Novel Non-Surgical Neuro-Immunomodulatory Treatment for Acquired Hydrocephalus
Abstract
Hydrocephalus, or water on the brain, describes the excess buildup of cerebrospinal fluid (CSF) within the brain. Hydrocephalus can arise from many different causes and affects people across the lifespan from newborns to the elderly. The most common cause of hydrocephalus that affects military Service Members and Veterans is post-traumatic hydrocephalus (PTH), which typically arises subacutely a few weeks after moderate to severe traumatic brain injury (TBI), or more chronically after serial, milder TBI such as from blast injuries. If too much CSF collects in the brain, then a person can develop symptoms from the increased pressure in the head, and even die without timely intervention. Currently, the only effective intervention for symptomatic hydrocephalus is surgical treatment. The most common form of surgical treatment is a shunt device to divert the excess CSF from the brain to another body cavity for absorption, such as the peritoneal cavity in the abdomen that surrounds the abdominal organs. After insertion, shunts are prone to malfunction or infection at any time over the lifespan, and additional surgery called a shunt revision is often required. Thus, an individual with a shunt must live reasonably close to a hospital with neurosurgical care at all times. Additionally, the person is always at risk for the family and job disruption caused by shunt problems, and the medical comorbidities associated with urgent surgeries and prolonged hospitalizations. Thousands of people in the U.S. live with CSF shunts, and the need for an effective, non-surgical treatment cannot be overemphasized. For this proposal, we have combined what we have learned from critical analyses of clinical practice with recent advances from our originally funded research effort to develop a new hypothesis and treatment strategy. We observed that chronic inflammation is a self-propagating, critical component of most forms of hydrocephalus. In addition, we found that animals with TBI and the highest levels of inflammation both in their brains and throughout their bodies, are at the greatest risk for developing severe hydrocephalus. We also discovered that we could prevent PTH from arising by early and sustained treatment with high doses of two naturally occurring hormones that are known to safely enhance brain repair, erythropoietin and melatonin. In addition to preventing the hydrocephalus with a non-surgical cocktail of medications, we also observed improvement in the diffuse brain damage that often accompanies hydrocephalus on neurological exam, and with sophisticated brain imaging. Here, we propose to build on what we have learned to design a novel, second-generation, orally administered, neuroreparative drug cocktail that acts synergistically to restore CSF dynamics and prevent PTH. Specifically, we will use a new drug class of drugs called prolyl hydroxylase inhibitors, together with high dose melatonin, to target ongoing inflammation after TBI. We predict this new class of drugs will more effectively synergize with melatonin, and thus be more effective in repairing damage to cells that leads to hydrocephalus. We also predict that these drugs may be safer for adults than erythropoietin. We will test whether the drug cocktail changes the secretion of beneficial and toxic factors into the CSF. In addition, we will explore in detail how the drug cocktail repairs the brain damage that leads to CSF accumulation, and prevent or treat hydrocephalus. These studies will link abnormalities in CSF production, movement, and absorption, with the body’s immune system. Uniquely, we will focus on CSF dynamics as a whole, as well as brain function (cognition, posture, walking ability) and brain structure at the same time. Finally, we will use our new understanding of hydrocephalus to develop blood tests to determine who needs what treatment when and for how long. We will also investigate whether sophisticated brain imaging with magnetic resonance imaging (MRI
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210462
Entities
People
- Lauren Jantzie
Organizations
- Johns Hopkins University
- United States Army