Bilirubin as an endogenous modulator of neurotrophin redox signaling

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

Research output: Contribution to journalArticle

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 μM) drastically decreases nerve growth factor (NGF)/brain-derived neurotrophic factor signaling to Akt and extracellular signal-regulated kinases (ERKs), indicating a direct interference of the molecule with crucial prosurvival signaling pathways. This effect likely involves the scavenging capacity of bilirubin, the 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, further upstream, 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.

Original languageEnglish
Pages (from-to)2235-2249
Number of pages15
JournalJournal of Neuroscience Research
Volume86
Issue number10
DOIs
Publication statusPublished - Aug 1 2008

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Nerve Growth Factors
Bilirubin
Oxidation-Reduction
Extracellular Signal-Regulated MAP Kinases
Nitric Oxide
Phosphorylation
Intercellular Signaling Peptides and Proteins
Nitric Oxide Synthase Type I
Nerve Growth Factor
Calcium
PC12 Cells
Brain-Derived Neurotrophic Factor
Mitogen-Activated Protein Kinase Kinases
Hydrogen Peroxide
Dissection
Reactive Oxygen Species
Transcription Factors
Antioxidants
Pharmacology
Neurons

Keywords

  • CREB
  • Heme oxygenase
  • Nitric oxide
  • ROS

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mancuso, C., Capone, C., Ranieri, S. C., Fusco, S., Calabrese, V., Eboli, M. L., ... Pani, G. (2008). Bilirubin as an endogenous modulator of neurotrophin redox signaling. Journal of Neuroscience Research, 86(10), 2235-2249. https://doi.org/10.1002/jnr.21665

Bilirubin as an endogenous modulator of neurotrophin redox signaling. / Mancuso, Cesare; Capone, Caterina; Ranieri, Sofia Chiatamone; Fusco, Salvatore; Calabrese, Vittorio; Eboli, Maria Luisa; Preziosi, Paolo; Galeotti, Tommaso; Pani, Giovambattista.

In: Journal of Neuroscience Research, Vol. 86, No. 10, 01.08.2008, p. 2235-2249.

Research output: Contribution to journalArticle

Mancuso, C, Capone, C, Ranieri, SC, Fusco, S, Calabrese, V, Eboli, ML, Preziosi, P, Galeotti, T & Pani, G 2008, 'Bilirubin as an endogenous modulator of neurotrophin redox signaling', Journal of Neuroscience Research, vol. 86, no. 10, pp. 2235-2249. https://doi.org/10.1002/jnr.21665
Mancuso C, Capone C, Ranieri SC, Fusco S, Calabrese V, Eboli ML et al. Bilirubin as an endogenous modulator of neurotrophin redox signaling. Journal of Neuroscience Research. 2008 Aug 1;86(10):2235-2249. https://doi.org/10.1002/jnr.21665
Mancuso, Cesare ; Capone, Caterina ; Ranieri, Sofia Chiatamone ; Fusco, Salvatore ; Calabrese, Vittorio ; Eboli, Maria Luisa ; Preziosi, Paolo ; Galeotti, Tommaso ; Pani, Giovambattista. / Bilirubin as an endogenous modulator of neurotrophin redox signaling. In: Journal of Neuroscience Research. 2008 ; Vol. 86, No. 10. pp. 2235-2249.
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