A study published on Jul. 6 by investigators at University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center reports that inhibiting the immune system enzyme 15-PGDH could help prevent neurodegeneration in Parkinson's disease.
The research team, led by Andrew A. Pieper and Sanford Markowitz, previously identified a promising drug target for neurodegenerative conditions such as Alzheimer's disease and traumatic brain injury. Their earlier work demonstrated that blocking 15-PGDH provided significant neuroprotection by reducing reactive oxygen species in the brain.
In their latest collaborative effort with Min-Kyoo Shin of Seoul National University, the researchers applied this approach to three models of Parkinson's disease. They observed similar protective effects and gained further insight into how 15-PGDH inhibition works. The findings were recently published in Redox Biology and suggest that drugs already being developed for other uses could be repurposed to slow or prevent neurodegeneration in Parkinson's patients.
Dr. Markowitz said, "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. This provides new mechanistic insight into how 15-PGDH inhibitors could target and prevent neurodegeneration in Parkinson's disease." Previous work from the team showed high central nervous system penetration of their inhibitor SW033291 with sustained levels in both brain and plasma for up to six hours.
Clinical safety data support further development: Phase 1 trials of another inhibitor, MF-300, showed no toxicity, while individuals with biallelic mutations disabling 15-PGDH only consistently exhibited congenital digital clubbing. Dr. Markowitz said, "Encouragingly, both pharmaceutical and biotechnology companies have initiated development of 15-PGDH 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." Notably, benefits were seen even when pathological α-synuclein accumulation remained unchanged.
Dr. Pieper said, "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... potent therapeutic effect can be achieved by targeting the brain's damage and inflammatory response to primary drivers of disease." The next phase will focus on understanding downstream signaling pathways related to normal brain function and degeneration.
