RESUMO
Decreased expression of prosurvival and progrowth-stimulatory pathways, in addition to an environment that inhibits neuronal growth, contribute to the limited regenerative capacity in the central nervous system following injury or neurodegeneration. Membrane/lipid rafts, plasmalemmal microdomains enriched in cholesterol, sphingolipids, and the protein caveolin (Cav) are essential for synaptic development/stabilization and neuronal signaling. Cav-1 concentrates glutamate and neurotrophin receptors and prosurvival kinases and regulates cAMP formation. Here, we show that primary neurons that express a synapsin-driven Cav-1 vector (SynCav1) have increased raft formation, neurotransmitter and neurotrophin receptor expression, NMDA- and BDNF-mediated prosurvival kinase activation, agonist-stimulated cAMP formation, and dendritic growth. Moreover, expression of SynCav1 in Cav-1 KO neurons restores NMDA- and BDNF-mediated signaling and enhances dendritic growth. The enhanced dendritic growth occurred even in the presence of inhibitory cytokines (TNFα, IL-1ß) and myelin-associated glycoproteins (MAG, Nogo). Targeting of Cav-1 to neurons thus enhances prosurvival and progrowth signaling and may be a novel means to repair the injured and neurodegenerative brain.
Assuntos
Caveolina 1/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Colesterol/metabolismo , Citocinas/farmacologia , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Associada a Mielina/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Especificidade de Órgãos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sinapsinas/metabolismoRESUMO
BACKGROUND: Children who do not produce single words by the expected age have been described as 'late talkers' or as demonstrating 'late language emergence' (LLE). Although their short-term growth in vocabulary is often strong, longer-term consequences of LLE remain in dispute. It has been argued that the majority of school-age children who had LLE move into the average range for narrative production, though studies have not examined narrative comprehension. It has also been argued that school-age children with LLE score in the average range on standardized tests of syntax, though studies have not examined performance in conversational contexts. AIMS: This article compared school-age children with and without histories of LLE for performance on standardized narrative comprehension and production tasks, as well as the use of complex sentences and relative clauses in narration and conversation. Both complex syntax and relative clause use are reduced in children with specific language impairment (SLI), so these structures may be useful as indicators of linguistic weakness. METHODS & PROCEDURES: The participants were twenty-two 8-year-old children, divided into two groups. Eleven children who had been diagnosed with LLE at 30 months were compared with a control group of 11 children with typical development (TD). All participants completed a standardized test of narrative comprehension and production and a 10-min conversational sample. Both narrative and conversational samples were analysed for the number of complex sentences and relative clauses. OUTCOMES & RESULTS: Overall results indicated that children with a history of LLE did not have comprehension or production scores that were significantly different from the TD group on the standardized narrative test; nor did groups differ for production of complex sentences or relative clauses in narrative samples. However, a significant difference was found for the production of complex sentences in conversational samples, with the children diagnosed with LLE producing fewer complex sentences than the TD group. There was no difference between groups for relative clause use in conversation or in narratives. CONCLUSIONS & IMPLICATIONS: These data suggest that children with a history of LLE may exhibit age-appropriate performance on a standardized narrative test, but still lack the syntactic complexity of their TD peers in conversation. Assessments for school-age children with a history of language delay should include analysis of syntactic complexity in conversation to identify continuing weakness. Future research should examine use of other specific types of complex structures (e.g. infinitival and clausal complements) in this population, as well the feasibility of increasing complex sentence production through intervention. In addition, future studies should examine whether this decreased production of complex syntax in conversation is noted by naive listeners.
Assuntos
Transtornos do Desenvolvimento da Linguagem/diagnóstico , Testes de Linguagem , Estudos de Casos e Controles , Criança , Feminino , Humanos , Linguística , Masculino , Análise Multivariada , Narração , TexasRESUMO
Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH(2)-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to produce cardiac protection from ischemia-reperfusion injury.