Estradiol attenuates programmed cell death after stroke-like injury.

Abstract

Estradiol is a known neurotrophic and neuroprotective factor. Our previous work demonstrated that replacement with physiological concentrations of estradiol protects the cortex against middle cerebral artery occlusion (MCAO)-induced cell death. The cerebral cortex exhibits caspase-dependent programmed cell death (PCD) in many models of focal cerebral ischemia. We hypothesized that estradiol attenuates PCD during stroke injury. The current study explored the temporospatial pattern of markers of PCD, their relationship to the evolution of injury, and their modulation by estradiol. Rats were ovariectomized and treated with either estradiol or vehicle. One week later, rats underwent MCAO, and brains were collected at 1, 4, 8, 16, and 24 hr. We assessed the temporospatial evolution of infarction volume, DNA fragmentation, and levels of spectrin cleavage products in ischemic cortex. Estradiol led to a delay and attenuation of injury-mediated DNA fragmentation as early as 8 hr after MCAO. Estradiol also dramatically reduced the level of the 120 kDa caspase-mediated spectrin breakdown product (SBDP120) at 4 hr but not at 8 or 16 hr. The SBDP150, produced by caspase and calpain, showed peak levels at 16 hr but was not altered by estradiol. These results strongly suggest that estradiol protects the ischemic cortex by attenuating PCD, thereby reducing caspase activity, DNA fragmentation, and subsequently, overall cell death. These studies deepen our understanding of the mechanisms underlying estrogen-mediated neuroprotection.

• Authors: Shane W Rau, Dena B Dubal, Martina Böttner, Lynnette M Gerhold, Phyllis M Wise
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 23 Issue 36 Pg. 11420-6 (Dec 10 2003) ISSN: 1529-2401 [Electronic] United States
• PMID: 14673006 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Neuroprotective Agents
• Spectrin
• Estradiol
• Casp3 protein, rat
• Caspase 3
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3
• Caspases (metabolism)
• Cerebral Cortex (metabolism, pathology)
• DNA Fragmentation
• Estradiol (therapeutic use)
• Female
• Infarction, Middle Cerebral Artery (metabolism, pathology, prevention & control)
• Kinetics
• Neuroprotective Agents (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Spectrin (metabolism)