Table 5.
Examples of the effects of intermittent hypoxia exposure with favorable neurological impact.
| Subjects | Time of hypoxia | Hypoxia method | Hypoxia dosage | Outcome | References |
|---|---|---|---|---|---|
| Rats | 6 h, 12 h, or 1, 4, 7, 14, or 21 d | HC | BP = 380 Torr (≈5,500 m) |
↑Hct ↑GLUT-1 ↑VEGF ↑brain HIF-1α until 14 d ↓brain HIF-1α at 21 d |
Chávez et al., 2000 |
| Cell culture | 4 h | NH | 1%O 2 + 5%CO2 + N2 | ↑HIF-1α (NO interferes expression) | Agani et al., 2002 |
| Rats (male) | 11–13 min | Ischemia | Ischemia after cardiac arrest | ↑HIF-1α 12 h−7 d ↑IGF-1 |
Chavez and LaManna, 2002 |
| Rats (male) (3 groups) | 4 h/d for 2 wk | HC | 3,000 m 5,000 m Control normoxic |
↑BrdU-labeled cells in SVZ and DG (NPC) in rat brain | Zhu et al., 2005 |
| Astrocytes and NPC culture from brain cortex of newborn rats | 6, 12, 18, and 24 h | NH | 1%O2 + 5%CO2 + N2 (astrocytes) | ↑Migration of NPC by hypoxia-induced astrocytes (maximal at 18 h) | Xu et al., 2007 |
| Neuronal cultures of 16–18 days old fetuses of Sprague–Dawley rats | 6 h “ischemia” 48 h “reperfusion” |
NH | Anoxic atmosphere (5%CO2 + 95%N2) | Mitochondrial dysfunction & ER stress ⇒ neuronal apoptosis ↑Bcl-2 ⇒↓Apoptosis |
Zhang et al., 2008 |
| Rats (n = 122) -Ischemia MCA n = 42 -Ischemia MCA + post-cond n = 42 -Control group n = 40 |
60 min MCA ischemia post-cond (60 min after reperfusion): reperfusion for 30 s, MCA occluded for 5 cycles × 30 s | Ischemia (MCA occlusion) |
Unknown (ischemia) | ↑Bcl-2 ↑Hsp70 ↓Cytochrome c
↓Bax translocation to the mitochondria ↓Caspase-3 ↓Infarct volume ↓Oxidative stress ↑Neurologic scores |
Xing et al., 2008 |
| Neonatal mice: acute IH and control group | 40 min 20 × (1:1) | NH | FiO2 = 0.10 (10% O2) | ↑SVZ derived NPC in vitro | Ross et al., 2012 |
| Rats (n = 55) Groups: with or without MCAO and/or IH, and/or zidovudine |
4 h/d for 7 d | NH | FiO2 = 0.12 (12% O2) | Post brain ischemia: ↑Synaptogenesis via BDNF ↑Neurogenesis ↑Spatial learning and memory |
Tsai et al., 2013 |
| TBI medical history human males. 4 groups: -Exercise and SES (n = 5) -Cycling (n = 5) -IHH and SES (n = 6) -Control (n = 5) |
2 h/d × 3 d/wk for 12 wk | HC | 4,500 m | ↑CPC No changes in psychological tests ↑Aerobic capacity or workload |
Corral et al., 2014a |
| Mice (wildtype vs. Notch1 KO) | 4 h/d during consecutive 28 d | HC | 2,000 m | ↑Notch1 ↑Hypoxia induced neurogenesis |
Zhang K. et al., 2014a |
| Newborn mice with brain injury 3 Groups (n = 373) -Hypoxia separated from the mother -Normoxia separated from the mother Control with mother |
20 events/h, 6 h/d from postnatal day 6 (P6) to P10 | NH | FiO2 = 0.08 (8% O2) | Control mice: ↑Hippocampal angiogenesis ↑Neurogenesis ↑Short-term memory indices Brain-injured mice: ↓Injury size ↓Memory impairments |
Bouslama et al., 2015 |
| Rats (n = 48) hypocampal CA1 region. 4 groups with or without ischemia-reperfusion and IHH | Hypoxia for 4 d once a day I/R 8 min |
In vivo
I/R |
Unknown (ischemia) | ↑Surviving cells in the hippocampal CA1 in IHH+IR ↑Bcl-2 |
Wu et al., 2015 |
| Rats with C2 medular hemisection (n = 32) | IHT 10 × (5:5) intervals (total 95 min) for 7 d | NH | FiO2 = 0.105 (10.5% O2) | ↑Breathing capacity ↑Contralateral diaphragm (adenosine dependent) −2° intercostal muscle (adenosine independent) |
