Researchers discover potential new treatment for Parkinson's disease, other neurodegenerative conditions
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Parkinson's disease (PD) is the second most common form of neurodegenerative disease and afflicts more than 10 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.
The collaborative study, co-led by Andrew A. Pieper, MD, Ph.D., and Sanford Markowitz, MD, Ph.D., 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.
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.
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.
Protection seen across Parkinson's models
Now, in collaboration with Min-Kyoo Shin, Ph.D., 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, published in 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 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."
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/Nox2. This provides new mechanistic insight into how 15-PGDH inhibitors could target and prevent neurodegeneration in Parkinson's disease."
Repurposing path gains support
Previous work from the research team demonstrated high CNS penetration of the 15-PGDH inhibitor SW033291, which 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 I 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 I clinical trials. Our results now provide the rationale to repurpose such agents for the treatment of PD," Markowitz said.
Benefit without altering α-synuclein
Notably, 15-PGDH-mediated protection in one model driven by pathological accumulation of α-synuclein, which 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 Pieper.
Tracing the pathway upstream
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.
Publication details
Young-Kwang Kim et al, Inhibiting 15-PGDH restores redox homeostasis and confers neuroprotection in Parkinson's disease, Redox Biology (2026). DOI: 10.1016/j.redox.2026.104285
Journal information: Redox Biology
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