We are evaluating the effects of prior exposure to stress on brain tissue and functional outcome after ischemic stroke in rats and mice. The first phase of these studies found that pre-stroke social stress increases inflammation in the brain and worsens the ischemic injury, and progesterone treatment reduces this inflammatory response. We are now analyzing how stress increases the inflammatory response to the evolution of a stroke. In the “two-hit model of neuroinflammation,” the first hit is the prolonged stress which leads to the release of stress hormones like cortisol which prime inflammatory cells already resident in the brain, as well as most other organs. These primed cells then secrete chemical danger signals called “alarmins” that can increase the severity of the injury by making more inflammatory factors through the cell machinery called the “inflammasome.” The second hit is the stroke itself, which injures and kills nerve cells and activates the inflammasome. When you have high stress combined with stroke, the inflammasome is overactivated, and a vicious cycle of more inflammation and more cell death makes it much harder for any therapy or spontaneous recovery process to work.

We now think the most promising stroke treatment targets are microglia and their mitochondria — the energy generators in all cells, including those which trigger inflammation. Even without a stroke, chronic stress can injure mitochondria, which then produce free radicals, and this causes the release of alarmins that elicit and potentiate inflammation. Our current and future plans include in vitro studies testing the hypothesis that progesterone can modify the phenotypic expression of microglia from inflammatory producers to increasing expression of trophic support factors. This is accomplished, in part, by preventing stress damage to mitochondria. There are progesterone receptors all over mitochondria, and in the presence of the hormone, disruption is reduced, and energy metabolism is normalized.

This ongoing research is an entirely new approach to the treatment of severe stroke, and quite possibly other diseases of the brain. If we are successful, we will have identified a specific target—repairing damage to mitochondria—as a testable and pragmatic approach to stroke Neurotherapy. We are now preparing a manuscript entitled “Progesterone reduces alarmin HMGB1 release and stress-induced NLRP3inflammasome priming following ischemic brain injury” for submission to Brain, Behavior, and Immunity.