Alberto Arregui

Reduced mitochondrial respiration in mouse cerebral cortex during chronic hypoxia.

Respiratory activity and NADH CoQ reductase (complex I) and cytochrome c oxidase (complex IV) activities were measured in free (non-synaptosomal) mitochondria isolated from cerebral cortex of male Balb/c mice exposed to intermittent hypobaric hypoxia (450 Torr; 4300 m) for 21 days and compared to normoxic (sea level) controls. In the hypoxic we found a 47% reduction of oxygen uptake during state 3 (ADP and substrate present), 12% reduction during state 4 (no ADP present) and 20% reduction in the uncoupled respiration rate with pyruvate plus malate as substrates. Respiratory control ratio (RCR) decreased by 24%. No change in the ADP/O ratio was seen. NADH CoQ reductase activity decreased by 30% and cytochrome c oxidase by 17%, suggesting that under conditions of chronic hypoxia, the reductions of mitochondrial respiratory activities are caused, at least in part, by enzymatic alterations of the electron transport chain (complex I and complex IV). The decreased activity of these enzymes could contribute to alterations in neuronal activity by reducing brain energy metabolism during development under conditions of chronic hypoxia.

High prevalence of migraine in a high‐altitude population

In an epidemiologic study at high altitude and sea level, we found a 12.4% prevalence rate of migraine in the high-altitude and 3.6% in the sea-level populations. In both locations, women had a greater frequency of headaches, although the differences were less at high altitude due to a high frequency of migraine among men who were miners. Possible aggravating factors among miners include working extra hours or night shifts in the mines.

Migraine, polycythemia and chronic mountain sickness

In the epidemiological study among 379 adult men with permanent residence at 4300 meters (14,200 feet), we found 32.2% with migraine (mostly migraine with aura), 15.2% with tension-type headache (episodic more than chronic), and 7.2% with other headaches. The frequency of migraine increased with age from 30.1% in the 20–29 year age group to 36.8% in the 50–59 year group. Episodic tension-type headaches also showed this trend. We found an age-specific increase in the frequency of high hemoglobin (Hb > 213 g/l), low oxygen saturation (O2 saturation <81.5%), and high chronic mountain sickness scores. Male migraineurs and those with more than two headaches per month had the highest hemoglobin levels and chronic mountain sickness scores when compared with high altitude men without headaches.

Chronic hypoxia induces modification of the N-methyl-d-aspartate receptor in rat brain

This study examined [3H]MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor in membranes prepared from cerebral cortex, hippocampus and corpus striatum of 3 week old rats exposed to 10 weeks of intermittent hypobaric hypoxia (4300 m; 450 Torr) and compared results with those of normoxic controls. The cortex, hippocampus and striatum of hypoxic animals had a 36, 35 and 31% reduction in binding sites (Bmax) and a 29, 32 and 17% decrease (reflecting increased affinity) in the dissociation constant (Kd) when compared to controls. In the cerebral cortex, both glutamate (100 microM) and glycine (10 microM) enhanced 3[H]MK-801 binding by two to 3-fold. Coagonist glutamate, however, had a higher EC50 (0.44 microM) in the hypoxic cortical membranes when compared to controls (0.28 microM). No significant differences were found in the EC50 of glycine. The results show that the NMDA receptor is altered in several brain regions of rats developing in a hypoxic environment.

Energetic metabolism in mouse cerebral cortex during chronic hypoxia.

We measured the activities of Na(+)K(+) ATPase and of enzymes of the glycolytic pathway, Krebs cycle, and the respiratory chain in cerebral cortex of mice exposed to chronic hypoxia for three weeks and compared their values with those of sea level controls. There were no differences in Na(+)K(+) ATPase activity or in the activity of glycolytic enzymes. In the Krebs cycle, a 66% increase of succinate dehydrogenase activity was found due to a lower Km. In contrast, respiratory chain cytochrome oxidase activity was reduced by 12% in mice exposed to hypoxia. This suggested that the metabolic demand would be satisfied despite the respiratory chain depression (cytochrome oxidase), probably due to anaerobic energy production within the mitochondria (succinate dehydrogenase).

Autoradiographic evidence for increased dopamine uptake sites in striatum of hypoxic mice

Ligand binding to dopamine uptake sites, D1 and D2 dopamine receptors was measured autoradiographically in brain sections of mice exposed to intermittent hypobaric hypoxia (450 Torr; 4,300 m) for 14 days and compared to sea level controls. Desipramine-insensitive [3H]mazindol, [3H]SCH23390 and [3H]YM-09151-2 were used respectively for the labeling of the three binding sites. After 14 days, the striatum of hypoxic mice showed a significant 21% increase in dopamine uptake sites, one of the loci of action of cocaine. A similar (28%) but non-significant increase was found in the ventral tegmental area. No changes were seen in the activities of D1 or D2 receptors in several areas examined including the substantia nigra and the striatum.

Is Depression the Link Between Suicide and High Altitude

Hypoxia is characteristic of living at high altitude. Animal and human studies have shown that chronic hypoxia is associated with changes in the brain. Neurological symptoms are common in high altitude populations. Headaches, paresthesias, physical and mental fatigue have been described at high altitude (Arregui et al 1991; Appenzeller et al. 2002; Winslow and Monge 1987). Furthermore, these symptoms are frequent in Monge’s disease or chronic mountain sickness (CMS), a disease that develops after many years of residing at high altitude. It is characterized by excessive erythrocytosis, hypoxemia, headache, dizziness, tinnitus, breathlessness, sleep disturbances, physical and mental fatigue and dilation of the veins (Winslow and Monge 1987). Notable among CMS symptoms is migraine headache, which is particularly frequent at high altitude, being approximately 4 times more frequent than sea level populations 1 (Fig. 1). The recent retrospective study by Brenner et al. (2011) involving most U.S. counties, which spanned 20 years, reported a dramatic increase of suicide in high altitude populations. This finding was independent of demographic factors usually associated with suicide such as age, race, gender, or income. The higher suicide rate at high altitude is not explained by increased overall mortality since there is a negative correlation between altitude and overall mortality. Previous findings from our group may shed some light on this finding (Arregui 1995; Arregui et al 1995). Using epidemiological surveys we described an increased prevalence of depression in men living at high altitude compared with those living at sea level (see Fig 1A). Moreover, migraines and CMS occur more frequently at high altitude. In addition, depression is associated with the presence of migraines and CMS at high altitude (Arregui et al 1995) (see Fig 1B). Depression is responsible for the majority of suicide cases worldwide (Henriksson et al. 1993). Therefore, increased depression prevalence at high altitude populations may explain the association of increased suicide rate at high altitude (Brenner et al. 2011). Currently, the contribution of migraine in the association between suicide and high altitude is not entirely clear. However, migraine is also a risk factor for psychiatric disorders, including depression (Pompili et al. 2010). Both, depression and migraine are associated with serotonin related abnormalities, and both are part of the chronic mountain sickness symptomatology. However, further reFIG. 1. Odds ratios for high altitude and neuropsychiatric symptoms. (A). High altitude is associated with the presence of migraine and depression. The rates of migraine and depression were compared in high altitude and sea level natives. (B). At high altitude (4300 m) depression is associated with the occurrence of migraine and chronic mountain sickness (CMS). Odds ratios and 95% confidence intervals were calculated from Arregui et al. 1991*, Arregui 1995, and Arregui et al 1995 using 2 · 2 contigency tables through StatCalc utility software (Epi Info 2010, CDC Atlanta, Georgia).