Dichotomous effects of chronic intermittent hypoxia on focal cerebral ischemic injury.
OBJECTIVE
Obstructive sleep apnea, a condition associated with chronic intermittent hypoxia (CIH), carries an increased risk of stroke. However, CIH has been reported to either increase or decrease brain injury in models of focal cerebral ischemia. The factors determining the differential effects of CIH on ischemic injury and their mechanisms remain unclear. Here, we tested the hypothesis that the intensity of the hypoxic challenge determines the protective or destructive nature of CIH by modulating mitochondrial resistance to injury.


METHODS
Male C57Bl/6J mice were exposed to CIH with 10% or 6% O2 for ≤35 days and subjected to transient middle cerebral artery occlusion. Motor deficits and infarct volume were assessed 3 days later. Intraischemic cerebral blood flow was measured by laser-Doppler flowmetry and resting cerebral blood flow by arterial spin labeling MRI. Ca2+-induced mitochondrial depolarization and reactive oxygen species production were evaluated in isolated brain mitochondria.


RESULTS
We found that 10% CIH is neuroprotective, whereas 6% CIH exacerbates tissue damage. No differences in resting or intraischemic cerebral blood flow were observed between 6% and 10% CIH. However, 10% CIH reduced, whereas 6% CIH increased, mitochondrial reactive oxygen species production and susceptibility to Ca2+-induced depolarizations.


CONCLUSIONS
The influence of CIH on the ischemic brain is dichotomous and can be attributed, in part, to changes in the mitochondrial susceptibility to injury. The findings highlight a previously unappreciated complexity in the effect of CIH on the brain, which needs to be considered in evaluating the neurological effect of conditions associated with cyclic hypoxia.
From the Feil Family Brain and Mind Research Institute (K.A.J., P.Z., G.F., P.M.P., C.C., V.P., G.M., C.I.) and Department of Radiology (H.U.V.), Weill Cornell Medical College, New York; and Department of Natural Sciences, Baruch College, City University of New York (P.M.P.).
Katherine A
KA
Jackman
Ping
P
Zhou
Giuseppe
G
Faraco
Pablo M
PM
Peixoto
Christal
C
Coleman
Henning U
HU
Voss
Virginia
V
Pickel
Giovanni
G
Manfredi
Costantino
C
Iadecola
D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species
free radicals; mitochondria; sleep apnea syndromes; stroke