Session Information
Date: Sunday, October 7, 2018
Session Title: Parkinsonism, MSA, PSP (Secondary and Parkinsonism-Plus)
Session Time: 1:45pm-3:15pm
Location: Hall 3FG
Objective: To evaluate PBT434 in a transgenic mouse model of multiple system atrophy (MSA)
Background: PBT434 is a novel quinazolinone inhibitor of iron-mediated protein accumulation and aggregation. In multiple animal models of Parkinson disease, PBT434 reduces alpha-synuclein aggregation and oxidative stress, preserves neurons and improves motor function (DOI 10.1186/s40478-017-0456-2). A transgenic model of MSA (PLP-alpha-Syn) overexpresses alpha-synuclein, has parkinsonian deficits and manifests oligodendroglial pathology (DOI:10.1016/j.expneurol.2010.05.008). Orally administered PBT434 readily penetrates the blood brain barrier and is well-tolerated in rat and dog toxicology studies. The affinity of PBT434 for iron is greater than that of alpha-synuclein but lower than that of endogenous iron trafficking proteins, e.g., ferritin.
Methods: PBT434 or vehicle was administered orally for 4 months at 30 mg/kg/day starting at age 7 or 12 months. Mice were culled at 11 or 16 months of age. Nigral neuron counts were assessed at 11 and 16 months and glial cell inclusions (GCI) of the substantia nigra (SN) and pons at 16 months were assessed by stereology. Western blot analysis was used to assess aggregated alpha synuclein. The pole test was done at 11 and 16 months.
Results: At 11 and 16 months, PBT434 reduced alpha-synuclein aggregation (P=0.025 and 0.005, respectively) and preserved SN neurons (P=0.086 and 0.001, respectively). At 16 months, PBT434 reduced the number of GCI in SN and pons (P=0.0007 and 0.001, respectively). PBT434 improved motor function on the pole test at 16 months (P=0.049).
Conclusions: PBT434 reduced alpha-synuclein aggregation and glial cell inclusions, preserved SN neurons and improved motor function in an animal model of MSA. PBT434 is a small molecule iron chaperone with potential for treating MSA.
To cite this abstract in AMA style:
D. Finkelstein, P. Adlard, N. Stefanova, D. Stamler. PBT434 prevents the accumulation of glial cell inclusions and insoluble alpha-synuclein in a mouse model of Multiple System Atrophy [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/pbt434-prevents-the-accumulation-of-glial-cell-inclusions-and-insoluble-alpha-synuclein-in-a-mouse-model-of-multiple-system-atrophy/. Accessed May 19, 2025.« Back to 2018 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/pbt434-prevents-the-accumulation-of-glial-cell-inclusions-and-insoluble-alpha-synuclein-in-a-mouse-model-of-multiple-system-atrophy/