Cleveland Researchers Identify 15-PGDH as Promising Drug Target for Parkinson's Disease
核心洞察
Inhibition of the enzyme 15-PGDH (搜索) restored redox homeostasis and protected against neuroinflammation, neuronal cell death, and motor impairment in three mouse models of Parkinson's disease (搜索).
Both human PD brain tissue and mouse models showed abnormally elevated levels of 15-PGDH (搜索), with neuroprotection achieved independently of changes in α-synuclein pathology.
The 15-PGDH (搜索) inhibitor MF-300 has already completed Phase 1 clinical trials with no observed toxicity, supporting the rationale for repurposing existing agents for PD treatment.
A collaborative research team from University Hospitals (搜索), Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center has identified inhibition of the enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH (搜索)) as a promising therapeutic strategy to slow or prevent neurodegeneration in Parkinson's disease (搜索) (PD). The findings, published in the scientific journal Redox Biology, build on the team's prior award-winning work and provide new mechanistic insight into how targeting this immune system enzyme could protect the brain.
Parkinson's disease (搜索) is the second most common form of neurodegenerative disease, afflicting more than ten million people worldwide. While current therapies address disease symptoms, they do not prevent the underlying neurodegeneration that drives the disease.
Elevated 15-PGDH (搜索) in Human and Mouse PD Tissue
The research team, co-led by Andrew A. Pieper, MD, PhD, and Sanford Markowitz, MD, PhD, in collaboration with Min-Kyoo Shin, PhD, of Seoul National University, examined 15-PGDH (搜索) expression across three different mouse models of PD as well as human PD brain tissue. "We were encouraged to see that both human Parkinson's disease (搜索) brain tissue and the brains of our three mouse models showed abnormally elevated levels of 15-PGDH," said Dr. Pieper, the Morley-Mather Chair of Neuropsychiatry at University Hospitals (搜索). "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."
Mechanistic Trio Identified
Dr. Markowitz, the Ingalls Professor of Cancer Genetics and Distinguished University Professor at the Case Comprehensive Cancer Center, detailed the downstream pathways involved. "We were excited to find that inhibiting 15-PGDH (搜索) mediated neuroprotection through downregulating a trio of the dopaminergic neuronal cell death mediator lipocalin-2 (搜索) (Lcn2), the pro-inflammatory cytokine interleukin-1β (搜索), and the reactive oxygen generator Cybb/Nox2 (搜索)," he said. "This provides new mechanistic insight into how 15-PGDH inhibitors could target and prevent neurodegeneration in Parkinson's disease (搜索)."
Independence from α-Synuclein Pathology
Notably, 15-PGDH (搜索)-mediated protection in a model driven by pathological accumulation of α-synuclein—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. Dr. Pieper noted that this finding parallels the team's recent discovery that 15-PGDH-mediated neuroprotection in an amyloid-based Alzheimer's disease (搜索) 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."
Clinical Translation Pathway
Previous work from the research team demonstrated high CNS penetration of the 15-PGDH (搜索) inhibitor SW033291, 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 (搜索) 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.
Future Directions
Next steps in this research will focus on exploring downstream signaling pathways to better understand how 15-PGDH (搜索) 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.
The collaborative study was previously recognized with the 2025 Cozzarelli Prize in Biomedical Sciences for its foundational work published in Proceedings of the National Academy of Sciences (PNAS), which showed that 15-PGDH (搜索) inhibition was potently neuroprotective in models of Alzheimer's disease (搜索) and traumatic brain injury by restraining the production of reactive oxygen species that damage the brain.