RESUMO
Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) belong to the protein family of neurotrophins. They both display profound neuromodulatory functions and are essentially involved in the survival and homeostatic maintenance of central and peripheral neurons during development and adulthood. Moreover, NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross talk between neurons and immune cells. Neurotrophic factors have been implicated in pathophysiological mechanisms of many diseases of the nervous and the immune system, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), neuropathy, pain, allergic bronchial asthma (BA) and neurotrophic keratitis. For all these diseases research has reached the point of creating strategies for therapeutic intervention with neurotrophins. In this review, we present an overview of the pathophysiology, therapeutic interventions and strategies concerning NGF and BDNF in the mentioned diseases.
Assuntos
Asma/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/uso terapêutico , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Dor/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Asma/fisiopatologia , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/fisiopatologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Ceratite/tratamento farmacológico , Ceratite/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Receptores de Fator de Crescimento Neural/metabolismoRESUMO
Despite the availability of atypical antipsychotics, the treatment of negative symptoms in schizophrenia remains a challenge. This study was designed to confirm the positive effect observed in our pilot study with paroxetine as augmentation to antipsychotics in the treatment of negative symptoms in chronic schizophrenia. Twenty-nine patients with chronic schizophrenia, as defined by DSM-IV, who scored at least 20 points on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) were randomized for treatment with 30 mg paroxetine or placebo in a double-blind, placebo-controlled study for 12 weeks. Ratings included the PANSS, the Hamilton Rating Scale for Depression (HAM-D) and scales for extrapyramidal side-effects. An intention-to-treat analysis was based on the 25 patients who were available for at least one follow-up assessment. The last observation carried forward principle was applied. The mean score of the negative subscale of the PANSS decreased in both groups. Using an analysis of covariance, there was a significant treatment effect with paroxetine compared to placebo with respect to negative symptoms (-4.53; 95% confidence interval -9.054 to -0.015). The mean HAM-D scores remained almost constant. The study suggests the efficacy of paroxetine with respect to the treatment of negative symptoms in chronic schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Paroxetina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto , Doença Crônica , Manual Diagnóstico e Estatístico de Transtornos Mentais , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paroxetina/administração & dosagem , Placebos , Psicologia do Esquizofrênico , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Índice de Gravidade de DoençaRESUMO
Kleine-Levin syndrome (KLS) is commonly described as a self-limiting disorder exhibiting episodes of hypersomnia and psychiatric symptoms but without any enduring disabilities. Recently, some authors have reported persistent or even progressive memory deficits associated with the disorder. Nevertheless, literature about cognitive disturbances in KLS is rare. Our report describes a patient with deficits of visual and verbal recall after remission of an episode, as well as selective deficits of visual recall 6 months later. Neuropsychological testing is necessary in all patients with KLS to further characterize the profile and impact of associated cognitive deficits.
Assuntos
Síndrome de Kleine-Levin/complicações , Síndrome de Kleine-Levin/diagnóstico , Síndrome de Kleine-Levin/psicologia , Transtornos da Memória/etiologia , Adulto , Humanos , Masculino , Rememoração Mental/fisiologia , Testes NeuropsicológicosRESUMO
We report on the successful use of continuation electroconvulsive therapy (ECT) as prophylactic treatment of relapse in a case of confusion psychosis. The 20-year-old patient exacerbated in an almost annual rhythm and had been characterized as pharmacologically treatment-resistant since he failed to respond to any psychopharmacological therapy including sufficient clozapine as well as mood-stabilizing and sedating pharmacological treatments. After the diagnosis of confusion psychosis, the patient received ECT as monotherapy and showed a marked reduction of symptoms. Continuation ECT was then conducted for 7 months after the patient was discharged from hospital. Two years later, our patient is still in remission while continuation ECT has been tapered; no prophylactic psychotropic medication was prescribed in the last 2 years. Implications of this case on the therapy of confusion psychosis as well as on the diagnostic classification of confusion psychosis within our current systems are discussed.
Assuntos
Confusão/complicações , Confusão/terapia , Eletroconvulsoterapia/métodos , Transtornos Psicóticos/complicações , Transtornos Psicóticos/terapia , Adolescente , Humanos , Masculino , Indução de Remissão , Prevenção SecundáriaRESUMO
Massive elevations of serum creatine kinase (CK) can occur in a significant number of patients treated with neuroleptics in the absence of neuroleptic malignant syndrome (NMS). We report two cases of CK-elevations associated with quetiapine treatment, which disappeared after drug discontinuation. To our knowledge, case number one is the first case of quetiapine-induced CK elevation in a neuroleptic-naïve patient. We thus suggest CK assessment when myalgia occurs with neuroleptic treatment.
Assuntos
Antipsicóticos/efeitos adversos , Creatina Quinase/sangue , Dibenzotiazepinas/efeitos adversos , Adulto , Idoso , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Clozapina/uso terapêutico , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/enzimologia , Dibenzotiazepinas/uso terapêutico , Humanos , Masculino , Mianserina/análogos & derivados , Mianserina/uso terapêutico , Mirtazapina , Olanzapina , Dor/etiologia , Transtornos Psicóticos/sangue , Transtornos Psicóticos/tratamento farmacológico , Fumarato de QuetiapinaRESUMO
This report focuses on the successful treatment of a most acute case of confusion psychosis according to the concept of Karl Leonhard. The 18-year-old patient was hospitalized three times before the current episode and his case has been characterized as pharmacologically treatment-resistant psychosis since he failed to respond to any psychopharmacological therapy including sufficient clozapine medication. In the patient's history, typical and atypical antipsychotic as well as mood-stabilizing and sedating pharmacological treatments have been conducted. However, only adverse effects could be observed. When receiving electroconvulsive monotherapy (ECT), the patient showed a marked reduction of symptoms while experiencing no adverse effects. The implications of this finding are discussed with regard to Leonhard's diagnostic system.
