Role of stat/cart pathway in estrogen-mediated
neuroprotection
Nabil Alkayed, M.D., Ph.D. – Principal Investigator

Postmenopausal women are at high risk for stroke, but the benefit of hormone replacement therapy in stroke prevention remains controversial. 

Using middle cerebral artery occlusion experimental models, we have found that females sustain significantly smaller infarcts following cerebral ischemia compared to age-matched males.  This sex difference in infarct size disappeared after ovariectomy and was restored by estrogen replacement, indicating that estrogen is a factor in female-specific neuroprotection from stroke.

The mechanism of action by estrogen in neuroprotection is unclear, but it involves the induction of neuroprotective genes.  We have uncovered a novel genetic program triggered by estrogen and linked to signal transducers and activators of transcription (STAT) which mediate the upregulation of cocaine and amphetamine regulated transcript (CART) in ischemic brain.  CART is a secretory neuropeptide expressed in rat and human brain and has been implicated in a variety of brain functions.  

In these studies, we are using in vitro and in vivo models of neuronal injury to examine

1) the effects of estrogen on CART levels and distribution in brain, 2) the mechanism of CART gene upregulation by estrogen, and 3) the role of CART in estrogen-mediated neuroprotection.

This research is funded by the National Institutes of Health.