Insights Into How Estrogen Works May Lead To Improved Stroke Treatments

Researchers from the University of North Texas Health Science Center at Fort Worth and the University of Florida’s McKnight Brain Institute collaborated to discover a critical form estrogen takes that enables it to protect brain cells.

“We discovered a major mechanism by which estrogen protects nerve cells,” said James Simpkins, PhD, director of UNTHSC’s Institute for Aging and Alzheimer’s Disease Research. “We now know how estrogen keeps brain cells alive even when exposed to an insult like stroke, Alzheimer’s disease or Parkinson’s disease.”

If a compound can retain estrogen’s protective benefits and reduce the side effects because the estrogen is produced in a controlled fashion in the body, it could change the way strokes, heart attacks, and chronic conditions such as Alzheimer’s disease are treated, he said. “Essentially, patients will be able to take advantage of the good effects of estrogen while minimizing the bad effects.”

The research findings are published in the September 22 issue of the Proceedings of the National Academy of Science.

Simpkins’ lab in Fort Worth has already begun evaluating compounds based on this discovery. Production of such a drug will require several years of additional experimentation and clinical testing, he said.

Key to the discovery of the compound was the unraveling of the mystery of how the body naturally regenerates estrogen after a stroke.

“During a stroke, free radicals damage important cells in the body, most notably nerve cells,” said Laszlo Prokai, PhD, a chemist with UF’s College of Pharmacy. “Many of the debilitating effects come not from the primary incident — the clogging of the arteries and the shortage of blood — but after the surgeon opens an artery, for example, and the blood starts flowing through the previously blocked territory. Then the reactive oxygen species, or free radicals, just start going rampant.”

Free radicals are unbalanced molecules than have lost an electron and try to stabilize themselves by stealing an electron from a nearby molecule, which creates a jumble of high energy particles that ricochet wildly and damage cells. In the case of stroke, the hydroxyl radical — a chemical compound consisting of one atom of hydrogen and one of oxygen — does a large part of the damage.

Estrogen comes to the rescue by capturing the hydroxyl radical.

“In layman’s terms, a spill occurs when the blood starts flowing into the blocked territory, and the overflow hydroxyl radical is the spill,” Prokai said. “The estrogen is the mop, soaking up the hydroxyl radicals before they do damage. But when the mop is saturated, you have to squeeze it to continue mopping. This mechanism has never been fully understood before.”

When the estrogen and hydroxyl radicals combine, an unusual molecule called a quinol is produced. In this form, the hydroxyl radicals are harmless, but the estrogen is no longer useful as an antioxidant. Prokai investigated and discovered chemicals in the body transform the quinol back to estrogen, effectively wringing out the mop and making it useful again.

“It has been talked about for years that estrogen somehow participates in an (antioxidant) cycle, and until this work, no one really knew what the cycle was,” said Bruce McEwen, PhD, a professor of neuroendocrinology at Rockefeller University in New York. “The cycle implies that estrogen doesn’t have to be used up, that it can be rejuvenated to produce a chemical shield that gets rid of free radicals. Further, you can use tiny amounts of the estrogen derivative to set off this cycle. Showing a mechanism in which these effects can take place is an important step forward.”

In terms of therapies, scientists believe administering the quinol — the saturated mop — will deliver the protective benefits of estrogen, because the body will naturally wring it out and convert it to estrogen, while side effects associated with direct estrogen therapy, such as feminization in men, may remain in check.

The compound could eventually be a viable alternative to hormone replacement therapy, which is a combination of estrogen plus progestin, a synthetic substance that mimics the hormone progesterone to oppose estrogen’s undesirable effects on the uterus. While the natural loss of estrogen as women age may contribute to higher risk of stroke and heart disease, the American Heart Association does not advise women to take hormone replacement therapy. Furthermore, scientists at the National Heart, Lung, and Blood Institute in 2002 stopped a large study of such therapy because it increased the risk of invasive breast cancer and blood clots in the legs and lungs and failed to protect women from stroke.