Assessment of potential protective effect on dopaminergic neuron by an Fas-associated factor 1 inhibitor treatment using [¹⁸F]FE-PE2I PET in a Parkinson’s disease mouse model

Objectives: Fas-associated factor 1 or FAF1 is a Fas-binding protein implicated in neuronal cell death and may be an integral component of progressive neurodegeneration in Parkinson’s disease (PD) pathogenesis. We performed [¹⁸F]FE-PE2I PET studies in a MPTP mouse model of PD to examine potential protective effect on dopaminergic (DA) neuron by curbing the Fas mediated cell death pathway after the treatment of a FAF1 inhibitor, KR-33493 (KM-819) (Kainos Medicine, Inc., Seongnam, Korea).

Methods: PD mouse model was generated by subacute MPTP treatment (20 mg/kg/day i.p. for 5 days consecutively) in C56BL/6 mice. Subsequently the PD mouse model underwent daily treatment with KR-33493 (KM-819) (20 mg/kg/day p.o. for 6 days). We performed [¹⁸F]FE-PE2I PET studies repeatedly in the same animals before and after MPTP or KR-33493 (KM-819) treatment to monitor changes in the striatal dopamine transporter (DAT) activity those were represented by changes (%) in [¹⁸F]FE-PE2I BP_ND estimates compared to the baseline.

Results: Baseline [¹⁸F]FE-PE2I PET images clearly visualized the striatal DAT activity with [¹⁸F]FE-PE2I BP_ND [mean ± SEM] = 1.64 ± 0.18. PD mouse model successfully generated by the subacute MPTP treatment showing reduced striatal DAT activity in the range of -75.30 to -88.70%baseline change in BP_ND. Finally, KR-33493 (KM-819) treatment in PD mouse model resulted in recovered striatal DAT activity in the range of -64.60 to -81.80%change in BP_ND compared to the baseline or 6.90 to 17.40%point increase compared to those of PD mouse model.

Conclusion: Data demonstrated that curbed Fas mediated cell death pathway by FAF1 inhibitor is linked to protective effects on the striatal DA neurons in this PD mouse model. Results also support potency of KR-33493 (KM-819) as a therapeutic drug for PD treatment. Research Support: This research was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, South Korea (HI14C1072) and the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning, South Korea (NRF-2015R1D1A1A02061707).