Hypoxia triggers neuroprotective alterations in hippocampal gene expression via a heme-containing sensor.
Sublethal ischemia or hypoxia triggers adaptive changes that protect the brain against future hypoxic/ischemic damage. Preexposure of in vitro hippocampal slices to brief periods of hypoxia increases the resistance of Schaffer collateral-CA1 synaptic potentials to further, longer periods of hypoxia that would otherwise cause an irreversible loss of synaptic transmission. Since hypoxia has been shown to cause alterations in the patterns of protein synthesis, we hypothesized that newly-expressed proteins might mediate hypoxia-induced neuroprotection. We report here that the induction of neuroprotection by hypoxic preconditioning in rat hippocampal slices is blocked by either cycloheximide, a protein synthesis inhibitor, or by Actinomycin D, an inhibitor of RNA synthesis. In contrast, pharmacological blockade of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) subtypes of glutamate receptors did not prevent the induction of neuroprotection by hypoxia. Carbon monoxide (CO), which can lock heme moieties in their oxygenated configurations, did prevent hypoxia from inducing neuroprotection. We conclude that hypoxia activates protective mechanisms via deoxygenation of a heme moiety, triggering expression of gene products which protect synaptic function from subsequent hypoxic damage.
Gage
A T
AT
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461-1602, USA.
Stanton
P K
PK
D000222:Adaptation, Physiological; D000818:Animals; D015374:Biosensing Techniques; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D006418:Heme / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D002534:Hypoxia, Brain / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin; D006418:Heme; D003513:Cycloheximide