RESUMO
OBJECTIVE: The objective of this study was to evaluate brain lithium levels using (7) Li magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. METHOD: Twenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naïve. At endpoint, patients underwent a (7) Li-MRS scan and brain lithium concentrations were calculated. RESULTS: A significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = -0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. CONCLUSION: These findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with (7) Li-MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted.
Assuntos
Antimaníacos/farmacocinética , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Depressão/metabolismo , Compostos de Lítio/farmacocinética , Adulto , Antimaníacos/uso terapêutico , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Depressão/sangue , Depressão/tratamento farmacológico , Feminino , Humanos , Compostos de Lítio/uso terapêutico , Espectroscopia de Ressonância Magnética/métodos , MasculinoRESUMO
Reduced phospholipase A2 (PLA2) activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) participate in the production of beta-amyloid plaques and of neurofibrillary tangles, which are two neuropathological hallmarks of Alzheimer's disease (AD). Experimental evidences suggest a neuroprotective effect of the cholinesterase inhibitor donepezil in the treatment the disease. The aims of the present study were to evaluate in AD patients the effects of treatment with donepezil on PLA2 activity and GSK3B level. Thirty patients with AD were treated during 6 months with 10 mg daily of donepezil. Radio-enzymatic assays were used to measure PLA2 activity and Elisa assays for GSK3B level, both in platelets. Before treatment and after 3 and 6 months on donepezil, AD patients underwent a cognitive assessment and platelet samples were collected. Values were compared to a healthy control group of 42 sex- and age-matched elderly individuals. Before treatment, iPLA2 activity was lower in patients with AD as compared to controls (p < 0.001). At baseline, no differences were found in GSK3B level between both groups. After 3 and 6 months of treatment, we found a significant increase in iPLA2 activity (p = 0.015 and p < 0.001, respectively). iPLA2 increment was related to the cognitive improvement during treatment (p = 0.037). After 6 months, we found an increase in phosphorylated GSK3B (p = 0.02). The present findings suggest two possible mechanisms by which donepezil delays the progression of AD. The increment of iPLA2 activity may reduce the production of beta-amyloid plaques, whereas the phosphorylation of GSK3B inactivates the enzyme, reducing thus the phosphorylation of tau protein.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Plaquetas/enzimologia , Inibidores da Colinesterase/uso terapêutico , Quinase 3 da Glicogênio Sintase/metabolismo , Fosfolipases A2 do Grupo VI/metabolismo , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Análise de Variância , Donepezila , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Fosforilação , Fatores de TempoRESUMO
OBJECTIVE: Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. METHODS: We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were 'brain-derived neurotrophic factor,''Bcl-2,''mitogen-activated protein kinases,''neuroprotection,''calcium,''bipolar disorder,''mania,' and 'depression.' RESULTS: The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. CONCLUSION: Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder.
Assuntos
Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Antimaníacos/uso terapêutico , Atrofia/metabolismo , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cálcio/metabolismo , Humanos , Lítio/uso terapêutico , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The hyperphosphorylation of tau is a central mechanism in the pathogenesis of Alzheimer's disease (AD). Lithium is a potent inhibitor of glycogen synthase kinase-3beta (GSK3ß), the most important tau kinase in neurons, and may also affect tau phosphorylation by modifying the expression and/or activity of other kinases, such as protein kinase A (PKA), Akt (PKB), and calcium calmodulin kinase-II (CaMKII). The aim of the present study is to determine the effect of chronic lithium treatment on the protein expression of tau and its major kinases in cortical and hippocampal neurons, at distinct working concentrations. Primary cultures of cortical and hippocampal neurons were treated with sub-therapeutic (0.02 mM and 0.2 mM) and therapeutic (2 mM) concentrations of lithium for 7 days. Protein expression of tau and tau-kinases was determined by immunoblotting. An indirect estimate of GSK3ß activity was determined by the GSK3ß ratio (rGSKß). Statistically significant increments in the protein expression of tau and CaMKII were observed both in cortical and hippocampal neurons treated with subtherapeutic doses of lithium. GSK3ß activity was increased in cortical, but decreased in hippocampal neurons. Distinct patterns of changes in the expression of the remaining tau tau-kinases were observed: in cortical neurons, lithium treatment was associated with consistent decrements in Akt and PKA, whereas hippocampal neurons displayed increased protein expression of Akt and decreased PKA. Our results suggest that chronic lithium treatment may yield distinct biological effects depending on the concentration range, with regional specificity. We further suggest that hippocampal neurons may be more sensitive to the effect of lithium, presenting with changes in the expression of tau-related proteins at subtherapeutic doses, which may not be mirrored by the effects observed in cortical neurons.
