$2.5 million grant to study neonatal cerebral vascular disease pathology

The National Institute of Neurological Disorders and Stroke has awarded $2.5 million to a research duo at Le Bonheur Children’s Hospital and the University of Tennessee Health Science Center (UTHSC) for a project aimed at finding new ways to treat brain damage caused by lack of oxygen at birth. Le Bonheur Neonatologist Massroor Pourcyrous, MD, is co-investigator alongside principal investigator Helena Parfenova, PhD, professor in the Department of Physiology at UTHSC.

Massroor Pourcyrous, MD

For more than 25 years, productive collaboration between Parfenova, a basic scientist, and Pourcyrous, a clinical scientist, has centered on prevention and treatment of cerebrovascular disease that occurs due to devastating neonatal brain disorders, including epilepsy and asphyxia. With this new award, the team will focus on novel mechanisms that could keep the brain and its blood vessels working properly in newborns when they experience prolonged asphyxiation.

Neonatal asphyxia is a leading cause of neurodevelopment issues. Early research suggests an enzyme called Nox4 is the main producer of harmful oxygen particles in the brain’s blood vessels when a newborn does not get enough oxygen. On the other hand, H2S, a gas enzymatically produced by astrocytes, acts as an antioxidant, protecting cells from damage. Building on this knowledge, Parfenova and Pourcyrous are proposing a new form of neurovascular cell-directed therapy that combines selectively blocking the Nox4 enzyme while increasing the body’s H2S-based antioxidant defenses.

“Nox4 selective inhibitor is available on market and is recognized as a clinically safe drug,” said Pourcyrous. “The combination therapy may represent promising candidates for the development of a new drug for neonatal hypoxic ischemic encephalopathy.”

Using a combination of complementary techniques, the team will seek answers to three specific questions: first, whether blocking Nox4 enzyme activity can protect the blood vessels in the brain from being damaged by asphyxia; second, whether boosting the body’s natural H2S antioxidant system can protect astrocytes from damage resulting from asphyxia; and lastly, whether a combined neurovascular-targeted treatment using antioxidants that stop Nox4 and substances that increase H2S, supplemented by therapeutic hypothermia, can prevent
cerebrovascular disease caused by prolonged neonatal asphyxia.

The research is unique in its combination of practical experiments on the whole brain’s blood flow with an investigation of cellular and molecular details behind diseases of these blood vessels.

“Preventing neonatal cerebral vascular disease will help prevent neonatal encephalopathy and improve health of a new generation,” Parfenova said. “This project may lead to the development of new relevant neurovascular-targeting treatments to fully protect the neonatal brain during asphyxia. Importantly, we collected sufficient preliminary data to support our hypothesis on neurovascular cell-directed combination therapy for neonatal cerebral vascular disease.”