Cerebral formation of free radicals during hypoxia does not cause structural damage and is associated with a reduction in mitochondrial PO2; evidence of O2-sensing in humans?

Abstract

Cellular hypoxia triggers a homeostatic increase in mitochondrial free radical signaling. In this study, blood was obtained from the radial artery and jugular venous bulb in 10 men during normoxia and 9 hours hypoxia (12.9% O(2)). Mitochondrial oxygen tension (p(O(2))(mit)) was derived from cerebral blood flow and blood gases. The ascorbate radical (A(•-)) was detected by electron paramagnetic resonance spectroscopy and neuron-specific enolase (NSE), a biomarker of neuronal injury, by enzyme-linked immunosorbent assay. Hypoxia increased the cerebral output of A(•-) in proportion to the reduction in p(O(2))(mit), but did not affect NSE exchange. These findings suggest that neuro-oxidative stress may constitute an adaptive response.

Figure 1

Cerebral formation of the ascorbate radical (A^•−) during hypoxia. (A) Oxidation of the ascorbate monoanion (AH⁻) by an initiating species (R^•) with a one-electron reduction potential (E°′) greater than +282 mV yields the domesticated ascorbate radical (A^•−). The unpaired electron is delocalized over a highly conjugated tricarbonyl π-system rendering it resonance stabilized, facilitating direct detection by electron paramagnetic resonance (EPR) spectroscopy. Note the increase in the systemic and cerebral formation of A^•− during 9 hours passive exposure to hypoxia. Digits below each spectrum represent EPR signal intensities in arbitrary units (AU) (double integral, which is directly proportional to the concentration of A^•−). (B) Relationship between the reduction (Δ, calculated as the hypoxic minus the normoxic control value) in mitochondrial PO₂ ( ) and increase in the cerebral output of ascorbate radicals (A^•−).