Assuntos
Hipocampo/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Neurônios/efeitos dos fármacos , Proteínas tau/metabolismo , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Cloreto de Lítio/administração & dosagem , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos WistarRESUMO
There is increasing evidence suggesting that one of the most relevant pathophysiological features of Alzheimer's disease (AD) is neuroinflammation, which plays an important role in the production and regulation of AD-related proteins (amyloid beta (Aß) and Tau) and exacerbates AD pathology. Neuroinflammation can also be induced by systemic influences (factors from outside the central nervous system). However, the role of systemic inflammation in AD pathophysiology is much less understood. Thus, our main objective in this study was to verify whether the presence of serum cytokines (IL-1ß, IL-6, IL-10, IL-12, and TNF-α) affects different AD biomarkers: Aß1-42 and Tau protein levels, hippocampal volumes (HV), and default mode network functional connectivity (DMN FC) in healthy elderly controls, amnestic mild cognitive impairment (aMCI) patients due to AD, and mild AD patients. To accomplish this, we acquired 3-T MRI, blood, and cerebrospinal fluid (CSF) samples from 42 healthy controls, 55 aMCI patients due to AD, and 33 mild AD patients. Comparing the groups, we found that the mild AD patients presented smaller HV, disrupted DMN FC, and proportionally less IL-1ß than the controls. The aMCI patients only differed from the controls in DMN FC. In intra-group comparison, aMCI and mild AD with detectable levels of cytokines (TNF-α, IL-1ß, IL-10, and IL-12) had decreased DMN FC. On the other hand, patients with detectable levels of IL-10 and IL-12 presented a more favorable AD biomarkers profile (larger HV, more CSF Aß1-42, and less p-Tau), indicating a possible protective role of these ILs. Our findings indicate a possible relationship between systemic inflammation with DMN FC disruption, hippocampal atrophy, and CSF protein levels in the subjects with mild AD and aMCI.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/complicações , Inflamação/líquido cefalorraquidiano , Inflamação/complicações , Idoso , Doença de Alzheimer/diagnóstico por imagem , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Citocinas/líquido cefalorraquidiano , Feminino , Humanos , Inflamação/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
Laminin (LN) plays a major role in neuronal differentiation, migration and survival. Here, we show that the cellular prion protein (PrPc) is a saturable, specific, high-affinity receptor for LN. The PrPc-LN interaction is involved in the neuritogenesis induced by NGF plus LN in the PC-12 cell line and the binding site resides in a carboxy-terminal decapeptide from the gamma-1 LN chain. Neuritogenesis induced by LN or its gamma-1-derived peptide in primary cultures from rat or either wild type or PrP null mice hippocampal neurons, indicated that PrPc is the main cellular receptor for that particular LN domain. These results point out to the importance of the PrPc-LN interaction for the neuronal plasticity mechanism.
Assuntos
Laminina/metabolismo , Neuritos/fisiologia , Proteínas PrPC/metabolismo , Animais , Células Cultivadas , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Camundongos , Neurônios/metabolismo , Neurônios/ultraestrutura , Fragmentos de Peptídeos/metabolismo , Proteínas PrPSc/genética , Ligação Proteica , Ratos , Células Tumorais CultivadasRESUMO
OBJECTIVE: To determine the frequency and features of psychiatric morbidity in a cross-section of 38 outpatients with neurocysticercosis. METHODS: Diagnosis of neurocysticercosis was established by CT scan, MRI and CSF analysis. Psychiatric diagnoses were made by using the Present State Examination and the Schedule for Affective Disorders and Schizophrenia. Lifetime version; cognitive state was assessed by Mini-Mental State Examination and Strub & Black's Mental Status Examination. RESULTS: Depression was the most frequent psychiatric diagnosis (52.6%) as shown by PSE. Active disease and intracranial hypertension were associated with higher psychiatric morbidity, and previous history of mood disorders was strongly related to current depression. CONCLUSIONS: Depression syndromes are frequent in patients with neurocysticercosis. The extent to which organic mechanisms related to brain lesions may underlie the observed mental changes is yet unclear, though the similar sex distribution of patients with and without depression, as well as the above mentioned correlations, provide further evidence of the role played by organic factors in the cause of these syndromes. The results of this study are discussed in the light of the data available for other organic psychiatric disorders.
