Abstract
Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics
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11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
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Animals
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Blotting, Western / methods
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Cell Count / methods
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Cell Death / drug effects
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Cell Death / genetics
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Culture Techniques
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Estrogen Receptor alpha
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Glucocorticoids / antagonists & inhibitors*
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Hippocampus / drug effects
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Hippocampus / physiology
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Humans
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Immediate-Early Proteins
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Immunohistochemistry / methods
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Indoles
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Kainic Acid / toxicity
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Male
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Microtubule-Associated Proteins / metabolism
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Models, Molecular
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Neurons / drug effects
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Neurons / physiology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary / physiology
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RNA, Messenger / metabolism
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Rats
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism
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Receptors, Glucocorticoid / genetics
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Receptors, Glucocorticoid / metabolism*
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism
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Recombinant Fusion Proteins / pharmacology*
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Stress, Physiological / genetics
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Stress, Physiological / metabolism*
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Transgenes
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Translocation, Genetic / physiology
Substances
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ESR1 protein, human
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Estrogen Receptor alpha
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Glucocorticoids
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Immediate-Early Proteins
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Indoles
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Microtubule-Associated Proteins
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NR2D NMDA receptor
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Nuclear Proteins
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RNA, Messenger
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Receptors, Estrogen
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Receptors, Glucocorticoid
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Receptors, N-Methyl-D-Aspartate
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Recombinant Fusion Proteins
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DAPI
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Fibroblast Growth Factors
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11-beta-Hydroxysteroid Dehydrogenase Type 2
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Protein Serine-Threonine Kinases
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serum-glucocorticoid regulated kinase
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Kainic Acid