Journal
JOURNAL OF NEUROCHEMISTRY
Volume 108, Issue 5, Pages 1143-1154Publisher
WILEY
DOI: 10.1111/j.1471-4159.2008.05846.x
Keywords
antioxidant; apoptosis; neuroglobin; neuro-protection; oxidative stress; synchrotron radiation; X-ray fluorescence imaging
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Funding
- Commonwealth of Australia
- US Department of Energy, Office of Science [W-31-109-Eng-38]
- ARC Research Fellowship [DP034325]
- National Heart Foundation [G 07S30435]
- ARC Discovery [DP0664706]
- ARC Professorial Fellowship [DP0208409]
- Australian Research Council [DP0208409, DP0664706] Funding Source: Australian Research Council
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Oxidative stress is associated with the pathology of acute and chronic neurodegenerative disease. We have cloned a human neuroglobin (Nb) construct and over-expressed this protein in cultured human neuronal cells to assess whether Nb ameliorates the cellular response to experimental hypoxia-reoxygenation (H/R) injury. Parental cells transfected with a blank (pDEST40) vector responded to H/R injury with a significant decrease in cellular ATP at 5 and 24 h after insult. This was coupled with increases in the cytosolic Ca2+, and the transition metals iron (Fe), copper (Cu), and zinc (Zn) within the cell body, as monitored simultaneously using X-ray fluorescence microprobe imaging. Parental cell viability decreased over the same time period with a similar to 4 to 5-fold increase in cell death (maximum similar to 25%) matched by an increase in caspase 3/7 activation (peaking at a 15-fold increase after 24 h) and condensation of beta-actin along axonal processes. Over-expression of Nb inhibited ATP loss and except for significant decreases in the sulfur (S), chlorine (Cl), potassium (K) and Ca2+ contents, maintained cellular ion homeostasis after H/R insult. This resulted in increased cell viability, significantly diminished caspase activation and maintenance of the beta-actin cytoskeletal structure and receptor-mediated endocytosis. These data indicate that bolstering the cellular content of Nb inhibits neuronal cell dysfunction promoted by H/R insult through multiple protective actions including: (i) maintenance of cellular bioenergetics; (ii) inhibition of Ca2+ influx; (iii) a reduction in cellular uptake of Fe, Cu and Zn at the expense of S, Cl and K; and (iv) an enhancement of cell viability through inhibiting necrosis and apoptosis.
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