RESUMEN
Aggregation of α-synuclein (α-Syn) is implicated in the pathogenesis of Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Therefore, the removal of α-Syn aggregation could lead to the development of many new therapeutic agents for neurodegenerative diseases. In the present study, we succeeded in generating a new α-Syn stably expressing cell line using a piggyBac transposon system to investigate the neuroprotective effect of the flavonoid kaempferol on α-Syn toxicity. We found that kaempferol provided significant protection against α-Syn-related neurotoxicity. Furthermore, kaempferol induced autophagy through an increase in the biogenesis of lysosomes by inducing the expression of transcription factor EB and reducing the accumulation of α-Syn; thus, kaempferol prevented neuronal cell death. Moreover, kaempferol directly blocked the amyloid fibril formation of α-Syn. These results support the therapeutic potential of kaempferol in diseases such as synucleinopathies that are characterized by α-Syn aggregates.
Asunto(s)
Amiloide/efectos de los fármacos , Autofagia , Quempferoles/farmacología , Neuroblastoma/tratamiento farmacológico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Sustancias Protectoras/farmacología , alfa-Sinucleína/toxicidad , Amiloide/metabolismo , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Neuroblastoma/etiología , Neuroblastoma/metabolismo , Neuroblastoma/patología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patologíaRESUMEN
The addition-type ozone oxidation of silylalkenes is a highly efficient reaction to provide synthetically versatile α-silylperoxy carbonyl compounds. To gain insight into the reaction mechanism, we performed a computational study, which revealed that the reaction proceeds via [1,2]-Brook rearrangement-type silyl migration of primary ozonide. In sharp contrast to the addition-type reactions, the ozone oxidation of α-alkoxysilylalkenes proceeds in a cleavage-type manner to afford excellent yields of silacarboxylic acid esters via the 1,3-cycloelimination of primary ozonide prior to 1,2-silyl migration.
