RESUMO
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
Schizophrenia has been suggested as a syndrome of accelerated aging. Telomere length (TL) decrease is considered one biological marker associated with age and can be accelerated by pathological characteristics present in schizophrenia. Several studies evaluated TL in schizophrenia, but the results are still controversial. The aim of this study was to conduct a meta-analysis of the existing results of TL in leukocytes of individuals with schizophrenia compared to healthy controls. A search was performed in PubMed, using the keywords 'telomere schizophrenia' and 'telomere psychosis'. We included data from original articles that measured TL in leukocytes of human patients with schizophrenia and healthy control subjects. 45 articles were found, but only 7 met our criteria. Telomere length of controls was not statistically different from that of patients with schizophrenia (p=0.07). Crossvalidation with the leave-one-out method resulted in a significant model (p=0.03) in which TL of individuals with schizophrenia is smaller than control (SMD=0.38; 95% CI=[0.05, 0.72]). We also propose a biological pathway through which schizophrenia could promote telomere erosion and how antipsychotics might compensate this loss. There are few studies made on this subject with diverse methodology and heterogeneous sample. Some articles did not consider other possible influences on TL. Overall our results suggest that TL is decreased in schizophrenia. Although this is consistent with the idea of accelerated aging, schizophrenia is a complex disease and there are several factors that influence TL that should be controlled in future studies.
Assuntos
Leucócitos/patologia , Esquizofrenia/genética , Esquizofrenia/patologia , Encurtamento do Telômero/fisiologia , Humanos , PubMed/estatística & dados numéricosRESUMO
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.