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Article
Nature Neuroscience  7, 947 - 953 (2004)
Published online: 8 August 2004; | doi:10.1038/nn1296

Restructuring the neuronal stress response with anti-glucocorticoid gene delivery

D Kaufer1, 3, W O Ogle1, Z S Pincus1, 4, K L Clark1, A C Nicholas1, K M Dinkel1, 5, T C Dumas1, D Ferguson6, A L Lee1, M A Winters7 & R M Sapolsky1, 2

1  Department of Biological Sciences, Stanford University, Stanford, California, USA.

2  Departments of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.

3  Department of Neurosurgery, Stanford University, Stanford, California, USA.

4  Department of Biomedical Informatics, Stanford University, Stanford, California, USA.

5  Leibniz Institute for Neurobiology, Magdeburg, Germany.

6  Department of Psychiatry, Stanford University, Stanford, California, USA.

7  Department of Infectious Diseases, Stanford University, Stanford, California, USA. D.K., W.O.O. and Z.S.P. contributed equally to this work.

Correspondence should be addressed to D Kaufer danielak@stanford.edu
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.

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Nature Neuroscience
ISSN: 1097-6256
EISSN: 1546-1726
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