Increased hypoxic tolerance by chemical inhibition of oxidative phosphorylation: "chemical preconditioning".
A short ischemic episode preceding sustained ischemia is known to increase tolerance against ischemic cell death. We report early-onset long-lasting neuroprotection against in vitro hypoxia by preceding selective chemical inhibition of oxidative phosphorylation: "chemical preconditioning." The amplitude of CA1 population spikes (psap) in hippocampal slices prepared from control animals (control slices) was 31 +/- 27% (mean +/- SD) upon 45-min recovery from 15-min in vitro hypoxia. In slices prepared from animals treated in vivo with 20 mg/kg 3-nitropropionate (3-np) 1-24 h prior to slice preparation (preconditioned slices), psap improved to 90 +/- 15% (p < 0.01). Posthypoxic oxygen free radicals were reduced to 65 +/- 10% (mean +/- SD) of control in preconditioned slices (p < 0.05). Posthypoxic neuronal density improved from 52 +/- 15% (mean +/- SD) in control slices to 97 +/- 23% in preconditioned slices (p < 0.001). Glibenclamide, an antagonist at KATP-channels, partly reversed increased hypoxic tolerance. We conclude that chemical preconditioning induces early-onset long-lasting tolerance against in vitro hypoxia. Ultimately, this strategy may be applicable as a neuroprotective strategy in humans.
Riepe
M W
MW
Department of Neurology, Humboldt University, Berlin, Germany.
Esclaire
F
F
Kasischke
K
K
Schreiber
S
S
Nakase
H
H
Kempski
O
O
Ludolph
A C
AC
Dirnagl
U
U
Hugon
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy; D015687:Cell Hypoxia / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005609:Free Radicals; D005905:Glyburide / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002534:Hypoxia, Brain / Q000188:drug therapy; D008297:Male; D009243:NAD / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009574:Nitro Compounds; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D005609:Free Radicals; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D015221:Potassium Channels; D011422:Propionates; D017382:Reactive Oxygen Species; D009243:NAD; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid; D005905:Glyburide