Therapeutic benefit can be achieved by targeting the brain's response, not the disease itself.
For the more than ten million people living with Parkinson's disease, existing treatments offer relief from symptoms but cannot halt the slow erosion of the neurons that govern movement. Researchers at Case Western Reserve University and affiliated institutions have now identified a promising foothold in that deeper struggle: an enzyme called 15-PGDH, whose inhibition appears to shield brain cells from the inflammation and oxidative damage that drive neurodegeneration. The discovery carries unusual practical weight because drugs targeting this same enzyme are already moving through clinical development for other conditions, compressing the distance between laboratory insight and potential therapy.
- Parkinson's disease continues to outpace medicine's best efforts, with current drugs managing tremors and rigidity while the underlying neuron death proceeds unchecked in over ten million patients worldwide.
- Elevated levels of the enzyme 15-PGDH were found in human Parkinson's brain tissue, and in three separate mouse models its inhibition suppressed a cascade of damaging actors — including a protein that kills dopamine neurons and a key generator of oxidative stress.
- Crucially, neuroprotection was achieved in one model even without clearing alpha-synuclein, the misfolded protein long considered the disease's primary driver, suggesting the brain's inflammatory response itself may be a viable therapeutic target.
- The path to clinical use is shorter than usual: one 15-PGDH inhibitor, MF-300, has already cleared Phase 1 safety trials, and another developed by the same team crosses the blood-brain barrier and sustains therapeutic levels for hours.
- Humans born with genetic mutations that fully disable 15-PGDH show only a benign cosmetic effect, lending additional confidence to the enzyme's safety as a long-term drug target.
Parkinson's disease is the world's second most common neurodegenerative condition, quietly stripping movement from more than ten million people while available medications address only the surface of the problem. No approved therapy slows or stops the death of the brain cells at the disease's core.
A research team at University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center — led by Andrew Pieper and Sanford Markowitz — had previously shown that inhibiting an enzyme called 15-PGDH could protect brain tissue in Alzheimer's disease and traumatic brain injury, work recognized with the 2025 Cozzarelli Prize in Biomedical Sciences. They have now applied the same logic to Parkinson's, testing the approach across three mouse models of the disease and examining postmortem human brain tissue from Parkinson's patients. Both lines of evidence pointed in the same direction: the enzyme is abnormally elevated in the diseased brain, and blocking it restores a measure of chemical balance by suppressing three harmful actors — a protein that kills dopamine-producing neurons, a pro-inflammatory molecule, and a generator of reactive oxygen species.
One finding stood out for its implications: in one mouse model, this protection occurred even without reducing alpha-synuclein, the misfolded protein widely believed to be the primary driver of Parkinson's. This raises the possibility that treating the brain's inflammatory response to disease — rather than the disease trigger itself — could be enough to preserve neurons and function.
The practical case for moving quickly is unusually strong. One 15-PGDH inhibitor, MF-300, has already completed Phase 1 clinical trials without safety concerns. Another, developed within Markowitz's own laboratory, crosses the blood-brain barrier efficiently and maintains effective concentrations in brain tissue for hours. Genetic evidence adds further reassurance: people born without any functional 15-PGDH experience only a benign change in finger and toe shape, suggesting the enzyme can be safely suppressed over time.
The team has published their findings in Redox Biology and is now turning to the questions that will shape clinical translation — how the enzyme becomes elevated in the first place, and which downstream pathways matter most for therapeutic effect. The convergence of biological insight and existing drug development creates a rare opportunity to move from discovery toward patients faster than the usual timeline allows.
Parkinson's disease quietly steals movement from more than ten million people around the world. It is the second most common neurodegenerative disease, and the medications available today do something important but ultimately limited: they ease the symptoms. They do not stop the underlying decay of brain cells that defines the disease itself.
A team of researchers at University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center has been working on a different approach. Several years ago, they published findings showing that blocking a particular enzyme—one called 15-PGDH—could protect brain tissue from damage in conditions like Alzheimer's disease and traumatic brain injury. That work earned them the 2025 Cozzarelli Prize in Biomedical Sciences. The mechanism was elegant: by inhibiting this enzyme, they could reduce the production of harmful molecules called reactive oxygen species that accumulate in damaged brain tissue and drive further deterioration.
