Intracranial hemorrhage and inflammation
Research on vascular permeability, drug candidate provides insights into this life-threatening event.
Intracranial hemorrhage is one of the most dangerous types of stroke, with a devastating mortality rate. Understanding the role of inflammation in intracranial hemorrhage may be a critical step toward improving treatments and bringing those death rates down.
That will be the crux of the session on Thursday titled “Bench to Bedside and Beyond — What Do We Know About the Role of Inflammation in an Intracranial Hemorrhage?”
In managing intracranial hemorrhages, the impact of vascular permeability is an important, related question, said Sahily Reyes-Esteves, MD, PhD, neurology instructor at the University of Pennsylvania’s Perelman School of Medicine.
“Intracranial hemorrhages inherently cause a breakdown of the blood-brain barrier and a spillage of blood contents into the brain parenchyma,” Reyes-Esteves said. “However, beyond the initial hematoma, we have learned that there are persistent waves of barrier leakiness that contribute to the inflammatory response” after the hemorrhage.
“Is it all bad? Is it all good? The answer is probably somewhere in the middle,” she said. “Understanding the nuances in this balance is important to understanding how vascular permeability affects outcomes after intracranial hemorrhage.”
Reyes-Esteves will discuss those questions and more in her presentation, “The Role of Vascular Permeability in Neuroinflammation After intracranial hemorrhage.” She said vascular permeability’s impact is the subject of much research.
“Clinically, we have long observed that cerebral edema after intracranial hemorrhage is associated with worse outcomes,” she said. “Does vascular permeability inherently lead to edema and bad outcomes? Perhaps not. Current research is looking to understand the role of the peripheral and brain intrinsic immune response in vascular permeability after intracranial hemorrhage and how it impacts ‘good’ or ‘bad’ healing.”
The difference between that “good” and “bad” healing is not as black-and-white as it seems. There has long been an impression that the inflammatory response after intracranial hemorrhage was all bad, Reyes-Esteves said, but that may not be the case.
“I think it is important as clinicians to understand not just the detrimental effects of inflammation, but the potentially beneficial ones as well, as they can inform the development of new therapies that harness the immune response for brain healing,” she said.
Also at Thursday’s session, a researcher will describe a novel drug candidate that could decrease inflammation and cerebral edema in the wake of intracerebral hemorrhage – which is a subset of intracranial hemorrhage. Linda Van Eldik, PhD, director of the Sanders-Brown Center on Aging and co-director of the Kentucky Neuroscience Institute at the University of Kentucky, said the drug candidate, MW189, is a molecule that could be used at a specific point after intracerebral hemorrhage.
“In intracerebral hemorrhage, inflammation occurs in a well-defined time frame after injury and is amenable to intervention in the critical care setting,” she said. “Our novel drug candidate is a brain-penetrant small molecule that selectively reduces injury-induced, detrimental proinflammatory cytokine responses without suppressing the normal physiological levels and functions of the inflammatory response.”
Van Eldik said MW189 has completed phase 1a and 1b studies in healthy adult volunteers and is now in a phase 2a clinical trial in patients who have had an intracerebral hemorrhage.
“The hope is that by reducing the injury-induced increases in proinflammatory cytokines, we will prevent the downstream brain swelling and nerve cell damage that frequently occurs,” she said.
Although the road to fully implemented drug treatments is a long one, Van Eldik said MW189 is being developed with the idea of prioritizing what mechanisms to target and what compounds have the best chance of success. Neuroinflammation is a well-validated mechanism, especially for acute brain injuries, that can be targeted successfully for therapeutic development.
“To hit the bull’s-eye, we must hit the right targets with the right drugs at the right time,” she said. “And we feel that our novel small molecule compounds that were prioritized in development based on their drug-like properties and their selective action show promise to become future effective therapies for multiple central nervous system disorders.”
