Bilirubin as an endogenous modulator of Neurotrophin redox signaling

Cesare Mancuso, Salvatore Fusco, Giovambattista Pani, Caterina Capone, Sofia Chiatamone Ranieri, Maria Luisa Eboli, Paolo Preziosi, Tommaso Galeotti, Vittorio Calabrese

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59 Citazioni (Scopus)

Abstract

Bilirubin is neurotoxic upon excess accumulation in the brain, but it also plays important physiological roles related to its antioxidant properties. Here we report that exposure of PC12 and primary rat cerebellar granule neurons to bilirubin (0.5-10 M) drastically decreases NGF/BDNF signaling to Akt and extracellular signals regulated kinases (ERKs), indicating a direct interference of the molecule with crucial pro-survival signaling pathways. This effect likely involves the scavenging capacity of bilirubin, this latter being able to inhibit, in PC12 cells, accumulation of intracellular reactive oxygen species and phosphorylation of Akt and ERKs in response to extracellular hydrogen peroxide. Interestingly, in the absence of exogenous growth factor, bilirubin elicited the phosphorylation of ERKs and of the cAMP Responsive Element Binding (CREB) transcription factor, a signature of NGF-dependent survival signaling. These growth factor-like signaling effects were paralleled by the induction of the neuronal nitric oxide synthase (nNOS) and generation of nitric oxide (NO). Pharmacological dissection of the signaling cascade triggered by bilirubin revealed that phosphorylation of ERKs requires NO signaling through soluble guanylyl cyclase and, at a further upstream level, influx of extracellular calcium is necessary for nNOS induction and NO release, likely through calcium dependent phosphorylation of CREB. Importantly, the cascade elicited by bilirubin through NO and ERK is cytoprotective, as revealed by exacerbated bilirubin toxicity in cultures treated by either NOS or MEK inhibitors. Taken together these observations indicate an important action of bilirubin on redox signaling by neurotrophins, with either inhibitory or agonistic effects based on growth factor availability.
Lingua originaleEnglish
pagine (da-a)2235-2249
Numero di pagine15
RivistaJournal of Neuroscience Research
Stato di pubblicazionePubblicato - 2008

Keywords

  • Bilirubin
  • Bilirubina
  • CREB1
  • Cell death
  • Cellule Neuronali
  • Morte cellulare
  • Neuronal cells
  • Neurotrofine
  • Neurotrophin
  • Nitric Oxide
  • Ossido Nitrico
  • Protein Fosforilazione
  • Protein phosphorylation
  • Signal Transduction
  • Trasduzione del Segnale
  • nNOS

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