Preclinical Testing of a TRPV4 Antagonist for the Treatment of Hydrocephalus in a Porcine Model
Abstract
The focus of our proposed research is to develop drugs that can be used to treat hydrocephalus. Hydrocephalus is a general term for excess cerebrospinal fluid (CSF) in the brain; babies can be born with this or it can happen because of conditions such as traumatic brain injury (TBI), infection, or hemorrhage. If too much CSF collects in the brain, a person can develop symptoms from the increased pressure in the head, with pain, vision problems, walking abnormalities, and cognitive changes that, if left untreated, can result in death. Currently, the only effective intervention for hydrocephalus is brain surgery. Shunts, the most common treatment, require that a tube is implanted in the brain in order to drain the excess CSF to another part of the body. After insertion, shunts are prone to malfunction or infection at any time over the lifespan, and additional surgery is often required. Thus, an individual with a shunt must live reasonably close to a hospital with neurosurgical care available at all times. There are no long-term, effective drugs to treat hydrocephalus, and this represents a large, world-wide medical need. We are addressing this need by conducting studies to try to find safe and effective compounds that can be developed as drugs to treat all forms of hydrocephalus. Our challenge, therefore, is to discover versatile, safe drugs for use on the battlefield, athletic facility or in geriatric and pediatric clinical wards. To address this challenge, we have identified a type of compound, called TRPV4 antagonists, that are effective in treating hydrocephalus in several rat models of hydrocephalus. The next step in the progression to treatment in humans is to test the compounds in a large animal model. We have formed a collaboration with a scientist who developed a pig model of hydrocephalus due to brain bleeds. We will use this model to test whether a form of TRPV4 antagonists that can be taken by mouth decreases their hydrocephalus. Relevance to Topic Areas: The proposed studies are applicable to the Neurosciences Portfolio Category and primarily to the Hydrocephalus Topic Area. Since it is our hypothesis that TRPV4 antagonists will be effective for the treatment of multiple forms of hydrocephalus, these studies are also applicable to the Topic Area of Trauma since many trauma patients experience post-traumatic hydrocephalus. The proposed studies address two of the Strategic Goals, namely, to conduct Foundational Studies and also the Treatment Goal due to the translational nature of the proposed preclinical studies. Applicability and Impact of the Research: People of all ages are at risk for hydrocephalus, including military Service Members. Traumatic brain injuries suffered by our military personnel, especially those who have served in Iraq and Afghanistan, have increased the numbers of those living with post-traumatic hydrocephalus (PTH). The incidence of PTH has been reported to be as high as 86% of severe head injury patients. Injured Soldiers treated in the field may not have timely access to neurosurgical care and advanced diagnostic testing, leading to under-reporting of the condition. Even if the hydrocephalus resolves in time, there may be long-lasting effects such as pain, vision changes, walking problems, and even personality changes. Retired military personnel are more likely to be at risk for hydrocephalus that develops after a stroke or from a poorly understood condition called idiopathic normal pressure hydrocephalus. The latter affects the elderly with symptoms that mimic other neurodegenerative diseases such as Alzheimer’s and Parkinson disease. Young military families are more likely to be affected by childhood forms of the disease, most commonly caused by brain bleeds in premature births, spina bifida, or trauma, all which result in chronic hydrocephalus. Civilian populations of similar ages are also affected by the multiple forms of hydrocephalus. In summary, the proposed studies,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310401
Entities
People
- Bonnie Blazer-Yost
Organizations
- Indiana University
- United States Army