Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

Abstract

This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to hypoxia (12.9% O(2)). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and headache were determined with clinically validated questionnaires. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites. Neuron-specific enolase (NSE), S100beta, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous concentration difference (a-v(D)) and net cerebral output of lipid-derived alkoxyl-alkyl free radicals and lipid hydroperoxides (P < 0.05 vs. normoxia) that correlated with the increase in AMS/headache scores (r = -0.50 to -0.90, P < 0.05). This was associated with a reduction in a-v(D) and hence net cerebral uptake of plasma nitrite and increased cerebral output of 3-NT (P < 0.05 vs. normoxia) that also correlated against AMS/headache scores (r = 0.74-0.87, P < 0.05). In contrast, hypoxia did not alter the cerebral exchange of S100beta and both global cerebral oxidative metabolism (cerebral metabolic rate of oxygen) and neuronal integrity (NSE) were preserved (P > 0.05 vs. normoxia). These findings indicate that hypoxia stimulates cerebral oxidative-nitrative stress, which has broader implications for other clinical models of human disease characterized by hypoxemia. This may prove a risk factor for AMS by a mechanism that appears independent of impaired BBB function and cerebral oxidative metabolism.

Nitric oxide metabolites in goldfish under normoxic and hypoxic conditions

“…A similar decrease in plasma nitrite was reported in European flounder exposed to hypoxia for two days (Jensen, 2009a). Likewise, in humans, both plasma nitrite and plasma nitrate decrease by close to 40% following exposure to hypoxia (12.9% O 2 ) for 9h (Bailey et al, 2009). These results seem to support the idea that NOS activity is compromised by the lack of O 2 .…”

Investigation of Whole-Brain White Matter Identifies Altered Water Mobility in the Pathogenesis of High-Altitude Headache

“…An alternative physiologically plausible explanation is that the current data represent the early effects of moderate hypoxemia (SaO 2 B81%), whereas the investigation of Schoonman et al, 4 although shorter in duration, signifies a more advanced state because of the use of a slightly more aggressive protocol (SaO 2 B75% to 80%) and because participants remained in the supine position for the entire experiment, a position that is more likely to cause larger increases in intracranial pressure. 20,21 The lack of molecular evidence for breakdown of the bloodbrain barrier in similar models to the current investigation 10,11 and the accumulation of intracellular water identified herein, alongside extracellular edema identified previously, 4 hints toward the premorbid onset of regionally specific intracellular water. This may be followed by intracellular accumulation of osmotically active ions and a transcapillary flux of Na þ in an attempt to rebalance extracellular ion homeostasis.…”

“…Subsequently, we explored the relationship between the development of a specific acute mountain sickness symptom, headache, with changes in brain water mobility and content after 2 hours (presymptomatic) and 10 hours (symptomatic) in hypoxia. Given the lack of molecular evidence for breakdown of the bloodbrain barrier in hypoxia, 10,11 but evidence for the accumulation of both extracellular and intracellular water, 3,4,8 we hypothesized that early hypoxia (2 hours) will be characterized by a reduction in mean diffusivity and increased fractional anisotropy but no change in T 2 in line with a fluid shift into the intracellular space. In contrast, more prolonged hypoxia (10 hours) will be associated with reduced mean diffusivity but increased fractional anisotropy and T 2 , which would suggest an increase in brain edema.…”

Reduced metabolic rate and oxygen radicals production in stored insect sperm

“…It is also possible that a hypoxic pathway of sperm metabolism is induced in the female. However, there are at least two arguments that call for caution in accepting the latter hypothesis as a general explanation: (i) cell metabolism under hypoxia commonly results in significant ROS production [42,44] and (ii) hypoxic/ anaerobic glycolysis may be limited as it mainly occurs in the cytoplasm, which is barely present in sperm cells.…”