Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: Possible implications for Parkinson's disease

Giuseppe Filomeni, Ilaria Graziani, Daniela de Zio, Luciana Dini, Diego Centonze, Giuseppe Rotilio, Maria R. Ciriolo

Research output: Contribution to journalArticle

Abstract

This study aims to elucidate the processes underlying neuroprotection of kaempferol in models of rotenone-induced acute toxicity. We demonstrate that kaempferol, but not quercetin, myricetin or resveratrol, protects SH-SY5Y cells and primary neurons from rotenone toxicity, as a reduction of caspases cleavage and apoptotic nuclei are observed. Reactive oxygen species (ROS) levels and mitochondrial carbonyls decrease significantly. Mitochondrial network, transmembrane potential and oxygen consumption are also deeply preserved. We demonstrate that the main event responsible for the kaempferol-mediated antiapoptotic and antioxidant effects is the enhancement of mitochondrial turnover by autophagy. Indeed, fluorescence and electron microscopy analyses show an increase of the mitochondrial fission rate and mitochondria-containing autophagosomes. Moreover, the autophagosome-bound microtubule-associated protein light chain-3 (LC3-II) increases during kaempferol treatment and chemical/genetic inhibitors of autophagy abolish kaempferol protective effects. Autophagy affords protection also toward other mitochondrial toxins (1-methyl-4-phenyilpiridinium, paraquat) used to reproduce the typical features of Parkinson's disease (PD), but is inefficient against apoptotic stimuli not directly affecting mitochondria (H 2O 2, 6-hydroxydopamine, staurosporine). Striatal glutamatergic response of rat brain slices is also preserved by kaempferol, suggesting a more general protection of kaempferol in Parkinson's disease. Overall, the data provide further evidence for kaempferol to be identified as an autophagic enhancer with potential therapeutic capacity.

Original languageEnglish
Pages (from-to)767-785
Number of pages19
JournalNeurobiology of Aging
Volume33
Issue number4
DOIs
Publication statusPublished - Apr 2012

Keywords

  • Autophagy
  • Kaempferol
  • Mitochondria
  • Mitochondrial toxins
  • Neuroprotection
  • Oxidative stress
  • Parkinson's disease

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

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