Assuntos
Encefalopatias/parasitologia , Cisticercose/complicações , Transtorno Depressivo/etiologia , Adulto , Encefalopatias/complicações , Cisticercose/psicologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/parasitologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de RiscoRESUMO
CONTEXT: Most double-blind studies of efficacy and tolerability of sertraline as compared to tricyclics in the treatment of late-life major depression have used amitriptyline as a standard, leading to the inevitable conclusion that the former drug is better tolerated than the latter, with both being equally efficacious. OBJECTIVE: To compare the antidepressant efficacy and tolerability of sertraline (50 mg/day) and imipramine (150 mg/day) in the first 6 weeks of the treatment of major depression in the elderly. DESIGN: A randomized double-blind parallel study with 6 weeks of follow-up. SETTING: The psychogeriatric clinic at the Institute of Psychiatry, Hospital das Clínicas, Faculty of Medicine of the University of São Paulo. PARTICIPANTS: 55 severe and moderately depressed non-demented outpatients aged 60 years or more. INTERVENTION: Patients were assigned to sertraline 50 mg/day or imipramine 150 mg/day. MAIN MEASUREMENTS: CAMDEX interview. Psychiatric diagnosis followed the guidelines for "Major Depressive Episode" according to DSM-IV criteria. Severity of symptoms was evaluated using the "CGI" and "MADRS" scales. Cognitive state was assessed using the Mini-Mental State Examination. Side effects were assessed using the "Safetee-Up" schedule. RESULTS: Both groups had a significant decrease in depressive symptoms according to the MADRS scores after 6 weeks of treatment (P = 0.01). No significant differences between groups were detected regarding treatment outcome (t = 0.4; P = 0.7). Although the dropout rate was greater in the imipramine group, the overall tolerability among patients who completed the 6-week trial was similar in both test groups. CONCLUSIONS: Both sertraline and imipramine exhibited good efficacy and an acceptable side-effect profile for elderly depressed patients after 6 weeks of antidepressant treatment.
Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Depressão/tratamento farmacológico , Imipramina/uso terapêutico , Sertralina/uso terapêutico , Idoso , Método Duplo-Cego , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Resultado do TratamentoRESUMO
Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. More recently, based on findings from translational research, lithium has also been regarded as a neuroprotective agent and a candidate drug for disease-modification in certain neurodegenerative disorders, namely, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and, more recently, Parkinson's disease (PD). The putative neuroprotective effects of lithium rely on the fact that it modulates several homeostatic mechanisms involved in neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Such a wide range of intracellular responses may be secondary to two key effects, that is, the inhibition of glycogen synthase kinase-3 beta (GSK-3ß) and inositol monophosphatase (IMP) by lithium. In the present review, we revisit the neurobiological properties of lithium in light of the available evidence of its neurotrophic and neuroprotective properties, and discuss the rationale for its use in the treatment and prevention of neurodegenerative diseases.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Compostos de Lítio/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Humanos , Compostos de Lítio/uso terapêutico , Doenças Neurodegenerativas/fisiopatologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs) in in vitro models of Alzheimer and Parkinson disease. Primary cultures of hippocampal and ventral mesencephalic neurons were treated for 24 h with amyloid beta (Abeta(1-42)) peptide 1-42 and 6-OHDA, respectively. DPCs isolated from adult rat incisors were previously cultured in tissue culture inserts and added to the neuron cultures 2 days prior to neurotoxin treatment. Cell viability was assessed by the MTT assay. The co-culture with DPCs significantly attenuated 6-OHDA and Abeta(1-42)-induced toxicity in primary cultures of mesencephalic and hippocampal neurons, and lead to an increase in neuronal viability in untreated cultures, suggesting a neurotrophic effect in both models. Furthermore, human dental pulp cells expressed a neuronal phenotype and produced the neurotrophic factors NGF, GDNF, BDNF, and BMP2 shown by microarray screening and antibody staining for the representative proteins. DPCs protected primary neurons in in vitro models of Alzheimer's and Parkinson's disease and can be viewed as possible candidates for studies on cell-based therapy.
