O'Donnell, Martha Eaton, PhD
Role of blood-brain barrier Na transporters in diabetic ischemic stroke
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Brain edema (swelling) is a major cause of brain damage in stroke and a leading cause of death in the U.S. today. High blood sugar (hyperglycemia), is a complicating factor present in about 30% of stroke patients. Hyperglycemic patients fare considerably worse in stroke. They have much more brain edema and significantly poorer outcomes following stroke. However, the reasons for this are poorly understood. Our previous studies suggest that stroke conditions cause sodium transporter proteins present in the smallest brain blood vessels (brain microvessels) to transport too much sodium and water from blood into the brain, causing edema.
Recently we have found evidence that hyperglycemia exaggerates this process, resulting in even greater edema and brain damage. With the support of this grant we will test whether therapeutic approaches aimed at inhibiting activity of sodium transporters in brain microvessels will reduce edema and brain damage in hyperglycemic stroke patients, providing a much needed therapy for this devastating type of stroke.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
This project addresses the growing problem of the greatly worsened stroke outcome that is observed in hyperglycemic patients. We know that diabetics fare worse in stroke and that hyperglycemia, independent of diabetes, causes greater brain edema and brain damage in ischemic stroke. However, the reasons for this are not well understood. In previous studies my laboratory has worked to better understand the causes of stroke-induced edema, a major cause of death and disability, with the goal of developing acute therapies that will reduce edema and injury in stroke. We have found that brain capillary ion transporters are major players in stroke-induced brain edema formation and that intravenous pharmacologic inhibition of these transporters reduces edema and improves neurological outcome in our rat model of ischemic stroke.
While this is a promising therapeutic approach for improving outcome in otherwise healthy stroke patients, if we are to develop effective therapies, we must design treatments that will work in hyperglycemic patients as well as normoglycemic patients. This is especially important given that ~30% of ischemic stroke patients are hyperglycemic. In preliminary studies we have found that hyperglycemia increases the abundance and activity of two sodium ion transporters in brain capillaries: Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE). Further, exposure of brain capillary endothelial cells to hyperglycemia produces a more robust stimulation of these ion transporters by factors present during ischemia than is observed under normoglycemic conditions.
Our preliminary studies also suggest that intravenous administration of drugs that specifically inhibit brain capillary NKCC and NHE will effectively decrease or abolish edema formation ischemic stroke. If successful, our studies will lead to new therapies for treatment of hyperglycemic stroke patients.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The incidence of diabetes and insulin resistance is increasing in our population. With aging also comes the increased possibility of experiencing an ischemic stroke. In addition to age, the presence of diabetes increases the chances of a person having an ischemic stroke. Our studies are designed to determine whether drugs that inhibit brain capillary sodium ion transporters will prevent the exacerbated brain edema and brain damage that occur in patients who have high blood glucose at the time of stroke.
If our studies successfully demonstrate that these drugs improve stroke outcome in our rat model of hyperglycemic stroke, the next step will be to move toward testing these drugs in humans. It is our hope that this relatively simple approach to reducing brain edema in stroke will add an important new tool for physicians in the fight against stroke-induced brain damage, including hyperglycemic patients. With the advent of clot busting drugs we learned that while a patient may be quite incapacitated at the start of a stroke, if the damaging processes can be arrested, brain tissue at risk of permanent damage can be salvaged with the result of an excellent stroke outcome. Given that brain capillary ion transporters are readily accessible to drugs by simple intravenous injection it would be irresponsible for us not to pursue this exciting new therapeutic avenue.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
I am passionate about finding new therapies for acute intervention in stroke. Given the large fraction of stroke patients who are hyperglycemic on admission to the emergency room, it is imperative that we direct our energies toward determining how to effectively treat stroke occurring in the context of diabetes and hyperglycemia. As a researcher, I have become increasingly aware of the magnitude of this problem, not to mention the fact that type II diabetes and insulin resistance "runs" in my own family and among my friends and acquaintances are both type I and type II diabetics. I have been working hard over the years to better understand just what causes the extensive brain damage in stroke and how, specifically, brain capillary processes contribute to that damage. At this juncture I am committed to using my skills and resources to find new therapies that will help hyperglycemic stroke patients.
In what direction do you see the future of diabetes research going?
I believe that diabetes research will move forward on several fronts. One important goal is reduce the complications of diabetes by better management of blood glucose levels, whether through stem cell generation of pancreatic beta islet cells or devices that precisely monitor blood glucose and deliver appropriate insulin levels with the same effectiveness and timeliness as a healthy pancreas. Another important goal is to reduce the incidence of type I diabetes by developing approaches to fight auto-immune processes that damage the pancreas and to reduce the incidence of type II diabetes through lifestyle education programs.
A third important goal, one that is the primary aim of my research, is to develop and refine effective therapies to reduce the pathologies associated with diabetes. I believe it is only through such a multi-pronged approach that our efforts will have the greatest impact on decreasing the damaging effects of diabetes that have such a high cost in terms of the health of the population and also dollars spent on medical care for these patients.
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