1. ¹Department of Biological Sciences, Stanford University, Stanford, California, USA
2. ²Stanford Stroke Center, Stanford University, Stanford, California, USA
3. ³Department of Neurosurgery, Stanford University, Stanford, California, USA

Correspondence: Dr MY Cheng, 371 Serra Mall, Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA. E-mail: mycheng@stanford.edu

Received 17 March 2008; Revised 9 July 2008; Accepted 5 August 2008; Published online 17 September 2008.

Abstract

Glucocorticoids (GCs) and estrogen can modulate neuron death and dysfunction during neurological insults. Glucocorticoids are adrenal steroids secreted during stress, and hypersecretion of GCs during cerebral ischemia compromises the ability of hippocampal and cortical neurons to survive. In contrast, estrogen can be neuroprotective after cerebral ischemia. Here we evaluate the protective potential of a herpes viral vector expressing a chimeric receptor (ER/GR), which is composed of the ligand-binding domain of the GC receptor (GR) and the DNA-binding domain of the estrogen receptor- (ER). This novel receptor can transduce an endangering GC signal into a protective estrogenic one. Using an in vitro oxygen glucose deprivation model (OGD), GCs exacerbated neuron death in primary cortical cultures, and this worsening effect was completely blocked by ER/GR expression. Moreover, blocking GC actions with a vector expressing a dominant negative GC receptor promoted neuron survival during postischemia, but not preischemia. Thus, gene therapeutic strategies to modulate GC and estrogen signaling can be beneficial during an ischemic insult.