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Colorado Center for Altitude Medicine and Physiology, Departments of Anesthesiology and Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA
The scientific basis for chemoprophylaxis relates principally to the drug's ability to increase chemosensitivity with attendant improvements in peripheral oxygen diffusion. However, its ability to suppress nuclear factor kappa B and meningeal release of substance P inhibiting the development of neurogenic edema and neurovascular headache
GABA-receptor-mediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges.
may prove equally important from a mechanistic perspective.
Despite expected improvements in arterial oxygenation, medroxyprogesterone did not influence the incidence or severity of AMS in a high-risk setting, although analyses were to some extent constrained by limited statistical power. However, as indicated by the authors, a noticeable trend was observed toward selectively lower AMS scores in the active drug trial, leading to the suggestion that a more sensitive scoring system may have essentially resurrected their statistically negative findings. My interpretation is somewhat different because I would like to contend that the choice of placebo may have proven the critical limiting factor that may have tempered any potential drug effect.
Recent evidence suggests that the neurological sequelae ubiquitous to AMS may have a free radical basis with selective increases observed in molecular footprints of free radical–mediated lipid peroxidation and sarcolemmal membrane permeability.
Oral administration of a potent cocktail of aqueous and lipid-phase antioxidant vitamins (250 mg of l-ascorbic acid, 100 IU of dl-α-tocopherol acetate, and 150 mg of α-lipoic acid bolus dose, 4 times daily) was subsequently shown to be an effective prophylactic
In the published study, the incorporation of l-ascorbic acid as the placebo treatment cannot therefore be considered pharmacologically inert, thus questioning its role as an effective comparator. Supplementation incorporated a daily bolus dose of 300 mg equivalent to 5 times the recommended daily allowance, which, over the duration of the experimental period, resulted in a cumulative intake of 2.1 g. This regimen would have been sufficient to saturate the intracellular concentration of ascorbate (achieved at 200 mg), although a larger dose would have been required to satisfy plasma saturation (1000 mg).
Ascorbate is a thermodynamically ideal terminal chain-breaking antioxidant capable of scavenging almost every oxidizing species generated in a biological system. This can be achieved both directly and indirectly. Direct scavenging involves the one electron oxidation of ascorbate to yield the ascorbate-free radical (A·−), a relatively unreactive intermediate that can donate an electron to other oxidizing species thereby preventing chain propagation of potentially damaging downstream redox reactions. Indirectly, ascorbate can reduce the oxidized form of Vitamin E (tocopheroxyl radical) back to its original form so that it can continue to function as the primary lipid-soluble chain-breaking antioxidant acting at the membrane-water interface. Because the therapeutic benefits of medroxyprogesterone were measured relative to this redox-active control, it is eminently plausible that the prophylactic benefits of the active drug were, at least to some extent, underestimated.
To address this possibility, albeit from a pharmokinetic perspective, I have examined how a similar dosing regime with ascorbic acid would have influenced the redox status of human blood using the only molecular technique available for the direct measurement of free radicals—electron paramagnetic resonance (EPR) spectroscopy.
Incorporating a double-blinded design and after ethical approval, peripheral venous blood was obtained from a resting 35-year-old man before and 1.5 hours after an oral bolus dose of l-ascorbic acid (6 × 50 mg). This procedure was repeated after 7 days supplementation with l-ascorbic acid (6 × 50 mg/d). Venous blood was mixed ex-vivo with the spin-trap α-phenyl-tert-butylnitrone (PBN) to extend the lifetime of biological radicals and thus facilitate EPR detection as previously described.
Separate samples of blood were mixed with a molar excess of dimethylsulfoxide (DMSO) to promote one-electron reversible oxidation of
Effects of l-ascorbic acid supplementation on the redox status of human blood (n = 1). Resting blood samples were obtained before (pre-bolus) and 1.5 hours after (post-bolus) oral ingestion of 6 × 50 mg l-ascorbic acid (phase 1). The same protocol was repeated after 7 days of l-ascorbic acid supplementation at a dose of 6 × 50 mg/d (phase 2). Blank spectra based on degassed toluene + α-phenyl-tert-butylnitrone (PBN) or dimethylsulfoxide only (excludes human serum). Axes for all respective ordinates are identically scaled. Note that the increase in ascorbate concentration (directly proportional to the amplitude of dimethylsulfoxide-A·-spectral peaks) was associated with a parallel decrease in PBN adduct concentration.
ascorbate to yield A·- that can also be detected via EPR. This is a measure of ascorbate concentration as opposed to de nouveau radical-induced A·- generation.
An overview of the experimental spectra obtained before and after supplementation with l-ascorbic acid is illustrated in the Figure. For the purposes of quantitative interpretation, the concentration of radical spins and ascorbate is directly proportional to the amplitude of spectral peaks. The PBN adducts exhibited the characteristic 6-line triplet-of-doublets spectrum and are consistent with the trapping of lipid-derived oxygen-centered alkoxyl or carbon-centered alkyl species (aN = 13.6 Gauss [G], ) formed distal to the primary-production pathway. A single doublet was also observed and is characteristic of the A·- ().
Supplementation successfully increased the venous concentration of ascorbate as indicated by a clear increase in the signal intensity of DMSO-A·-, which equated to an absolute increase of 36 μmol/L and 26 μmol/L (relative to baseline control) for phase 1 and phase 2 of the study, respectively. The corresponding scavenging capacity of venous blood increased considerably, as indicated by the decreased concentration of secondary/tertiary lipid-derived radical species.
Thus, it would seem that oral provision of l-ascorbic acid at the moderate doses prescribed in the present study would have enhanced the scavenging of biologically relevant free radical species generated even under resting conditions at sea level. This effect would probably be accentuated after either a passive or active ascent to high altitude because both physical activity and inspiratory hypoxia exert independent pro-oxidant effects, thus compounding the radical burden experienced by the mountaineer.
Therefore, in light of existing evidence in support of the neuro-oxidative hypothesis and the present albeit preliminary findings, future trials examining the neuroprophylactic benefits of progestin administration deserve to be encouraged.
References
Wright A.D.
Beazley M.F.
Bradwell A.R.
et al.
Medroxyprogesterone at high altitude: the effects on blood gases, cerebral regional oxygenation, and acute mountain sickness.
GABA-receptor-mediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges.
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