CLEVELAND – Parkinson’s disease (PD) is the second most common form of neurodegenerative disease and afflicts more than ten million people worldwide. While current therapies address disease symptoms, they do not prevent the underlying neurodegeneration that drives the disease.
Investigators at University Hospitals , Case Western Reserve University , and the Louis Stokes Cleveland VA Medical Center previously identified a new and promising drug to treat neurodegenerative conditions, including Alzheimer’s disease (AD) and traumatic brain injury in a study published in the scientific journal Proceedings of the National Academy of Sciences ( PNAS ).
The collaborative study, co-led by Andrew A. Pieper, MD, PhD, and Sanford Markowitz, MD, PhD , and awarded the 2025 Cozzarelli Prize in Biomedical Sciences , showed that inhibition of an enzyme in the immune system, known as 15-PGDH (15-hydroxyprostaglandin dehydrogenase), was potently neuroprotective by restraining the production of reactive oxygen species that damage the brain.
Dr. Pieper is the Morley-Mather Chair of Neuropsychiatry at University Hospitals, and the Rebecca E. Barchas, MD, DLFAPA, Professor of Translational Psychiatry at Case Western Reserve University. He also serves as director of the Brain Health Medicines Center at Harrington Discovery Institute at UH, and psychiatrist and investigator in the Louis Stokes VA Geriatric Research Education and Clinical Center.
Dr. Markowitz is the Ingalls Professor of Cancer Genetics and Distinguished University Professor at the Case Comprehensive Cancer Center and Division of Hematology-Oncology Department of Medicine at Case Western Reserve and UH Seidman Cancer Center.
Now, in collaboration with Min-Kyoo Shin, PhD, former postdoctoral trainee in the Pieper Laboratory and current assistant professor at Seoul National University, they applied this same approach to three different models of PD and observed analogous protection while providing additional mechanistic insight.
Their findings, recently published in the scientific journal Redox Biology , suggest that drugs already in development for other conditions could potentially be repurposed to slow or prevent neurodegeneration in PD .
“We were encouraged to see that both human Parkinson's disease brain tissue and the brains of our three mouse models showed abnormally elevated levels of 15-PGDH,” explained Dr. Pieper. “Both genetic and pharmacologic inhibition restored redox homeostasis, which protected mice from the neuroinflammation, neuronal cell death, and motor impairment normally seen in these models of PD.”
Dr. Markowitz added, “We were excited to find that inhibiting 15-PGDH mediated neuroprotection through downregulating a trio of the dopaminergic neuronal cell death mediator lipocalin-2 ( Lcn2 ), the pro-inflammatory cytokine interleukin-1β, and the reactive oxygen generator Cybb/No x2. This provides new mechanistic insight into how 15-PGDH inhibitors could target and prevent neurodegeneration in Parkinson’s disease.”
Previous work from the research team demonstrated high CNS penetration of the 15-PGDH inhibitor SW033291, that was developed in the Markowitz Laboratory , with sustained drug levels in both brain and plasma for up to six hours, and near-complete ablation 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, as well as by findings from humans with biallelic inactivating mutations of 15-PGDH, in whom the only consistently observed phenotype is congenital digital clubbing.
“Encouragingly, both pharmaceutical and biotechnology companies have initiated development of 15-PGDH inhibitors for peripheral indications, and inhibitor MF-300 has already completed Phase 1 clinical trials. Our results now provide the rationale to repurpose such agents for the treatment of PD,” Dr. Markowitz said.
Notably, 15-PGDH-mediated protection in one model driven by pathological accumulation of α-synuclein, that is thought to cause the human disease, was achieved without any change in accumulation of pathologically phosphorylated α-synuclein. This demonstrates that therapeutic benefit can be achieved independently of this aspect of synuclein pathology.
“This work parallels our recent finding that 15-PGDH-mediated neuroprotection in an amyloid-based Alzheimer's disease mouse model occurred independently of changes in amyloid pathology, contributing to a growing body of evidence that potent therapeutic effect can be achieved by targeting the brain's damage and inflammatory response to the primary drivers of disease,” said Dr. Pieper.
Next steps in this research will focus on exploring downstream signaling pathways to better understand how 15-PGDH contributes to both normal brain function and neurodegeneration. Dissecting the contributions and interactions of these pathways will require targeted pharmacologic and genetic experimental approaches. Further investigation into the regulatory mechanisms governing Hpgd expression may help clarify the upstream processes that drive 15-PGDH elevation in PD.
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Pieper, A., Markowitz, S., et al. Inhibiting 15-PGDH restores redox homeostasis and confers neuroprotection in Parkinson’s disease. Redox Biology , 2026. DOI: https://doi.org/10.1016/j.redox.2026.104285
About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of more than 20 hospitals (including 5 joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, NEOMED, Oxford University, Technion Israel Institute of Technology, and National Taiwan University College of Medicine. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,400 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national and international ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report and UK Brand Finance. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn , Facebook and Twitter . For more information, visit UHhospitals.org .
About Case Western Reserve University
As one of the fastest-growing research universities in the United States, Case Western Reserve University is a force in career-defining education and life-changing research. Across our campus, more than 12,000 students from around the world converge to seek knowledge, find solutions and accelerate their impact. They learn from and collaborate with faculty members renowned for expertise in medicine, engineering, science, law, management, dental medicine, nursing, social work, and the arts. And with our location in Cleveland, Ohio—a hub of cultural, business and healthcare activity—our students gain unparalleled access to academic, research, clinical and entrepreneurial opportunities that prepare them to join our network of more than 125,000 alumni worldwide. Visit case.edu to see why Case Western Reserve University is built for those driven to be a force in the world.
About VA Northeast Ohio Healthcare System
Focusing on treating the whole Veteran through health promotion and illness prevention, VA Northeast Ohio Healthcare System provides comprehensive, seamless health care and social services for more than 140,000 Veterans across Northeast Ohio. With 17 locations of care, including 12 outpatient clinics, two community resource and referral centers, a psychosocial rehabilitation and recovery center, a chronic dialysis center, and an outpatient surgery center, VA Northeast Ohio Healthcare System’s quality services are easily accessible to Veterans in 21 counties. VA Northeast Ohio Healthcare System also contributes to the future of medicine through education, training, and research programs.
For more information about programs and services offered by VA Northeast Ohio Healthcare System, visit www.cleveland.va.gov or follow us on Facebook @ClevelandVAMC.
Redox Biology
Inhibiting 15-PGDH restores redox homeostasis and confers neuroprotection in Parkinson’s disease