Neurorestorative Effects of a Novel Fas-Associated Factor 1 Inhibitor in the MPTP Model: An [18F]FE-PE2I Positron Emission Tomography Analysis Study

• Published in: Frontiers in pharmacology 2020-06, Vol.11, p.953-953
• Main Authors: Park, Hyun Soo, Song, Yoo Sung, Moon, Byung Seok, Yoo, Sung-Eun, Lee, Jae Moon, Chung, Yeon-Tae, Kim, Eunhee, Lee, Byung Chul, Kim, Sang Eun
• Format: Article
• Language: English
• Subjects: Fas-associated factor 1 inhibitor; KM-819; non-displaceable binding potential; Parkinson’s disease; Pharmacology; positron emission tomography
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2020.00953

Fas-associated factor 1 (FAF1), a Fas-binding protein, is implicated in neuronal cell death in Parkinson’s disease (PD). We examined the effects of a novel FAF1 inhibitor, KM-819, in dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model using [ 18 F]FE-PE2I positron emission tomography (PET). The MPTP model was generated with subacute MPTP treatment (20 mg/kg/day, i.p.) for 5 consecutive days in C57bl/6J mice. This study included three groups: the control group (treatment with saline only), the MPTP model group with KM-819 treatment (20 mg/kg/day p.o.) for 6 days, and the MPTP model group without KM-819 treatment. [ 18 F]FE-PE2I PET studies were conducted in the same animals before and after MPTP with or without KM-819 treatment to monitor changes in striatal dopamine transporter activity indicated by non-displaceable binding potential (BP ND ) of [ 18 F]FE-PE2I, and the expression levels of tyrosine hydroxylase were assessed using immunohistochemistry before and after KM-819 treatment. After MPTP injection, decreased striatal BP ND was observed in the MPTP model group compared with the control group. Striatal BP ND increased in the MPTP model group with KM-819 treatment, but not in the MPTP model group without KM-819 treatment. The tyrosine hydroxylase expression levels also significantly increased in the MPTP model group with KM-819 treatment compared with the control group. This study indicates that inhibition of the Fas-mediated cell death pathway by KM-819 has neurorestorative effects in striatal dopamine neurons in the MPTP model. Further studies would be needed to investigate the potential of KM-819 as a therapeutic drug for PD treatment.