication. She also reported an improvement in the quality of her sleep with diminished awakenings during the night, decreased vocalizations, and the tension associated with their emission, decreased anxiety and a decreased frequency of paroxysmal dystonia.


Assuntos
Cannabis , Dronabinol/uso terapêutico , Alucinógenos/uso terapêutico , Abuso de Maconha/tratamento farmacológico , Esclerose Múltipla/complicações , Esclerose Múltipla/terapia , Distonia Paroxística Noturna/etiologia , Distonia Paroxística Noturna/terapia , Fitoterapia/métodos , Tiques/etiologia , Tiques/terapia , Adulto , Feminino , Humanos , Masculino
9.
Metabolism ; 56(7): 947-53, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17570257

RESUMO

Moderate alcohol consumption has been linked to lower incidence of coronary artery disease due to increased plasma high-density lipoprotein (HDL), whereas heavy drinking has the opposite effect. Because of the crucial role of HDL in reverse cholesterol transport and positive correlation of HDL sphingomyelin (SM) content with cholesterol efflux, we have compared HDL SM content with its reverse cholesterol transport capacity both in rats fed ethanol on long-term basis and alcoholic individuals. In rats, SM HDL content was decreased in the ethanol group (-15.4%, P < .01) with a concomitant efflux decrease (-21.0%, P < .01) compared to that in controls. Similarly, HDL from the ethanol group, when compared with HDL from the control group, exhibited 13.8% (P < .05) less cholesterol uptake with control-group hepatocytes and 35.0% (P < .05) less cholesterol uptake with ethanol-group hepatocytes. Conversely, hepatocytes from the ethanol group, when compared with hepatocytes from the control group, exhibited 31.0% (P < .01) less cholesterol uptake with control-group HDL and 48.0% (P < .01) less with ethanol-group HDL. In humans, SM content in plasma HDL was also decreased in chronically alcoholic individuals without liver disease (-51.5%, P < .01) and in chronically alcoholic individuals with liver disease (-51.3%, P < .01), compared with nondrinkers. Concomitantly, in alcoholic individuals without liver disease, both efflux and uptake were decreased by 83.0% and 54.0% (P < .01), respectively, and in chronically alcoholic individuals with liver disease by 84.0% and 61.0% (P < .01), respectively, compared with nondrinkers. Based on these findings, we conclude that long-term ethanol consumption significantly impairs not only cholesterol efflux function of HDL by decreasing its SM content but also cholesterol uptake by affecting presumably hepatocyte receptors for HDL.


Assuntos
Colesterol/metabolismo , Etanol/toxicidade , Lipoproteínas HDL/fisiologia , Esfingomielinas/análise , Adulto , Animais , Transporte Biológico/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Lipoproteínas HDL/análise , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Endogâmicos WF
10.
Eur Neuropsychopharmacol ; 17(1): 53-7, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16616833

RESUMO

NMDA receptor hypofunction (NRH) has been implicated in the pathophysiology of schizophrenia because of the ability of phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, to precipitate a schizophreniform psychosis. The possible role that NRH plays in the pathophysiology of schizophrenia stimulated characterization of behaviors elicited by PCP and its analogues. For example, MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist that binds with higher affinity to the same hydrophobic channel domain as PCP, raises the threshold voltage required for the electrical precipitation of tonic hindlimb extension in mice. This ability of MK-801 is significantly reduced following stress. We showed that an exogenously administered glycine prodrug (i.e., milacemide) was able to potentiate MK-801's antiseizure efficacy in unstressed mice and restore MK-801's antiseizure efficacy in stressed animals. d-Serine may serve as an endogenous agonist for the obligatory glycine co-agonist site on the NMDA receptor complex. Orally administered d-serine has been studied clinically as an adjuvant therapeutic intervention in schizophrenia. Thus, we were surprised at its inability to potentiate MK-801's antiseizure efficacy in either control or stressed animals. These data do not support the development of d-serine as a viable therapeutic intervention for schizophrenia and, possibly, other disorders.