Assuntos
Adrenérgicos/toxicidade , Peptídeos beta-Amiloides/toxicidade , Polpa Dentária/citologia , Polpa Dentária/fisiologia , Neurônios/efeitos dos fármacos , Oxidopamina/toxicidade , Fragmentos de Peptídeos/toxicidade , Análise de Variância , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura/métodos , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Hipocampo/citologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesencéfalo/citologia , Análise em Microsséries/métodos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Gravidez , RatosRESUMO
BACKGROUND: Previous studies have reported an association between executive dysfunction and the ability to perform activities of daily living (ADL)s among older adults. This study aims to examine the association between executive functions and functional status in a cross-section of older adults with varying degrees of cognitive impairment. METHODS: 89 individuals (mean age 73.8 years) were recruited at a memory clinic in São Paulo, Brazil. Subjects underwent evaluation, and were allocated into three diagnostic groups according to cognitive status: normal controls (NC, n = 32), mild cognitive impairment (MCI, n = 31) and mild Alzheimer's disease (AD, n = 26). Executive functions were assessed with the 25-item Executive Interview (EXIT25), and functional status was measured with the Direct Assessment of Functional Status test (DAFS-R). RESULTS: Significantly different total DAFS-R scores were observed across the three diagnostic groups. Patients with AD performed significantly worse in EXIT25 compared with subjects without dementia, and no significant differences were detected between NC and MCI patients. We found a robust negative correlation between the DAFS-R and the EXIT25 scores (r =-0.872, p < 0.001). Linear regression analyses suggested a significant influence of the EXIT-25 and the CAMCOG on the DAFS-R scores. CONCLUSION: Executive dysfunction and decline in general measures of cognitive functioning are associated with a lower ability to undertake instrumental ADLs. MCI patients showed worse functional status than NC subjects. MCI patients may show subtle changes in functional status that may only be captured by objective measures of ADLs.
Assuntos
Atividades Cotidianas/psicologia , Transtornos Cognitivos/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Brasil , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Grupos Controle , Avaliação da Deficiência , Feminino , Lobo Frontal/fisiopatologia , Avaliação Geriátrica , Humanos , Modelos Lineares , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/fisiopatologia , Transtornos da Memória/psicologia , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
Phospholipase A(2) (PLA(2)) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA(2) activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent (31)P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA(2) activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA(2) has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA(2) inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA(2) precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA(2) enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA(2) activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.
Assuntos
Doença de Alzheimer/fisiopatologia , Hipocampo/metabolismo , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/enzimologia , Fosfolipases A/metabolismo , Doença de Alzheimer/metabolismo , Animais , Plaquetas/metabolismo , Homeostase , Humanos , Fosfolipases A2 , Fosfolipídeos/metabolismoRESUMO
In neurons, phospholipase A2 (PLA2) plays a central role in the regulation of membrane phospholipid metabolism. We have addressed the pharmacological modulation of PLA2 in primary cultures of rat cortical neurons. Inhibition curves were obtained in 4 day-in-culture neurons treated for 30 minutes with either the dual PLA2 inhibitor methyl arachidonyl fluorophosphonate (MAFP), or the iPLA2 inhibitor bromoenol lactone (BEL). Full inhibition was achieved with 100 and 250 microM of MAFP, or 10 and 20 microM of BEL. Conversely, a dose-dependent activation of PLA2 was obtained with 10-20 microg/ml of melitin. PLA2 inhibition with MAFP or BEL was not acutely toxic for cultured neurons. However, sustained inhibition of the enzyme precluded the development of neurites, and resulted in long-term loss of neuronal viability. We present a model of pharmacological challenge of PLA2 in vitro, which can be further used to address the involvement of the enzyme in neurodevelopment and neurodegeneration models.
Assuntos
Córtex Cerebral/citologia , Neurônios/enzimologia , Fosfolipases A/metabolismo , Fosfolipídeos/metabolismo , Animais , Antígenos de Bactérias/farmacologia , Ácidos Araquidônicos/farmacologia , Membrana Celular/enzimologia , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Naftalenos/farmacologia , Degeneração Neural/metabolismo , Neurônios/citologia , Organofosfonatos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Fosfolipases A/antagonistas & inibidores , Fosfolipases A2 , Gravidez , Pironas/farmacologia , Ratos , Ratos WistarRESUMO
We investigated, with the aid of a radio-enzymatic method, the developmental changes in the activity of 85 kDa calcium-dependent cytosolic phospholipase A(2) (cPLA(2)) in pre-term embryonic rat brain and in primary cultures of cortical neurons. PLA(2) activity was highest in the brains of 18 day embryos (E18) and gradually decreased toward birth (E18 through E21). No significant differences were found regarding cPLA(2) activity in different topographies, namely hippocampus, cortex, and total brain. In primary cultures of E18/E19 cortical neurons, cPLA(2) activity was higher than the respective embryonic tissue activity, straight from early development. In vitro cPLA(2) activity peaked on the 4th day in culture, and decreased after the six days of incubation, when the cultures became mature. This result reinforces previous evidence that cPLA(2) plays an important role in the early development of the nervous system, and further suggests that it may be implicated in neurodevelopmental processes and in in vitro neuronal survival. We believe that we have produced a useful model for the tissue culture study of PLA(2) metabolism and biochemistry, which can be further addressed to the investigation of the biology of neurodegenerative and neuropsychiatric disorders.
