The effects of acidosis on chronically hypoxic neurons in culture.
Neuropathologic changes associated with perinatal hypoxic-ischemic events in the human infant most often result from chronic hypoxia rather than from acute asphyxia. To characterize the effects of acidosis associated with chronic hypoxia in developing neurons, cerebral cortical cultures obtained from fetal mice were exposed to 5% O2 continuously for either 24 or 48 h at 10 days after plating. At the conclusion of the hypoxic insult (HI), neuronal morphology was relatively intact for both conditions even though culture medium reflected significant reductions in pH and bicarbonate with elevation of lactate; cultures exposed to the longer HI manifested statistically greater aberrations from control values. Total benzodiazepine (BDZ) binding and clonazepam (CLO)-displaceable BDZ binding, reflecting the neuronal component of the receptor, were only modestly reduced immediately after HI, but were thereafter significantly and progressively lower over the 72 h normoxic recovery period. Although neuronal integrity was progressively diminished with both insults, morphology was always more normal and CLO higher in cultures subjected to 48-h HI compared to the 24-h HI (34.0 +/- 9.8 vs 1.8 +/- 1.1% of control values at 72 h, respectively; P less than 0.001). In contrast, values obtained for the glial marker Ro5-4864-displaceable BDZ binding were higher than control values for both conditions. Outcome was not influenced by removal of acidotic medium, nor by normalization of lactate. These data suggest that, with time, neurons in vitro adapt to severe hypoxia and that alterations in pH, lactate, and bicarbonate by themselves are probably not neurotoxic since the most acidotic cultures exhibited improved survival.
Sher
P K
PK
Division of Pediatric Neurology, University of Minnesota Medical School, Minneapolis 55455.
D000138:Acidosis / Q000473:pathology*; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001570:Benzodiazepinones / Q000378:metabolism; D001667:Binding, Competitive; D002478:Cells, Cultured; D002908:Chronic Disease; D002998:Clonazepam / Q000378:metabolism; D003470:Culture Media; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D012016:Reference Values; D013997:Time Factors
D001570:Benzodiazepinones; D003470:Culture Media; D001569:Benzodiazepines; C028513:4'-chlorodiazepam; D002998:Clonazepam