Assuntos
Maleato de Dizocilpina/uso terapêutico , Eletrochoque/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico , Convulsões/prevenção & controle , Serina/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Interações Medicamentosas , Masculino , Camundongos , Convulsões/etiologia
11.
CNS Spectr ; 12(12): 903-7, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18163035

RESUMO

Williams syndrome is a neurodevelopmental disorder that results from the deletion of approximately 25-30 genes spanning about 1.5 megabases in the q11.23 region of chromosome 7. Patients with this syndrome present with a combination of a distinctive elfin-like facial appearance; growth retardation; mild mental retardation; an inconsistent cognitive profile that includes visuospatial impairments with good facial discrimination and relatively preserved expressive language skills; and cardiovascular abnormalities. In addition, a striking behavioral feature of the syndrome is the high sociability and empathy that these patients show for others. The study of patients with "partial" deletions of the chromosome band 7q11.23, mutated genes in this region and knockout mice with deletions of specific genes in the homologous G1-G2 region of mouse chromosome 5 are clarifying some genotype/phenotype relationships. Furthermore, genes located in this region that are prominently expressed have been implicated in brain development and function. The neuropsychological profile of patients with Williams syndrome is heterogeneous, highlights important dissociations between cognitive functions and suggests that the behavioral dimensions of sociability, empathy, engageability, and talkativeness may be independent of, or not easily explained by, the cognitive deficits. Williams syndrome has enormous heuristic value because its pathological feature of heightened "sociability" can be a "deficit" symptom of major complex neuropsychiatric disorders, such as schizophrenia and autism. Data consistent with a core inability of patients with Williams syndrome to inhibit social approach suggest that this disorder may afford an opportunity to study the biological basis of the "drive" toward socialization. From a research perspective, the syndrome lends itself to neurobiological studies of sociability as a dimension that varies independently of cognition (or at least many separable cognitive processes). Importantly, from a clinical perspective, the syndrome challenges us to administer strategic psychosocial interventions that take advantage of the opportunities that "pathological" sociability provide, while avoiding its threats. An illustrative example of an effective strategically planned psychosocial intervention for a patient with Williams syndrome is briefly presented.


Assuntos
Deleção de Genes , Comportamento Social , Meio Social , Síndrome de Williams/genética , Adulto , Cromossomos Humanos Par 7/genética , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Feminino , Humanos , Relações Interpessoais , Testes Neuropsicológicos , Síndrome de Williams/epidemiologia
12.
CNS Spectr ; 12(4): 289-92, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17426666

RESUMO

A case is presented of a 56-year-old woman with a history of an eating disorder that preceded recognition of a mitochondrial myopathy. The possibility exists that her eating disorder was causally related to a more fundamental defect in mitochondrial oxidative metabolism. This case report highlights the phenotypic variability of mitochondrial myopathies. An increased risk of eating disorder may be associated with drugs that interfere with mitochondrial oxidative respiration.


Assuntos
Bulimia Nervosa/complicações , Síndrome MERRF/complicações , Apetite/genética , Bulimia Nervosa/genética , Bulimia Nervosa/psicologia , DNA Mitocondrial/genética , Diagnóstico Diferencial , Carboidratos da Dieta/administração & dosagem , Feminino , Predisposição Genética para Doença/genética , Humanos , Síndrome MERRF/genética , Síndrome MERRF/psicologia , Pessoa de Meia-Idade , Fenótipo
13.
Prog Neuropsychopharmacol Biol Psychiatry ; 30(8): 1369-80, 2006 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-16793187

RESUMO

Two members of the family of low-density lipoprotein receptors (i.e., very low-density lipoprotein [VLDL] receptor and apolipoprotein E [apoE] type 2 receptor) are expressed in brain, where they bind and transduce reelin, a secreted glycoprotein that shares structural analogies with extracellular matrix proteins. In the developing fetal brain, reelin-signal transduction is critical for the correct positioning of neurons and the formation of appropriate synaptic connections, whereas in the mature brain, reelin participates in the mediation of experience-dependent synaptic plasticity. An important "downstream" consequence of the reelin-signal transduction cascade is inhibition of the phosphorylation of tau, a protein that regulates microtubule assembly and stability. Importantly, hyperphosphorylated tau comprises the paired helical filament, whose pathological deposition as neurofibrillary tangles is implicated in Alzheimer's disease; hyperphosphorylated tau is also implicated in the pathogenesis of other neurodegenerative disorders. Isoforms of apoE may affect the binding of reelin to its cell surface receptors and, thereby, influence tau phosphorylation, whereas insulin, insulin-like growth factor-1, and the lithium ion have actions within the cell at the level of the specific tyrosine kinases involved in the phosphorylation of tau. These data support the exploration of pharmacotherapeutic interventions designed to prevent or reduce the burden of hyperphosphorylated tau. Impaired reelin-signal transduction due to an actual deficiency of reelin expression may occur in at least some patients with psychotic disorders, especially schizophrenia; conceivably, hyperphosphorylation of tau would result from deficient transduction of reelin in schizophrenia. Schizophrenia has been conceptualized as a neurodevelopmental disorder of impaired synaptic "connectivity", whose consequence does not become fully apparent until late adolescence or early adulthood. In summary, hyperphosphorylation of tau may be an underlying point of pathological convergence for several neuropsychiatric disorders, and prevention of tau hyperphosphorylation may be an important therapeutic target.