Navarrete-Opazo et al., 2015 |
| Rats (male) with Chronic Mild Stress induced depression (n = 60) and controls (n = 20) | 4 h/d for 2 wk | HC | 5,000 m | Avoid neuronal loss ↑Neurogenesis ↑BDNF–TrkB signaling |
Kushwah et al., 2016 |
| Rats (n = 195) 6 groups with chronic 5 wk stress and/or IHH or IMIP or antagonist of mitoKATP | 6 h/d for 28 days | HC | 5,000 m | ↑Expression and activity of mitoKATP
↓Cerebral ischemia injury ↓UCMS |
Zhang et al., 2016a |
| Rats with C2 medular hemisection (n = 27) with or without hypoxia + adenosine inhibitor | 8 wk post-lesion 5 min hypoxia, 5-min normoxic 10 times (95 min) 7 d, AIH 3/wk 8 wk |
NH | FiO2 = 0.105 (10.5% O2) | ↑Tidal volume and bilateral diaphragm activity (enhanced by adenosine receptor inhibitor) for 4 wk | Navarrete-Opazo et al., 2017b |
| Rats with spinal C2 hemisection. 1) 7d after lesion 2) 7wk after lesion + serotonin receptor antagonist |
IHT 10 × (5:5) intervals (total 110 min) | NH | FiO2 = 0.105 (10.5% O2) | ↑Breathing capacity Serotonin independent in acute (2wk) and serotonin dependent in chronic (8wk) |
Dougherty et al., 2017 |
| Humans incomplete spinal cord injured (n = 35): IH + BWSTT (n = 18) NX + BWSTT (n = 17) |
IHT 15 × (1.5:1.5) intervals for 5 consecutive d + 3 d/wk for 3 wk |
NH | FiO2 = 0.09 (9% O2) | ↑Walking recovery and endurance (up to 5wk) |
Navarrete-Opazo et al., 2017a |
| Rats (n = 12) | IHT 3 × (5:5) | NH | FiO2 = 0.11 (11% O2) alternating with hyperoxia FiO2 = 0.5 (O2 50%) | ↑or↓in firing rate of midcervical interneurons altering connectivity | Streeter et al., 2017 |
| Men with chronic incomplete spinal cord injury (n = 6) (double-blind, crossover study) | IHT 15 × (1.5:1) intervals for 5 consecutive d + hand opening practice | NH | FiO2 = 0.09 (9% O2) | ↑Hand dexterity, function, or opening in all participants | Trumbower et al., 2017 |
In IHT protocols hypoxia was alternated with room air (FiO2 = 0.209) if nothing else is indicated. AIH, acute intermittent hypoxia; BDNF, brain derived neurotrophic factor; Bcl-2, B cell lymphoma/leukemia-2; BP, barometric pressure; BrdU, 5-Bromo-2-deoxyuridine-5-monophosphate; BWSTT, body weight-supported treadmill training; CAO, carotid artery occlusion; CIHH, chronic intermittent hypobaric hypoxia; CPC, circulating progenitor cells; DG, dentate gyrus; FiO2, Fraction of inspired oxygen; GLUT-1, glucose transporter-1; HC, Hypobaric Chamber; Hct, hematocrit; HIF, Hypoxia inducible factor; Hsp70, heat shock protein70; IGF-1, insulin-like growth factor-1; IH, intermittent hypoxia; IHH, intermittent hypobaric hypoxia; IHT, intervallic hypoxic training alternating hypoxia and normoxia along the session; IMIP, imipramine; I/R, ischemia-reperfusion; KO, knockout mutant; MCA, medium cerebral artery; MCAO, middle cerebral artery occlusion; NH, normobaric hypoxia; NO, nitric oxide; NPC, neural progenitor cells; NX, normoxia (placebo); ER, endoplasmic reticulum; TBI, traumatic brain injury; UCMS, Unpredictable Chronic Mild Stress; VEGF, vascular endothelial growth factor; SES, surface electrical stimulation; SVZ, subventricular zone.