Protecting Brains from Stroke’s Cellular Stress

Across populations, the single greatest cause of disability, and second cause of mortality, is stroke. Half of the 16 million stroke victims worldwide become disabled when blood flow to their brain is interrupted, starving neurons of the oxygen and glucose they need to live. The health and economic burden on society is huge. It is remarkable, then, that just one drug is available to treat the cerebral blood clots behind most ischemic strokes, and this is only appropriate for use in 5-8% of patients. Called tPA, this substance naturally produced by the body is a complex character, whose effects are sometimes beneficial, sometimes harmful, likely depending on dose, form and context. At the same time, the death of brain cells associated with stroke is known to take place via many different routes. Dr. Benoit Roussel hopes to capitalize on that fact by gaining a precise understanding of one such chain of molecular events. This could open doors to developing new treatments that operate in the same way to save brain cells.
His preliminary results are both surprising and promising. He explains that, in stroke, cells starved of energy activate a cellular stress response; if this goes on too long, it will trigger the program for cell death. Dr. Roussel wondered what role the stroke drug tPA might play in this specific, little-studied scenario. To simulate the conditions of stroke, he grew mouse neurons in a chamber without oxygen and deprived them of glucose, then observed what happened when he added tPA. It turned out the drug was able to decrease the cellular stress reaction that would eventually have proven deadly to the cells. He is now picking apart the mechanisms that make this happen. Different steps along the path could become targets for new drugs with very precise action, capable of reducing cellular stress brought on by stroke and potentially avoiding the harmful effects of tPA. In a world where populations around the globe are getting older, increasing the risks associated with stroke, additional treatment options would make a critical difference.

Scientific title: Neuroserpin and the ER Stress Pathway: Two Ways to Investigate the Effects Of tPA in Cerebral Ischaemia