Assuntos
Doença de Alzheimer/etiologia , Demência/etiologia , Esquizofrenia/etiologia , Proteínas tau/metabolismo , Envelhecimento , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Humanos , Proteínas do Tecido Nervoso/metabolismo , Fosforilação , Receptores de LDL/metabolismo , Proteína Reelina , Serina Endopeptidases/metabolismo , Transdução de Sinais
14.
Eur Neuropsychopharmacol ; 16(8): 547-51, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16504486

RESUMO

Hyperphosphorylated tau protein is the basic structural component of the neurofibrillary tangle, a histopathological hallmark of Alzheimer's disease. The formation of hyperphosphorylated tau protein may impair learning and the synaptic plasticity of neurons. Tau is a protein that is associated with and stabilizes microtubules; hyperphosphorylated tau protein is unable to perform this stabilization function. The transduction of reelin, a protein that is crucial to neuronal migration and the formation of synaptic connections in the fetal brain, may have an equally important role in regulating at least some forms of learning and synaptic plasticity in the fully developed mature brain. Reelin transduction is mediated by receptors in the brain that are members of the superfamily of low-density lipoprotein receptors. An important downstream target of reelin signal transduction appears to be inhibition of an enzyme involved in the regulation of tau phosphorylation. The faulty transduction of the reelin signal may be a pathological mechanism leading to hyperphosphorylation of tau protein. Ultimately, inhibition of tau phosphorylation may be an important therapeutic target in Alzheimer's disease and other neuropsychiatric disorders.


Assuntos
Doença de Alzheimer/metabolismo , Moléculas de Adesão Celular Neuronais/fisiologia , Proteínas da Matriz Extracelular/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Serina Endopeptidases/fisiologia , Transdução de Sinais/fisiologia , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Humanos , Plasticidade Neuronal/fisiologia , Fosforilação , Proteína Reelina
15.
Brain Res Bull ; 69(6): 626-30, 2006 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-16716829

RESUMO

Abnormalities of NMDA receptor-mediated neurotransmission are involved in the pathophysiology of schizophrenia, Alzheimer's disease, substance abuse and seizure disorders. The NMDA receptor is implicated in schizophrenia because phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, binds to a hydrophobic domain within the channel, precipitating a schizophreniform psychosis in susceptible persons. Pharmacological, environmental, and genetic variables alter NMDA receptor-mediated neurotransmission. Inbred mouse strains differ in their sensitivity to some of the behavioral effects of MK-801 (dizocilpine), a PCP analogue. The NMDA receptor complex in the BALB/c strain could reflect a unique stoichiometric combination of receptor subunits resulting in a higher proportion of the channels in the open configuration, a higher affinity of MK-801 for its hydrophobic channel domain, and/or a combination of the above. The BALB/c mouse strain, "stressed" mice, and behavioral consequences of MK-801 administration represent models of altered glutamatergic neural transmission. We were interested in examining the effect of stress on the modulatory properties of d-serine and sarcosine. d-Serine is a naturally occurring glycine agonist that modulates the ability of l-glutamate to influence the opening of the NMDA receptor-associated ionophore, and sarcosine is a naturally occurring glycine reuptake inhibitor. The data suggest that 24h after stress, d-serine and sarcosine interact synergistically to reduce MK-801's ability to antagonize electrically precipitated tonic hindlimb extension. Under conditions of stress, modulatory effects of d-serine and sarcosine on the antiseizure effect of MK-801 are observed that are not apparent in the nonstress condition. The results could be relevant to the development of glycinergic interventions for the treatment of neuropsychiatric disorders.