Now the same team, led by Andrew Pieper and Sanford Markowitz, has applied that same strategy to Parkinson's disease. Working with Min-Kyoo Shin, a former postdoctoral researcher now at Seoul National University, they tested the approach in three different mouse models of the disease. What they found was encouraging: blocking 15-PGDH protected the mice from the neuroinflammation, cell death, and motor problems that typically emerge in these models. When they examined human brain tissue from Parkinson's patients, they saw the same pattern—abnormally high levels of the enzyme.
The mechanism appears to work through a specific chain of events. When 15-PGDH is inhibited, three key troublemakers are suppressed: lipocalin-2, a protein that drives dopamine-producing neuron death; interleukin-1β, a pro-inflammatory molecule; and a reactive oxygen generator called Cybb/Nox2. Together, these reductions restore what researchers call redox homeostasis—essentially, the brain's ability to manage oxidative stress and maintain chemical balance. Notably, this protection occurred in one model even without reducing the accumulation of alpha-synuclein, the misfolded protein thought to drive human Parkinson's disease. This suggests that therapeutic benefit might be achieved by treating the brain's inflammatory response to disease rather than targeting the disease driver itself.
What makes this finding particularly practical is that pharmaceutical and biotechnology companies are already developing drugs that inhibit 15-PGDH for other conditions. One candidate, MF-300, has already completed Phase 1 clinical trials without safety concerns. Another inhibitor, SW033291, developed in Markowitz's laboratory, crosses the blood-brain barrier effectively and maintains therapeutic levels in brain tissue for hours. The safety profile is further supported by observations of humans with genetic mutations that completely disable 15-PGDH; the only consistent health effect is congenital digital clubbing—a benign condition affecting finger and toe shape.
This convergence of findings and existing drug development creates a clear path forward: drugs already in the pipeline for other diseases could potentially be repurposed for Parkinson's. The researchers have published their results in the journal Redox Biology, laying out the rationale for clinical trials in Parkinson's patients. Their next steps involve deeper investigation into the signaling pathways downstream of 15-PGDH and the upstream mechanisms that cause the enzyme to become elevated in the first place. Understanding these details will be essential for optimizing treatment and potentially identifying which patients might benefit most from this approach.
Citações Notáveis
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. 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.— Dr. Andrew Pieper, University Hospitals and Case Western Reserve University
Inhibiting 15-PGDH mediated neuroprotection through downregulating a trio of the dopaminergic neuronal cell death mediator lipocalin-2, the pro-inflammatory cytokine interleukin-1β, and the reactive oxygen generator Cybb/Nox2.— Dr. Sanford Markowitz, Case Western Reserve University
A Conversa do Hearth Outra perspectiva sobre a história
Why does blocking this one enzyme seem to help across different neurodegenerative diseases—Parkinson's, Alzheimer's, brain injury?
Because the damage mechanism is similar. All these conditions involve the brain's immune system overreacting, producing toxic molecules, and killing neurons. 15-PGDH sits at a control point for that inflammatory cascade. Block it, and you dampen the whole response.
But if alpha-synuclein is what causes Parkinson's, and blocking 15-PGDH doesn't reduce alpha-synuclein, how does the protection actually work?
That's the insight. The protein itself might be the trigger, but it's the brain's reaction to it—the inflammation, the oxidative stress—that actually kills the cells. You can't always remove the trigger. But you can teach the brain to tolerate it better.
So these drugs already exist, or are being developed. Why haven't they been tested in Parkinson's patients yet?
Because nobody knew to look. The connection between 15-PGDH and Parkinson's is new. The drugs were being developed for cancer and other conditions. Now that the mechanism is clear, there's a reason to try them.
What's the risk? If you completely disable this enzyme, what happens?
We know from people born without it. They live normal lives. The only consistent finding is clubbed fingers and toes. That's a small price for slowing a disease that steals your movement.
How long until someone with Parkinson's could actually take one of these drugs?
That depends on whether companies want to fund the trials. The safety data is already there. It's a matter of will and resources. Years, probably. Not decades.