Assuntos
Confusão/terapia , Eletroconvulsoterapia , Transtornos Psicóticos/terapia , Doença Aguda , Adolescente , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Confusão/tratamento farmacológico , Confusão/psicologia , Resistência a Medicamentos , Discinesia Induzida por Medicamentos/complicações , Humanos , Masculino , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/psicologiaRESUMO
The neurotrophin hypothesis proposes that repetitive neuronal activity enhances the expression, secretion and actions of neurotrophins to modify synaptic transmission and connectivity thereby providing a connection between neuronal activity and synaptic plasticity. Moreover, there is ample evidence that neurotrophins have numerous neuroprotective effects under pathological conditions, which might be important in particular for neurodegenerative diseases such as Alzheimer' disease. Current research postulates that effects during brain development lead to defective neural connectivity and altered biochemical functioning resulting in cognitive, emotional and intentional dysfunction later in life. This implicates a possible role in most psychiatric diseases including affective and schizophrenic disorders. This hypothesis is mainly based on new experimental evidence showing that psychiatric disorders are associated with neuronal atrophy and cell loss, impairments of structural plasticity and cellular resilience due to neurodevelopmental disturbances and morphological abnormalities of the brain. Thus, the potential role of neurotrophins in psychiatric disorders has been studied in different ways. Animal studies indicate the involvement of neurotrophins in psychopharmacological therapies and they show that gene expression of cerebral neurotrophins is changed in animal models of several psychiatric disorders. Whether such alterations are causatively associated with increased neural plasticity, improved cognitive function and decreased depressive mood states remains to be elucidated in further studies including man (e.g. in postmortem studies of patients). Association studies tried to link different variants in genes coding for neurotrophins, they have not been conclusive however. They partially allow to separate different subgroups of patients with differing therapy response profiles or indicate an increased vulnerability for a specific disorder. Finally, neurotrophin serum changes have been observed in most psychiatric disorders. The question remains though whether these alterations represent primary-causal or secondary-reactive changes.In conclusion, the issue of neuroprotection and neurotrophins is recognised as an important new lead in the quest for a deeper understanding of psychiatric disorders and the mechanisms of action of psychopharmacological interventions.
Assuntos
Transtornos Mentais/fisiopatologia , Modelos Neurológicos , Fatores de Crescimento Neural/metabolismo , Doença de Alzheimer/sangue , Animais , Depressão/sangue , Humanos , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Família Multigênica , Fatores de Risco , Esquizofrenia/sangue , Estresse Fisiológico/complicações , Estresse Fisiológico/metabolismoRESUMO
Trypanothione reductase of Trypanosoma cruzi is a key enzyme in the antioxidant metabolism of the parasite. Here we report on the enzymic and pharmacological properties of trypanothione reductase using glutathionylspermidine disulfide as a substrate. 1. Both pH optimum (7.5) and the ionic strength optimum (at 30 mM) are unusually narrow for this enzyme. 40 mM Hepes, 1 mM EDTA, pH 7.5 was chosen as a standard assay buffer because in this system the kcat/Km ratio had the highest values for both natural substrates, glutathionylspermidine disulfide (2.65 x 10(6) M-1 s-1) and trypanothione disulfide (4.63 x 10(6) M-1 s-1). 2. Using the standardized assay, trypanothione reductase and the phylogenetically related host enzyme, human glutathione reductase, were studied as targets of inhibitors. Both enzymes, in their NADPH-reduced forms, were irreversibly modified by the cytostatic agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Nifurtimox, the drug used in the treatment of Chagas' disease, is a stronger inhibitor of glutathione reductase (Ki = 40 microM) than of trypanothione reductase (IC50 = 200 microM). 3. Of the newly synthesized trypanocidal compounds [Henderson, G. B., Ulrich, P., Fairlamb, A. H., Rosenberg, I., Pereira, M., Sela, M. & Cerami, A. (1988) Proc. Natl Acad. Sci., 85, 5374-5378] a nitrofuran derivative, 2-(5-nitro-2-furanylmethylidene)-N,N'-[1,4-piperazinediylbis (1,3-propanediyl)]bishydrazinecarboximidamide tetrahydrobromide, was found to be a better inhibitor for trypanothione reductase (Ki = 0.5 microM) than for glutathione reductase (IC50 = 10 microM). A naphthoquinone derivative, 2,3-bis[3-(2-amidinohydrazono)-butyl]-1,4-naphthoquinone dihydrochloride, turned out to be both an inhibitor (IC50 = 1 microM) and an NADPH-oxidation-inducing substrate (Km = 14 microM). This effect was not observed with human glutathione reductase. Such compounds which lead to oxidative stress by more than one mechanism in the parasite are promising starting points for drug design based on the three-dimensional structures of glutathione and trypanothione reductases.