Researchers from the University of Iowa (UI) and University Hospitals Cleveland Medical Center report that offspring can be protected from the effects of prenatal stress by administering a neuroprotective compound during pregnancy. The team published its study “Maternal P7C3-A20 Treatment Protects Offspring from Neuropsychiatric Sequelae of Prenatal Stress” in Antioxidants & Redox Signaling.
Working in a mouse model, Rachel Schroeder, a student in the UI Interdisciplinary Graduate Program in Neuroscience, drew a connection between the work of her two mentors, Hanna Stevens, MD, PhD, UI associate professor of psychiatry and Ida P. Haller Chair of Child and Adolescent Psychiatry, and Andrew A. Pieper, MD, PhD, a former UI faculty member. Pieper is now Morley-Mather Chair of Neuropsychiatry at Case Western Reserve University and Investigator and Director of the Neurotherapeutics Center at the Harrington Discovery Institute, University Hospitals Cleveland Medical Center.
Stevens’s lab studies the long-lasting impact of stress during pregnancy, which can lead to neuropsychiatric impairment in offspring during early life and in adulthood. Pieper’s lab focuses on discovery of neuroprotective treatments, exemplified by the pharmacologic agent used here, known as P7C3-A20, which has previously been shown to protect the adult brain from injury. Schroeder’s is the first to explore the therapeutic potential of prenatal exposure to P7C3 compounds.
“Impaired embryonic cortical interneuron development from prenatal stress is linked to adult neuropsychiatric impairment, stemming in part from excessive generation of reactive oxygen species in the developing embryo. Unfortunately, there are no preventive medicines that mitigate the risk of prenatal stress to the embryo, as the underlying pathophysiologic mechanisms are poorly understood. Our goal was to interrogate the molecular basis of prenatal stress-mediated damage to the embryonic brain to identify a neuroprotective strategy,” write the investigators.
“Chronic prenatal stress in mice dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis enzymes and cortical interneuron development in the embryonic brain, leading to axonal degeneration in the hippocampus, cognitive deficits, and depression-like behavior in adulthood. Offspring were protected from these deleterious effects by concurrent maternal administration of the NAD+-modulating agent P7C3-A20, which crossed the placenta to access the embryonic brain. Prenatal stress also produced axonal degeneration in the adult corpus callosum, which was not prevented by maternal P7C3-A20.”
“Prenatal stress dysregulates gene expression of NAD+-synthesis machinery and GABAergic interneuron development in the embryonic brain, which is associated with adult cognitive impairment and depression-like behavior. We establish a maternally directed treatment that protects offspring from these effects of prenatal stress.”
“NAD+-synthesis machinery and GABAergic interneuron development are critical to proper embryonic brain development underlying postnatal neuropsychiatric functioning, and these systems are highly susceptible to prenatal stress. Pharmacologic stabilization of NAD+ in the stressed embryonic brain may provide a neuroprotective strategy that preserves normal embryonic development and protects offspring from neuropsychiatric impairment.”
“Prenatal stress increases the risk for offspring to have neurodevelopmental problems,” Schroeder said. “We wanted to know whether the P7C3-A20 compound protected the embryonic brain from damage. Our results show that offspring are protected from the negative effects of stress when the mothers are treated with P7C3-A20 during the same time.”
Previous work by Pieper’s lab has shown that P7C3-A20 enables nerve cells to maintain normal levels of an energy molecule—nicotinamide adenine dinucleotide (NAD+), under toxic or injury conditions that are otherwise overwhelming and energy-depleting for the cell.
Schroeder’s research showed that chronic prenatal stress in mice disrupted the embryonic brain’s NAD+-synthesis machinery, which led to degeneration of nerve cell axons, learning deficits, and depression-like behavior when the offspring reached adulthood. Schroeder demonstrated that when prenatally-stressed pregnant mice were simultaneously treated with P7C3-A20, their offspring were protected from these negative effects.
“By stabilizing critical NAD+-producing mechanisms, we enabled the developing embryonic brain to continue developing normally despite the stress,” explained Schroeder.
“Though there are many challenges associated with administering medicines during pregnancy, Rachel Schroeder’s discovery represents an exciting move forward in understanding how prenatal stress harms the brain, and strategies for protecting the developing embryo,” added Pieper, who is also a psychiatrist at the Louis Stokes VA Medical Center in Cleveland.
This study represents an important proof of concept for a new approach to early prevention of neuropsychiatric problems, said Stevens.
“Neuropsychiatric problems are the most common chronic illnesses of young people, which means we need many more ways to protect the brain as it develops,” she continued. “Our lab is focused on mechanisms of brain development prenatally, a critical time when we could make a difference.”