Assuntos
Encéfalo/embriologia , Neurônios/enzimologia , Fosfolipases A/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/enzimologia , Desenvolvimento Embrionário e Fetal , Fosfolipases A2 , Ratos , Ratos Wistar , Fatores de TempoRESUMO
This study compared the efficacy and tolerability of 150 mg/day imipramine and 50 mg/day sertraline for the treatment of a major depressive episode (DSM-IV) in older adults (N = 55) in an 8-week, randomized, double-blind, controlled clinical trial. Intention-to-treat analysis (last observation carried forwards) showed a reduction of 50% or more on the baseline scores of the Montgomery-Asberg Rating Scale (MADRS) in 60.7% and 55.6% of patients receiving imipramine and sertraline, respectively (p = .698). Full remission of symptoms (MADRS < 9) was observed in 50.0% and 51.8% of patients, respectively (p = .891). Side effects were more frequent among patients treated with imipramine (86.7%) than among patients treated with sertraline (42.1%) (p = .008). Dropout rates were high in both groups (46.4% and 29.6% respectively, p =.200). These results indicate that imipramine and sertraline are equally effective for the treatment of major depression in later life, although adverse reactions are more frequent among subjects treated with imipramine than with sertraline.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Imipramina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Sertralina/uso terapêutico , Idoso , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos Tricíclicos/uso terapêutico , Brasil , Análise Custo-Benefício , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Imipramina/administração & dosagem , Imipramina/efeitos adversos , Masculino , Pacientes Desistentes do Tratamento , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Sertralina/administração & dosagem , Sertralina/efeitos adversos , Equivalência Terapêutica , Resultado do TratamentoRESUMO
Phospholipase A(2) (PLA(2)) controls the metabolism of phospholipids in cell membranes. In the brain, PLA(2) influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (Abeta), which are the major components of the senile plaques in Alzheimer's disease (AD). Reduced PLA(2) activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA(2) activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA(2) activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA(2)). PLA(2) activity was significantly lower in AD than in controls (p < 0.001). Mean PLA(2) activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA(2) activity was significantly correlated with a worse cognitive performance both at the MMSE (p = 0.001) and the cognitive sub-scale of the CAMDEX inventory (p = 0.002). Our data replicate previous findings of reduced platelet PLA(2) activity in AD. Both reduced PLA(2) activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA(2) inhibits the physiological secretion of the APP, a mechanism that increases Abeta formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA(2) values in platelets would be at a higher risk to develop AD during a longitudinal follow up.
