Means For Making Brain Cells Resistant To Stroke Discovered By Toronto Researchers

In a landmark study to be published in the prestigious international journal Science on Friday, June 11, 1999, researchers have discovered a critical mechanism that causes brain cells to be damaged by a stroke. By understanding this mechanism, researchers are now able to identify a new means for treating stroke by targeting a key chemical process in brain cells.

The research opens the door to new medications that would work to contain the effects of stroke to a core area by making brain cells in surrounding areas more resistant to stroke damage, thus minimizing the disabling impairments experienced by patients.

"This new knowledge will let us now concentrate on creating drugs that will minimize the number of brain cells affected during a stroke and improve patient outcomes," said neurosurgeon and Medical Research Council Clinician-Scientist Michael Tymianski, who is also an Associate Professor at the University of Toronto. When a stroke occurs, brain cells begin to die within minutes, due to a lack of oxygen. The number of cells that die, directly affect the degree to which a patient is left impaired. "Any means we have to increase the amount of time for brain cells to resist a stroke is an achievement that will benefit the health of many individuals."

Stroke is the third most common cause of death in Western society, after heart disease and cancer. During a stroke, a chemical chain reaction occurs in which cells are flooded with excessive amounts of calcium. Calcium (ions) activate enzymes that form free radicals which, in turn, cause cells to die. Free radicals are highly reactive molecules that interact with vital components such as genetic material, cell walls and other critical cell structures causing damage that may eventually become irreparable. Free radicals have been implicated in several other well known diseases including cancer and heart disease. In stroke, free radicals cause irreparable damage to critical components of the brain cells which leads to their death.

To unravel the mystery behind the mechanism that causes stroke, researchers began by looking at a previous discovery in Dr. Tymianski's laboratory. In the earlier study, they found that a key receptor, called NMDA, which sits on the surface of a cell, causes brain cells to be flooded with toxic quantities of calcium when stimulated.

In the current study, the research team focused on proteins (located inside cells) that interact with the NMDA receptor. They found that a specific protein (PSD-95) links toxic calcium ions that enter through the NMDA receptors to enzymes that form free radicals and, ultimately, trigger the stroke process. By modifying the activity of this one key protein, they were able to render brain cells resistant to stroke. The key to the chemical chain reaction for stroke, is the protein PSD-95. By targeting medication to neutralize or inactivate this protein, brain cells will be protected.

"This discovery is significant because to date clinical stroke testing using available experimental medications has shown no real benefit to patients. In fact, many have proven to have harmful side effects," said Dr. Tymianski. "This new knowledge will enable us and other researchers to develop these ideas further, ensuring that Canadians play a lead role in stroke treatments and, perhaps, prevention."

Dr. Tymianski noted that the work was a team effort, which included Ph.D. student Rita Sattler and Dr. John MacDonald at the University of Toronto.

The Toronto Western Hospital's Neurosciences Centre has a long history of innovative research and treatments that has earned its staff an international reputation for excellence. Many of the techniques and procedures first developed here are now being used by specialists around the world. The goal of improving patient care through original research-based initiatives drives staff of the Centre to constantly seek new therapies and technologies for treating neurological diseases.

The Toronto Western Hospital is a partner in the University Health Network (formerly The Toronto Hospital), along with Toronto General Hospital and Princess Margaret Hospital and is a fully affiliated with the University of Toronto. Building on the strengths and reputations of each of these remarkable hospitals, the University Health Network brings together the talent, resources, technology and skills that make it an international leader in health care, research and teaching.