RESUMO
BACKGROUND: Previously we have shown that developmental exposure to the heavy metal lead (Pb) resulted in latent cognitive impairment, upregulation of biomarkers and pathology associated with both the tau and amyloid pathways, however, the impact on Alpha Synuclein (α-Syn) and its relationship to these pathways and their connection to cognitive performance warrant further elucidation. OBJECTIVE: The present study determined the impact of developmental Pb exposure on the α-Syn pathways in a mouse model knock-out (KO) for murine tau gene and in differentiated human neuroblastoma SHSY5Y cell line exposed to a series of Pb concentrations. METHODS: Western blot analysis and RT-PCR were used to assess the levels of intermediates in the tau and α-Syn pathways following postnatal Pb exposure on aged mice lacking tau gene and in differentiated SHSY5Y cells on day 3 and day 6 after the Pb exposure had ceased. RESULT: Early life Pb exposure is accompanied by latent up-regulation in α-Syn in these mice. Furthermore, prior exposure to Pb in-vitro also resulted in an increase in α-Syn, its phosphorylated forms, as well as an increase in glycogen synthase kinase 3ß (GSK-3ß) and Caspase-3. CONCLUSION: An environmental agent can act as a latent inducer of both α-Syn and associated kinases that are involved in tau hyperphosphorylation and may allude to the interactive nature of these two neurodegenerative pathways.
Assuntos
Caspase 3/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Chumbo/toxicidade , Tauopatias/metabolismo , Regulação para Cima/efeitos dos fármacos , alfa-Sinucleína/metabolismo , Animais , Caspase 3/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroblastoma/patologia , Tauopatias/genética , Regulação para Cima/genética , alfa-Sinucleína/genética , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
BACKGROUND: Tangles are deposits of hyperphosphorylated tau, which are found in multiple neurodegenerative disorders that are referred to as tauopathies, of which Alzheimer's disease (AD) is the most common. Tauopathies are clinically characterized by dementia and share common cortical lesions composed of aggregates of the protein tau. OBJECTIVE: In this study, we explored the therapeutic potential of tolfenamic acid (TA), in modifying disease processes in a transgenic animal model that carries the human tau gene (hTau). METHODS: Behavioral tests, Western blotting and Immunohistochemical analysis were used to demonstrate the efficacy of TA. RESULTS: Treatment of TA improved improving spatial learning deficits and memory impairments in young and aged hTau mice. Western blot analysis of the hTau protein revealed reductions in total tau as well as in sitespecific hyperphosphorylation of tau in response to TA administration. Immunohistochemical analysis for phosphorylated tau protein revealed reduced staining in the frontal cortex, hippocampus, and striatum in animals treated with TA. CONCLUSION: TA holds the potential as a disease-modifying agent for the treatment of tauopathies including AD.
Assuntos
Cognição/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , ortoaminobenzoatos/farmacologia , Proteínas tau/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cognição/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos Transgênicos , Tauopatias/patologia , Tauopatias/psicologiaRESUMO
The concentration of 5-hydroxytryptamine (5-HT, Serotonin) varies as a result of physiological changes in the availability of its precursor tryptophan to the serotonergic neurons in the brain. Increase in brain tryptophan occurs following an increase in plasma tryptophan concentration. Tryptophan intake increases brain serotonin metabolism and enhances memory. The Present study was designed to investigate the effects of oral administration of tryptophan (TRP) at different doses (100, 300 and 500mg/kg) for two weeks on learning and memory functions and Neurochemical changes in rats. Control rats were given drinking water. Assessment of memory in rats was done by using the water Maze. on the 14th day trail training of water Maze was given to rats and after 1h of this 2nd trial of these rats were done. On the next day (After 24h of trail) long-term memories of these rats were monitored. After 1 hour of this all rats were killed by decapitation using guillotine. Brain and blood was collected and stored at -70°C. Neurochemical estimations of Plasma and brain tryptophan, 5-HT and 5-HIAA in brain were made by HPLC-EC. Result showed that administration of tryptophan enhanced performance on water Maze test. Tryptophan treated animals exhibited higher level of Plasma as well as brain tryptophan. 5-HT and 5-HIAA levels were also increased in tryptophan treated rats. Findings are discussed in context with the role of 5-HT metabolism in learning and memory process in rats. Results may help to understand the 5-HT changes following long term TRP administration in a dose dependent manner and will help to suggest the use of TRP in serotonin related illnesses.
