Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting more than 10 million people worldwide. Current treatments address the symptoms of the disease but cannot prevent the underlying neurodegeneration that causes the disease.
Researchers from University Hospitals, Case Western Reserve University, and Louis Stokes Cleveland VA Medical Center previously identified new and promising drugs to treat neurodegenerative diseases such as Alzheimer’s disease (AD) and traumatic brain injury in a study published in the journal Science. Proceedings of the National Academy of Sciences (PNAS).
The collaborative study, co-led by Andrew A. Pieper, MD, and Sanford Markowitz, MD, and awarded the 2025 Cozzarelli Prize in Biomedical Sciences, showed that inhibition of an immune system enzyme known as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has powerful neuroprotective effects by reducing the production of brain-damaging reactive oxygen species.
Dr. Pieper is the Maury Mather Professor of Neuropsychiatry at University Hospitals, Rebecca E. Birchas, MD, DLFAPA, and Professor of Translational Psychiatry at Case Western Reserve University. He also serves as director of the Center for Brain Health Medicine at California State University’s Harrington Discovery Institute and a psychiatrist and researcher at the Louis Stokes VA Geriatrics Research, Education, and Clinical Center.
Dr. Markowitz is the Ingalls Professor of Cancer Genetics and Distinguished University Professor in the Division of Hematology-Oncology at Case Comprehensive Cancer Center and Case Western Reserve and Seedman University Cancer Center.
Now, in collaboration with Dr. Min-Kyo Shin, a former postdoctoral fellow in Pieper’s lab and now an assistant professor at Seoul National University, we applied the same approach to three different PD models, observing similar protection while providing further mechanistic insights.
Their findings were recently published in a scientific journal redox biologysuggesting that drugs already in development for other conditions may be repurposed to slow or prevent neurodegeneration in PD..
We were encouraged to find that 15-PGDH levels were abnormally elevated in both human Parkinson’s disease brain tissue and the brains of three mouse models. Both genetic and pharmacological inhibition restored redox homeostasis and protected mice from neuroinflammation, neuronal cell death, and motor deficits typically seen in these PD models. ”
Dr. Andrew A. Pieper, MD, PhD, Maury Mather Professor, Department of Neuropsychiatry, University Hospital
Dr. Markowitz said, “Inhibition of 15-PGDH results in lipocalin-2, a dopaminergic neuronal cell death mediator.Lcn2), the proinflammatory cytokine interleukin-1β, and reactive oxygen generators Saib/No×2. This provides new mechanistic insights into how 15-PGDH inhibitors can target and prevent neurodegeneration in Parkinson’s disease. ”
The research team’s previous studies demonstrated high CNS permeability of SW033291, a 15-PGDH inhibitor developed in the Markowitz Institute, with sustained drug levels in both the brain and plasma for up to 6 hours and almost complete elimination of 15-PGDH enzyme activity in the brain. The clinical safety of 15-PGDH inhibition is supported by the absence of toxicity in a recent phase 1 clinical trial of the 15-PGDH inhibitor MF-300, and by the findings in humans with biallelic inactivating mutations of 15-PGDH, the only consistently observed phenotype being congenital finger clubbing.
“Encouragingly, both pharmaceutical and biotech companies have begun developing 15-PGDH inhibitors for peripheral indications, and the inhibitor MF-300 has already completed phase 1 clinical trials. Our results provide a rationale for repurposing these agents for the treatment of PD,” Dr. Markowitz said.
Remarkably, 15-PGDH-mediated protection in one model caused by pathological accumulation of α-synuclein, which is thought to be responsible for human disease, was achieved without altering the accumulation of pathologically phosphorylated α-synuclein. This indicates that therapeutic effects can be achieved independently of this aspect of synuclein pathology.
“This study parallels recent findings that 15-PGDH-mediated neuroprotection in an amyloid-based mouse model of Alzheimer’s disease occurred independently of changes in amyloid pathology, and contributes to the growing body of evidence that targeting the brain’s damaging and inflammatory responses to key drivers of the disease can yield powerful therapeutic effects,” said Dr. Pieper.
The next steps in this research will focus on investigating downstream signaling pathways to better understand how 15-PGDH contributes to both normal brain function and neurodegeneration. Targeted pharmacological and genetic experimental approaches are required to dissect the contributions and interactions of these pathways. Further investigation of regulatory mechanisms H.P.G.D. Expression may help elucidate the upstream processes that cause 15-PGDH elevation in PD.
sauce:
University Hospitals Cleveland Medical Center
Reference magazines:
Pieper, A.A. Others. (2026) Inhibiting 15-PGDH restores redox homeostasis and confers neuroprotection in Parkinson’s disease. redox biology. DOI: 10.1016/j.redox.2026.104285. https://www.sciencedirect.com/science/article/pii/S2213231726002843?via%3Dihub
