15-PGDH enzyme inhibition protects brain cells in Parkinson’s disease models

Scientists have identified a new approach that could help slow or even prevent the progression of Parkinson’s disease by repurposing drugs already being developed for other medical conditions.

The research, led by investigators at University Hospitals, Case Western Reserve University and the Louis Stokes Cleveland VA Medical Center, found that blocking an immune system enzyme called 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protected brain cells from damage in multiple models of Parkinson’s disease.

These build on the team’s previous work showing that inhibiting the enzyme could protect against neurodegeneration in Alzheimer’s disease and traumatic brain injury.

Protecting brain cells

Parkinson’s disease is the world’s second most common neurodegenerative disorder, affecting more than 10 million people globally. Although existing treatments can help manage symptoms, they do not stop the gradual loss of nerve cells that drives the disease.

To combat this, the researchers examined three different models of Parkinson’s disease and found elevated levels of the 15-PGDH enzyme in both human brain tissue and laboratory models. Blocking the enzyme restored the brain’s chemical balance and reduced the damage typically associated with the condition.

Parkinson’s disease is the world’s second most common neurodegenerative disorder, affecting more than 10 million people globally

“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 Andrew Pieper, the Morley-Mather Chair of Neuropsychiatry at University Hospitals. “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.”

The team also identified how the treatment works by reducing three key drivers of nerve cell damage and inflammation.

”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,” said Dr Sanford Markowitz, 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. ”This provides new mechanistic insight into how 15-PGDH inhibitors could target and prevent neurodegeneration in Parkinson’s disease.”

Potential to accelerate new treatments

One of the most significant aspects of the research is that drugs targeting 15-PGDH are already under development for other diseases. Earlier studies demonstrated that one experimental inhibitor reached the brain effectively and suppressed the enzyme’s activity, while another compound, MF-300, has already completed a Phase I clinical trial without significant safety concerns. 

One of the most significant aspects of the research is that drugs targeting 15-PGDH are already under development for other diseases

“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,” said Dr Markowitz. ”Our results now provide the rationale to repurpose such agents for the treatment of PD.”

If future clinical studies confirm these findings in people, repurposing existing compounds could significantly shorten the time needed to develop disease-modifying treatments compared with creating entirely new medicines.

Looking beyond the underlying pathology

The researchers also found that protecting brain cells did not depend on reducing the build-up of abnormal α-synuclein protein, which is widely believed to play a central role in Parkinson’s disease.

“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.

The next stage of the research will investigate how 15-PGDH contributes to both healthy brain function and neurodegeneration, with the aim of identifying additional targets that could lead to future treatments for Parkinson’s disease.