Development of Pharmacotherapies for the Treatment of Hydrocephalus
Abstract
Topic Area: Hydrocephalus Critical Problem: Hydrocephalus or “water on the brain” is a generalized term for the inappropriate build-up of fluid in the brain. This condition is often associated with children, where the hydrocephalus is very visible because the soft bones of the skull allow for the expansion of the entire head in response to the excess fluid. However, hydrocephalus can actually occur at any age and has many different causes including traumatic brain injury, infection, bleeding in the brain, tumors, or birth defects. Traumatic brain injury and the resulting post-traumatic hydrocephalus remain extremely relevant to military personnel. If left untreated, hydrocephalus results in progressive and irreversible brain and nerve degeneration, movement disorders, loss of bladder control, dementia, and even death. There are currently no drug treatments for hydrocephalus. Brain surgery to implant a device called a shunt to drain the excess fluid to other parts of the body, usually the abdomen, or a surgery to destroy part of the tissues that make cerebrospinal fluid are the only treatments and they remain the standard of care. Unfortunately, surgery always carries risks. Additionally, shunts often become blocked or infected, necessitating additional brain surgeries. If drugs could be developed to diminish the production of the cerebrospinal fluid, these would be a tremendous benefit to all hydrocephalic patients, but especially those who do not have easy emergency access to neurosurgical care, including those deployed in military situations. One roadblock to developing drugs to treat hydrocephalus is a lack of good animal and cell culture models that faithfully reproduce the disease. Our team has piloted the use of several new animal and cellular models of hydrocephalus with the idea of testing potential drugs that will improve the loss of brain function associated with this condition by ameliorating the build-up of fluid. Strikingly, our preliminary data in an animal model show that targeting a specific protein’s function with a particular class of drugs substantially decreases the severity of the hydrocephalus. We are currently testing how these drug-treated hydrocephalic animals perform in specific behavior tests (movement and memory). We have developed a cell model with our collaborators that will allow us to rapidly determine the effects of our candidate compounds on the fluid-producing cells in the brain. Importantly, it is these specific cells that are often the culprits in the hydrocephalic disease process. We have already determined that the candidate drug has an effect on the cultured cells consistent with the changes we see in the animal brains. We have established a team that includes basic scientists that are experts in cell biology, animal studies, behavioral testing, and magnetic resonance imaging techniques, as well as a neurosurgeon to advise the team on the direct applicability to human disease. This group of scientists and clinicians has already established a working relationship while conducting the pilot experiments that form the basis of the grant proposal. Applicability and Impact of Research: The proposed research has two overarching objectives: (1) to test the effectiveness of a novel class of drugs in hydrocephalic animal and cellular models and (2) to build a better understanding of both the animal and cellular models in order provide the research community at large with better tools to study the cause and treatment of hydrocephalus. In the long term, we hope these studies will result in drugs that can be used to treat this devastating disease and to avoid the necessity of brain surgery.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710537
Entities
People
- Bonnie Blazer-Yost
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army