Assuntos
Doença de Alzheimer/enzimologia , Plaquetas/enzimologia , Transtornos Cognitivos/enzimologia , Fosfolipases A/metabolismo , Idoso , Doença de Alzheimer/sangue , Biomarcadores/sangue , Transtornos Cognitivos/sangue , Feminino , Humanos , Masculino , Testes NeuropsicológicosRESUMO
Muscarinic agonists alter the metabolism of amyloid precursor protein, leading to an increase in alpha-secretase cleavage and a decreased production of amyloidogenic peptides; suggesting that these compounds might modify the Alzheimer's disease process. A second therapeutic target in AD is the accumulation of stably phosphorylated tau into neurofibrillary tangles; an early event correlating with cognitive impairment. Glycogen synthase kinase-3 (GSK-3beta) phosphorylates tau and is inhibited via protein kinase C (PKC). As certain muscarinic receptors are linked to PKC, we examined the effect of a range of agonists on GSK-3beta phosphorylation of tau. In neurons a nonspecific muscarinic agonist, carbachol, reduced tau phosphorylation. In nonneuronal cells expressing the ml receptor a range of ml agonists reduced transiently-expressed tau phosphorylation and altered its microtubulebinding properties. These findings link the two pathological process of AD-APP metabolism and tau phosphorylation - and suggest that muscarinic and other cholinergic compounds might have disease-modifying properties.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Proteínas Quinases Dependentes de Cálcio-Calmodulina/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Neurônios/efeitos dos fármacos , Receptores Muscarínicos/efeitos dos fármacos , Proteínas tau/efeitos dos fármacos , Acetilcolina/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Carbacol/farmacologia , Células Cultivadas/citologia , Células Cultivadas/metabolismo , Feto , Quinase 3 da Glicogênio Sintase , Quinases da Glicogênio Sintase , Cloreto de Lítio/farmacologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/metabolismo , Tetrazóis/farmacologia , Tiadiazóis/farmacologia , Proteínas tau/metabolismoRESUMO
OBJECTIVE: To determine the frequency and features of psychiatric morbidity in a cross section of 38 outpatients with neurocysticercosis. METHODS: Diagnosis of neurocysticercosis was established by CT, MRI, and CSF analysis. Psychiatric diagnoses were made by using the present state examination and the schedule for affective disorders and schizophrenia-lifetime version; cognitive state was assessed by mini mental state examination and Strub and Black's mental status examination. RESULTS: Signs of psychiatric disease and cognitive decline were found in 65.8 and 87.5% of the cases respectively. Depression was the most frequent psychiatric diagnosis (52.6%) and 14.2% of the patients were psychotic. Active disease and intracranial hypertension were associated with higher psychiatric morbidity, and previous history of mood disorders was strongly related to current depression. Other variables, such as number and type of brain lesions, severity of neuropsychological deficits, epilepsy, and use of steroids did not correlate with mental disturbances in this sample. CONCLUSIONS: Psychiatric abnormalities, particularly depression syndromes, are frequent in patients with neurocysticercosis. Although regarded as a rare cause of dementia, mild cognitive impairment may be a much more prevalent neuropsychological feature of patients with neurocysticercosis. The extent to which organic mechanisms related to brain lesions may underlie the mental changes is yet unclear, although the similar sex distribution of patients with and without depression, as well as the above mentioned correlations, provide further evidence of the part played by organic factors in the cause of these syndromes.
Assuntos
Encéfalo/parasitologia , Cisticercose/parasitologia , Cisticercose/psicologia , Adolescente , Adulto , Brasil , Transtornos Cognitivos/diagnóstico , Cisticercose/diagnóstico , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/psicologia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Tomografia Computadorizada por Raios XRESUMO
Brazil has been experiencing a steady increase in the elderly population during the past few years, and as a result old age health-related problems are increasing continuously in number. Psychiatric symptoms are among the most prevalent health problems of the elderly and are an important source of distress for patients and carers, being also associated with significant growth in the costs and demand for the provision of health care services. This study aimed to investigate the prevalence of mental health problems among the elderly attending a regional primary care unit in the city of São Paulo, Brazil. A total of 351 patients older than 60 were assessed during a 6-month period with the SRQ-20 (a scale for the detection of minor psychiatric problems), four questions on psychotic symptoms. AMTS (a scale for the assessment of cognitive functioning) and CAGE (a scale for the assessment of alcoholism); demographic variables were also recorded. Subjects' mean age was 71.22 (CI = 70.51-71.92) and 83.5% were female. Thirty-two per cent of subjects were considered 'cases' as they scored more than 7 on the SRQ-20 (26.8% of total), or more than 1 on the CAGE (1.4% of total), or at least 1 on the questions assessing psychotic symptoms (12.2% of total). There was a significant excess of women among those found to suffer from psychiatric problems (90.1% vs 80.4%). Cases were also more likely to be illiterate (23.4% vs 12.1%) and to have a lower income (2.21 vs 4.01 minimum wages). Depressive symptoms and tension were highly prevalent (72.9% of subjects). Somatic complaints and signs of inefficient functioning were also common (50.4% and 45.9% respectively). Only five patients answered affirmatively two or more CAGE questions and 12.2% scored at least 1 on the questions assessing psychotic symptoms. Cognitive deficit, as determined by the AMTS, was observed in 13.4% of the sample and was associated with ageing, being illiterate and having higher total SRQ-20 scores. We suggest, that the organization of health care services should take into account the needs of this population, and should also emphasize professional training for the correct assessment and treatment of the most frequent mental health problems in old age.