Free Radical-Mediated Damage to Barrier Function is not Associated with Altered Brain Morphology in High-Altitude Headache

Abstract

The present study combined molecular and neuroimaging techniques to examine if free radical-mediated damage to barrier function in hypoxia would result in extracellular edema, raise intracranial pressure (ICP) and account for the neurological symptoms typical of high-altitude headache (HAH) also known as acute mountain sickness (AMS). Twenty-two subjects were randomly exposed for 18 h to 12% (hypoxia) and 21% oxygen (O2 (normoxia)) for collection of venous blood (0 h, 8 h, 15 h, 18 h) and CSF (18 h) after lumbar puncture (LP). Electron paramagnetic resonance (EPR) spectroscopy identified a clear increase in the blood and CSF concentration of O2 and carbon-centered free radicals (P<0.05 versus normoxia) subsequently identified as lipid-derived alkoxyl (LO*) and alkyl (LC*) species. Magnetic resonance imaging (MRI) demonstrated a mild increase in brain volume (7.0+/-4.8 mL or 0.6%+/-0.4%, P<0.05 versus normoxia) that resolved within 6 h of normoxic recovery. However, there was no detectable evidence for gross barrier dysfunction, elevated lumbar pressures, T2 prolongation or associated neuronal and astroglial damage. Clinical AMS was diagnosed in 50% of subjects during the hypoxic trial and corresponding headache scores were markedly elevated (P<0.05 versus non-AMS). A greater increase in brain volume was observed, though this was slight, independent of oxidative stress, barrier dysfunction, raised lumbar pressure, vascular damage and measurable evidence of cerebral edema and only apparent in the most severe of cases. These findings suggest that free-radical-mediated vasogenic edema is not an important pathophysiological event that contributes to the mild brain swelling observed in HAH.

Acute high-altitude sickness

“…However, in AMS, lumbar punctures reveal an intact blood-brain barrier for large molecular weight proteins [38]. Furthermore, there are no significant associations of peripheral oedema [39], slight increase in brain volume [14], albuminuria [40] and leakage of fluorescent dye from retinal vessels [41] with AMS.…”

“…Direct measurements indicate that ICP appears to be normal in subjects with AMS at rest [38,44], but may increase with exercise or other factors that increase blood or intrathoracic pressure [45], due to decreased intracranial compliance. Disturbed autoregulation may occur in AMS [35,46] and could enhance pressure transduction to the brain, although findings are controversial [47].…”

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

“…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.…”

Hypoxia and oxidation levels of DNA and lipids in humans and animal experimental models

“…Sequential study designs are also used to a great extent in investigations of hypoxia by exposure in chambers or masks (42)(43)(44)(45)(46), but there are also well-controlled studies (47)(48)(49)(50)(51). Four of the well-controlled studies reported a relationship between exposure to hypoxia and oxidative damage to both DNA and lipids (47,48,50,51), whereas one investigation found no effect of hypoxia (49). Data based on sequential studies indicate hypoxia-induced effects on at least one biomarker of lipid or DNA oxidation (12-16, 20, 23, 24, 34-42, 45, 46), except two studies that happens to be short-term (less than 10 min) exposure to hypoxia (43,44).…”

“…For instance, oxygen level decreased over time in studies of the ascend to the summit of San Pedro y San Pablo volcano (46) and the simulated ascend to Mt Everest (37), but it is impossible to split the time component from the effect of hypoxia. Figure 1 outlines the results of an overall analysis where studies have been stratified into those with exposures lasting 1 h or less (43)(44)(45)48), between 1 and 24 h (16,42,46,47,50,51), and between 24 h and 8 weeks (12-16, 20, 23, 34-41). This analysis indicates that the effect observed after days or weeks of hypoxia is larger than at earlier time point, but it should also be recognized that most of these studies are poorly controlled and it may just be an effect of confounding factors.…”