Restructuring the neuronal stress response with anti-glucocorticoid gene delivery

D. Kaufer, W. O. Ogle, Z. S. Pincus, K. L. Clark, A. C. Nicholas, K. M. Dinkel, T. C. Dumas, D. Ferguson, A. L. Lee, M. A. Winters, R. M. Sapolsky

Research output: Contribution to journalArticle

68 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)947-953
Number of pages7
JournalNature neuroscience
Volume7
Issue number9
DOIs
StatePublished - Sep 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Kaufer, D., Ogle, W. O., Pincus, Z. S., Clark, K. L., Nicholas, A. C., Dinkel, K. M., Dumas, T. C., Ferguson, D., Lee, A. L., Winters, M. A., & Sapolsky, R. M. (2004). Restructuring the neuronal stress response with anti-glucocorticoid gene delivery. Nature neuroscience, 7(9), 947-953. https://doi.org/10.1038/nn1296