Assuntos
Receptores de N-Metil-D-Aspartato/fisiologia , Sarcosina/farmacologia , Serina/farmacologia , Estresse Fisiológico/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos , Análise de Variância , Animais , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletrochoque/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Convulsões/tratamento farmacológico , Convulsões/etiologia , Convulsões/fisiopatologia , Transmissão Sináptica/genética
16.
Clin Neuropharmacol ; 29(6): 361-3, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17095900

RESUMO

Sarcosinemia is a relatively rare autosomal recessive disorder that has a varied phenotypic presentation; rarely, it is associated with neurodevelopmental and neurological abnormalities. Sarcosine is a key intermediate in 1-carbon metabolism, and its elevation in blood and urine could reflect a deficient pool size of activated 1-carbon units. Sarcosine is also an inhibitor of an important glycine transporter in brain and is under clinical investigation as a glycinergic intervention for conditions with presumed N-methyl-d-aspartate (NMDA) receptor hypofunction, such as schizophrenia. Preclinical research with a mouse model that is used to study pharmacological modulation of endogenous NMDA receptor-mediated tone may clarify, at least in some instances, varied phenotypic presentations of sarcosinemia that are often clinically benign. Sarcosine's effectiveness as a glycinergic agonist intervention for NMDA receptor hypofunction depends on an interaction between genetic background and a stressful environmental insult. Thus, neurodevelopmental and neurological abnormalities may manifest rarely in sarcosinemia in the context of relatively unique genetic factors and fetal insult or stress.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Encéfalo , Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Sarcosina/metabolismo , Encéfalo/anormalidades , Encéfalo/crescimento & desenvolvimento , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/etiologia , Glicina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Humanos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos
17.
Psychiatry Res ; 145(2-3): 87-94, 2006 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-17074400

RESUMO

Diminished facial expressivity is a common feature of schizophrenia that interferes with effective interpersonal communication. This study was designed to determine if real-time visual feedback improved the ability of patients with schizophrenia to imitate and produce modeled facial expressions. Twenty patients with schizophrenia and 10 controls viewed static images of facial expressions and were asked to imitate them. Half of the images were imitated with the use of a mirror and half were imitated without the use of a mirror. In addition, we examined whether practice in imitating and producing expressions improved the ability of participants to generate facial expressions on their own, without the aid of a model or mirror. Participants' facial expressions were photographed with a digital camera and each was rated for accuracy in producing characteristic facial expressions. Patients with schizophrenia were less accurate in imitating and producing facial expressions than controls, and real-time visual feedback did not improve accuracy in either group. Preliminary findings suggest that exposure to model expressions and practice in generating these expressions can improve the accuracy of certain posed expressions in schizophrenia.


Assuntos
Expressão Facial , Comportamento Imitativo , Esquizofrenia , Psicologia do Esquizofrênico , Adulto , Emoções Manifestas , Retroalimentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos da Percepção/diagnóstico , Transtornos da Percepção/etiologia , Transtornos da Percepção/terapia , Ensino de Recuperação/métodos , Esquizofrenia/complicações , Percepção Visual
18.
Clin Neuropharmacol ; 28(1): 28-37, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15711436

