title: Neurohormetic responses of quercetin and rutin in a cell line over-expressing the amyloid precursor protein (APPswe cells).
abstract: BACKGROUND
  Plant secondary metabolites may induce adaptive cellular stress-responses in a variety of cells including neurons at the sub-toxic doses ingested by humans. Such 'neurohormesis' phenomenon, activated by flavonoids such as quercetin or rutin, may involve cell responses driven by modulation of signaling pathways which are responsible for its neuroprotective effects.
  
  
  OBJECTIVE
  We attempt to explore the molecular mechanisms involved in the neurohormetic responses to quercetin and rutin exposure, in a SH-SY5Y cell line which stably overexpresses the amyloid precursor protein (APP) Swedish mutation, based on a biphasic concentration-response relationship for cell viability.
  
  
  METHODS
  We examined the impact of both natural compounds, at concentrations in its hormetic range on the following cell parameters: chymotrypsin-like activity of the proteasome system; PARP-1 protein levels and expression and caspase activation; APP processing; and the main endogenous antioxidant enzymes.
  
  
  RESULTS
  Proteasome activities following quercetin or rutin treatment were significantly augmented in comparison with non-treated cells. Activity of caspase-3 was significantly attenuated by treatment with quercetin or rutin. Modest increased levels of PARP-1 protein and mRNA transcripts were observed in relation to the mild increase of proteasome activity. Significant reductions of the full-length APP and sAPP protein and APP mRNA levels were related to significant enhancements of α-secretase ADAM-10 protein and mRNA transcripts and significant increases of BACE processing in cells exposed to rutin. Furthermore, quercetin or rutin treatment displayed an overall increase of the four antioxidant enzymes.
  
  
  CONCLUSIONS
  The upregulation of the proteasome activity observed upon quercetin or rutin treatment could be afforded by a mild increased of PARP-1. Consequently, targeting the proteasome by quercetin or rutin to enhance its activity in a mild manner could avoid caspase activation. Moreover, it is likely that APP processing of cells upon rutin treatment is mostly driven by the non-amyloidogenic pathway leading to a putative reduction of βA production. Overall induction of endogenous antioxidant enzymes under quercetin or rutin treatments of APPswe cells might modulate its proteasome activity. We might conclude that quercetin and rutin might exert a neurohormetic cell response affecting various signaling pathways and molecular networks associated with modulation of proteasome function.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Sagrario
authors.initials: S
authors.lastname: Martín-Aragón
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Karim Lizeth
authors.initials: KL
authors.lastname: Jiménez-Aliaga
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Benedí
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain. Electronic address: bescos@ucm.es.
authors.forename: Paloma
authors.initials: P
authors.lastname: Bermejo-Bescós
mesh_terms: D000072197:ADAM10 Protein / Q000096:biosynthesis / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D018377:Neurotransmitter Agents / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000096:biosynthesis / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012431:Rutin / Q000494:pharmacology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D008565:Membrane Proteins; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D012431:Rutin; D011794:Quercetin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D053829:Amyloid Precursor Protein Secretases; C505407:CASP3 protein, human; D053148:Caspase 3; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: Caspase; Endogenous antioxidant enzymes; Flavonoids; PARP-1; Proteasome; α-secretase ADAM-10