RESUMO
BACKGROUND: Numerous studies suggested that PM2.5 exposure was associated with increased risk of Alzheimer's disease (AD). But the precise mechanisms by which PM2.5 contributed to AD pathogenesis have not been clarified. METHODS: In the presence or absence of neurons, oligomeric amyloid beta (oAß)-primed microglia were stimulated with PM2.5. Firstly, we determined the effects of PM2.5 exposure on neuronal injury and inflammation in neurons-microglia co-cultures. Then, we examined whether NLRP3 inflammasome activation was involved in PM2.5-induced inflammation. After that, we investigated whether PM2.5 exposure increased ROS level in oAß-stimulated microglia. At last, we examined whether ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. RESULTS: In the present study, we showed that PM2.5 exposure aggravated oAß-induced neuronal injury and inflammation in neurons-microglia co-cultures via increasing IL-1ß production. Further, PM2.5-induced IL-1ß production in oAß-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Meanwhile, PM2.5 exposure increased ROS level in oAß-stimulated microglia. ROS was required for PM2.5-induced IL-1ß production and NLRP3 inflammasome activation in oAß-stimulated microglia. More importantly, ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. CONCLUSIONS: For the first time, these results suggested that the effects of PM2.5 under AD context were possibly mediated by NLRP3 inflammasome activation, which was triggered by ROS. Taken together, these findings have deepened our understanding on the role of PM2.5 in AD pathogenesis.
Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/metabolismo , Material Particulado/toxicidade , Fragmentos de Peptídeos/toxicidade , Animais , Células Cultivadas , Técnicas de Cocultura , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Tamanho da Partícula , GravidezRESUMO
BACKGROUND: Many patients with Parkinson's disease (PD) suffer from sialorrhea. Sialorrhea is often treated with anticholinergics and botulinum toxin, but some adverse effects have limited the use of these treatments. Dihydroergotoxine mesylate is an α-adrenergic blocking agents as well as some affinities to the dopaminergic and serotonin (5-HT) receptors. In the current study, we examine the safety and efficacy of dihydroergotoxine mesylate in PD patients. METHODS: This study consisted of 2 phases. The intervention was 2.5-mg oral dihydroergotoxine mesylate twice daily in both phases. The first phase is a three-week open-label single-arm trial (nâ¯=â¯10). The second phase was a six-week randomized controlled trials with a crossover design (nâ¯=â¯20). Efficacy was assessed using the United Parkinson's Disease Rating Scale (UPDRS) sialorrhrea subscore and Sialorrhea Clinical Scale for PD (SCS-PD). RESULTS: In the first phase, the UPDRS sialorrhea score was 3.5⯱â¯0.53 vs. 1.9⯱â¯0.57 prior to and after the treatment (Pâ¯=â¯0.004). The SCS-PD score decreased from 15.8⯱â¯2.78 to 9.9⯱â¯3.00 after the treatment (Pâ¯=â¯0.005). The response rate (defined by at least 30% reduction in SCS-PD score) was 60%. In the second phase of crossover trial, the UPDRS sialorrhea score was 3.00⯱â¯0.56 in placebo weeks vs. 2.00⯱â¯0.65 on dihydroergotoxine in dihydroergotoxine weeks (Pâ¯=â¯0.001). The SCS-PD was 12.50⯱â¯2.84 and 9.25⯱â¯2.86 versus, respectively (Pâ¯<â¯0.001). The response rate was 10% and 55%, respectively (Pâ¯=â¯0.003). There were no significant adverse effects. CONCLUSIONS: Dihydroergotoxine mesylate is safe and effective for sialorrhea in PD patients.