RESUMO

The Lesch-Nyhan syndrome is a devastating sex-linked recessive disorder resulting from almost complete deficiency of the activity of hypoxanthine phosphoribosyltransferase (HPRT). The enzyme deficiency results in an inability to synthesize the nucleotides guanosine monophosphate and inosine monophosphate from the purine bases guanine and hypoxanthine, respectively, via the "salvage" pathway and an accelerated biosynthesis of these purines via the de novo pathway. The syndrome is characterized by neurologic manifestations, including the very dramatic symptom of compulsive self-mutilation. The neurologic manifestations may result, at least in part, from a mixture of neurodevelopmental (eg, a failure to "arborize" dopaminergic synaptic terminals) and neurotransmitter (eg, disruption of GABA and glutamate receptor-mediated neurotransmission) consequences. HPRT deficiency results in elevated extracellular levels of hypoxanthine, which can bind to the benzodiazepine agonist recognition site on the GABA(A) receptor complex, and the possibility of diminished levels of guanine-based purines in discrete "pools" involved in synaptic transmission. In addition to their critical roles in metabolism, gene replication and expression, and signal transduction, guanine-based purines may be important regulators of the synaptic availability of L-glutamate. Guanine-based purines may also have important trophic functions in the CNS. The investigation of the Lesch-Nyhan syndrome may serve to clarify these and other important neurotransmitter, neuromodulatory, and neurotrophic roles that guanine-based purines play in the central nervous system, especially the developing brain. A widespread and general deficiency of guanine-based purines would lead to impaired transduction of a variety of signals that depend on GTP-protein-coupled second messenger systems. This is less likely in view of a prominent localized pathologic effect of HPRT deficiency on presynaptic dopaminergic projections to the striatum. A possible more circumscribed effect of a deficiency of guanine-based purines could be interference with modulation of glutamatergic neurotransmission. Guanosine has been shown to be an important modulator of glutamatergic neurotransmission, promoting glial reuptake of L-glutamate. A deficiency of guanosine could lead to dysregulated glutamatergic neurotransmission, including possible excitotoxic damage. Unfortunately, although the biochemical lesion has been known for quite some time (ie, HPRT deficiency), therapeutically beneficial interventions for these affected children and adults have not yet emerged based on this elucidation. Conceivably, guanosine or its analogues and excitatory amino acid receptor antagonists could participate in the pharmacotherapy of this devastating disorder.


Assuntos
Hipoxantina Fosforribosiltransferase/deficiência , Síndrome de Lesch-Nyhan/metabolismo , Síndrome de Lesch-Nyhan/fisiopatologia , Transmissão Sináptica/fisiologia , Animais , Humanos
19.
Isr J Psychiatry Relat Sci ; 42(1): 33-44, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16134405

RESUMO

A convergence of preclinical pharmacology, and human autopsy and genetic data support the existence of reduced expression and function of the alpha7 nicotinic receptor in patients with schizophrenia. The alpha7 nicotinic receptor is a member of a family of ligand-gated ion channels. The alpha7 nicotinic receptor may play an essential role in auditory sensory gating and voluntary smooth pursuit eye movements, two psychophysiological functions that are abnormal in patients with schizophrenia and closely related unaffected biological relatives. Diminished expression or function of the alpha7 nicotinic receptor in schizophrenia has stimulated consideration of selective full or partial alpha7 nicotinic receptor agonists as possible therapeutic interventions for this disorder. Further, the availability of positive allosteric modulators of nicotinic receptors that can improve the efficiency of transduction of the acetylcholine signal and prevent the rapid desensitization of the receptor should encourage these novel treatment approaches (e.g., galantamine).


Assuntos
Receptores Nicotínicos/fisiologia , Esquizofrenia/fisiopatologia , Esquizofrenia/terapia , Movimentos Oculares/fisiologia , Humanos
20.
Schizophr Res ; 68(2-3): 363-72, 2004 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15099618

RESUMO

Clinicians rely on observational methods to assess obvious signs of postural abnormalities in schizophrenia, yet subtle signs of postural deficits may go unnoticed. Posture is controlled, in large part, by the cerebellum, which has been implicated in numerous reports of structural and functional deficits in schizophrenia. Given the possibility of an underlying disruption of cerebellar function in schizophrenia, this study used an objective, quantitative measure to assess the magnitude of postural stability in this disorder. A total of 36 schizophrenia patients and 36 non-psychiatric age-matched controls stood on a pressure-sensitive platform that recorded shifts in weight (body sway) through pressure points in the feet. Patients demonstrated more postural sway than did healthy controls (p<0.01). When patients with noticeable signs of tardive dyskinesia were removed from analyses, group differences remained (p<0.01). There was no significant correlation between neuroleptic medication level and degree of postural sway (r=0.16, p=0.37). These results indicate that patients with schizophrenia have subtle, yet quantifiable, disturbances in the control of posture and balance. Quantitative measures of postural sway may provide a more sensitive means of detecting disturbances of movement than do standard clinical observations alone.


Assuntos
Equilíbrio Postural/fisiologia , Postura/fisiologia , Esquizofrenia/diagnóstico , Adulto , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Discinesia Induzida por Medicamentos/diagnóstico , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/fisiopatologia , Exame Neurológico/instrumentação , Exame Neurológico/métodos , Exame Neurológico/estatística & dados numéricos , Equilíbrio Postural/efeitos dos fármacos , Propriocepção/efeitos dos fármacos , Propriocepção/fisiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia
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