Parkinson’s mouse study points to enzyme blocker as potential therapy
Researchers report that inhibiting 15-PGDH protected neurons and movement in three Parkinson’s disease mouse models.
By Tom Brennan · Health & Medicine Correspondent
3 min read
Researchers reported a potential route for slowing Parkinson’s disease by blocking an enzyme tied to brain inflammation and oxidative stress. The work matters because existing Parkinson’s treatments can ease symptoms, but University Hospitals Cleveland Medical Center says they do not stop the neurodegeneration that drives the disease.
The findings, published in Redox Biology, come from investigators at University Hospitals, Case Western Reserve University, the Louis Stokes Cleveland VA Medical Center and Seoul National University. The team tested inhibition of 15-PGDH, short for 15-hydroxyprostaglandin dehydrogenase, in three Parkinson’s disease mouse models.
According to the researchers, 15-PGDH levels were abnormally high in human Parkinson’s disease brain tissue and in the brains of all three mouse models. Blocking the enzyme genetically or with a drug restored redox balance and protected mice from neuroinflammation, nerve cell death and motor problems seen in the models, co-lead investigator Andrew A. Pieper said.
Focus on inflammation and oxidative damage
Parkinson’s disease is the second most common neurodegenerative disease and affects more than 10 million people worldwide, according to University Hospitals. The disease is marked by the loss of dopamine-producing neurons and progressive problems with movement, though the study focused on disease mechanisms rather than patient treatment.
The team’s approach builds on earlier work by Pieper and Sanford Markowitz, who had identified 15-PGDH inhibition as neuroprotective in other neurodegenerative conditions, including Alzheimer’s disease and traumatic brain injury. University Hospitals said that prior work linked the enzyme to production of reactive oxygen species, unstable molecules that can damage brain tissue.
In the Parkinson’s study, Markowitz said the protective effect involved reduced activity in three factors: lipocalin-2, interleukin-1β and Cybb/Nox2. The researchers described those factors as linked to dopamine neuron death, inflammation and reactive oxygen generation.
The study also found protection in a model driven by abnormal accumulation of α-synuclein, a protein associated with Parkinson’s disease, without reducing pathologically phosphorylated α-synuclein. Pieper said that result is consistent with the team’s Alzheimer’s disease work, where 15-PGDH-related protection occurred without changing amyloid pathology.
Drug repurposing remains early
The researchers said the findings could support repurposing 15-PGDH inhibitors already being developed for other conditions. They cited earlier work showing that SW033291, an inhibitor developed in the Markowitz laboratory, entered the central nervous system and maintained drug levels in brain and plasma for up to six hours while nearly eliminating 15-PGDH enzyme activity in the brain.
University Hospitals said safety support for the strategy includes a recent Phase I clinical trial of the 15-PGDH inhibitor MF-300 that found no toxicity, as well as observations in people with biallelic inactivating mutations of 15-PGDH. In those people, the only consistently observed trait was congenital digital clubbing, according to the researchers.
Markowitz said pharmaceutical and biotechnology companies have started developing 15-PGDH inhibitors for peripheral uses, and that MF-300 has completed Phase I testing. He said the new results provide a rationale for studying whether such drugs could be used for Parkinson’s disease.
The researchers said next work will examine downstream signaling pathways to clarify how 15-PGDH affects normal brain function and neurodegeneration. They also plan to study regulatory mechanisms that control Hpgd expression, which may help explain why 15-PGDH rises in Parkinson’s disease.
This story draws on original reporting from Medical Xpress.