Enzyme-blocking drugs show promise against Parkinson’s brain damage

Researchers have reported that inhibition of 15-hydroxyprostaglandin dehydrogenase was shown to protect neurons and improve motor function in mouse models of Parkinson’s disease in findings that could support repurposing of drugs currently under development

Parkinson’s disease is the second most common neurodegenerative disease, affecting more than 10 million people worldwide. While existing treatments can control symptoms, they do not treat the underlying neurodegeneration that drives the condition.

Researchers at Case Western Reserve University and the Louis Stokes Cleveland Veterans Affairs Medical Center, both of Cleveland, Ohio, USA, have now shown that drugs designed to inhibit 15-hydroxyprostaglandin dehydrogenase (15-PGDH) could help protect the brain from inflammatory and oxidative damage.

The work builds on earlier research from the same collaborative team that identified 15-PGDH inhibition as a promising therapeutic strategy for other neurodegenerative conditions, including Alzheimer’s disease and traumatic brain injury. This earlier study received the 2025 Cozzarelli Prize in Biomedical Sciences of the US National Academy of Sciences.

The research was co-led by Dr Andrew A. Pieper, the ‘Morley-Mather’ chair of neuropsychiatry at University Hospitals and Dr. Rebecca E. Barchas, professor of translational psychiatry at Case Western Reserve University, and Dr Sanford Markowitz, ‘Ingalls Professor’ of cancer genetics and distinguished university professor at Case Comprehensive Cancer Center, also of Cleveland.

In the latest study, the team collaborated with Dr Min-Kyoo Shin, an assistant professor at Seoul National University, to test the biological approach in three Parkinson’s disease models.

“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,” Dr Pieper said.

“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,” he added.

Excessive 15-PGDH activity may contribute to a harmful imbalance between reactive oxygen species (ROS) and antioxidant defences in the Parkinson’s brain. These chemically reactive molecules damage cells when the body fails to keep them under control. In the brain, this oxidative stress amplifies inflammation and contributes to neuronal death.

Parkinson’s disease particularly involves loss of dopamine-producing neurons which regulate movement. Damage to these cells causes the tremor, stiffness, slowness and impaired movement that characterise the condition.

“We were excited to find that inhibiting 15-PGDH mediated neuroprotection through downregulating three key mediators: lipocalin-2, interleukin-1β and the reactive oxygen generator Cybb/Nox2,” Markowitz said.

“This provides novel mechanistic insight into how 15-PGDH inhibitors could target and prevent neurodegeneration in Parkinson’s disease,” he added.

Cybb/Nox2 is a source of ROS in immune and inflammatory pathways while interleukin-1β is an inflammatory signalling protein and lipocalin-2 has been linked to neuronal injury.

Earlier work from the research team showed that the 15-PGDH inhibitor SW033291 had high central nervous system penetration and achieved near-complete suppression of 15-PGDH enzyme activity in the brain. There is also emerging support for the clinical safety of 15-PGDH inhibition with toxicity absent in a recent Phase I clinical trial of MF-300, and people with biallelic inactivating 15-PGDH mutations show only congenital digital clubbing*.

“Encouragingly, both pharmaceutical and biotechnology companies have initiated development of 15-PGDH inhibitors for peripheral indications, and MF-300 has already completed Phase I clinical trials,” said Markowitz.

“Our results now provide the rationale to repurpose such agents for Parkinson’s disease treatment,” he explained.

A notable finding came from a model driven by α-synuclein pathology – a protein strongly implicated in human Parkinson’s disease. Protection occurred without changes in pathologically phosphorylated α-synuclein accumulation, suggesting therapeutic benefit could occur independently of removing the initiating protein pathology itself.

Future research will examine downstream signalling pathways and investigate regulatory mechanisms governing Hpgd expression, the gene encoding 15-PGDH. Although findings remain preclinical, the study has identified a plausible disease-modifying strategy in Parkinson’s disease that could treat the biological damage underlying the condition, rather than symptoms alone.

* A condition present from birth in which the fingers or toes have a characteristic enlarged, rounded appearance – the nail beds soften and the tips of the digits become bulbous.

For further reading please visit: 10.1016/j.redox.2026.104285