A Novel Nonsurgical Approach to Treat Post-Traumatic Hydrocephalus
Abstract
This project is directed towards the FY20 PRMRP Topic Area of Hydrocephalus. We propose here a novel therapy that has Military Relevance Focus by addressing current gaps in the non-surgical treatment of hydrocephalus following traumatic brain injury, which is disproportionately common in military veterans. The objective of this project is to determine the feasibility of a new approach to treat hydrocephalus resulting from traumatic brain injury by using medications instead of surgery. Hydrocephalus is a condition that results from excess fluid inside the brain spaces called ventricles. It is not entirely clear why excess fluid accumulates following brain injury. There is evidence to suggest that proteins and other debris from the injury in the brain fluids will attract more fluid into the ventricles. This process is similar to our hand or leg swelling after injury due to damaged tissues. Therefore, it is logical to assume that clearing these proteins from the brain fluid will decrease the amount of fluid and return the ventricular size to normal. There is some evidence that brain has special transporters on the blood vessels to remove the proteins. These transporters are called “efflux transporters.” These transporters function differently in different people and under the influence of different medications. Whether efflux transporters play any part in clearing these proteins and therefore prevent or treat hydrocephalus is not proven. Our project will examine whether these efflux transporters play a role in how hydrocephalus develops following traumatic brain injury. We will create a rat model that simulates traumatic brain injury by injecting blood into the ventricles. We will use magnetic resonance scans to look at how severe the hydrocephalus is in different animals. First, we will look at genetically abnormal rats where efflux transporters are knocked out resulting in very low function and in genetically abnormal rats where these same transporters are hyperfunctioning. If the hydrocephalus is severe when the transporters are knocked out and milder if the transporters are hyperfunctioning, then we would have demonstrated that these transporters play a role. Next, we will test the same hypothesis by using medications. We will use medications that block the transporter function (which should make hydrocephalus worse) and medications that increase transporter function (which should make hydrocephalus better). These experiments, if successful, will have demonstrated that impaired efflux transporter function will result in hydrocephalus and treatment of hydrocephalus can be accomplished by medications that increase transporter function. Overall, this study will advance the treatment of hydrocephalus significantly by offering the option of medication instead of surgery. In addition, certain individuals have poorly functioning transporter function either constitutionally (genetic differences) or from other medications that they may be on. The results of this study will help us to identify people at risk for hydrocephalus (by testing some of their genes) and to optimize treatment of hydrocephalus by changing the drugs that might potentially prevent transporter function to remove the proteins. Our research is particularly relevant to military veterans, as traumatic brain injury is one of the invisible wounds of war and one of the signature injuries of troops wounded in Afghanistan and Iraq. Nearly 30 percent of patients with severe brain injuries develop post-injury hydrocephalus. Having hydrocephalus significantly increases disability. Currently, the only treatment option for hydrocephalus is insertion of a tube called a shunt into the brain to drain the excess fluid into the abdomen in order to prevent death or disability. The shunts are prone to blockage and infection, which will need more surgeries. It is not uncommon to have multiple shunt surgeries once a person has a shunt. In addition, shunt can fail to work at a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110096
Entities
People
- Satish Krishnamurthy
Organizations
- State University of New York Upstate Medical University
- United States Army