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
Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
Department of Transdisciplinary Studies Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
Front Pharmacol. 2020 Jun 25;11:953. doi: 10.3389/fphar.2020.00953. eCollection 2020.
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 [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. [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) of [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 was observed in the MPTP model group compared with the control group. Striatal BP 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.
Fas相关因子1（FAF1）是一种与Fas结合的蛋白质，与帕金森病（PD）中的神经元细胞死亡有关。我们使用[F]FE-PE2I正电子发射断层扫描（PET），在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中研究了新型FAF1抑制剂KM-819对多巴胺能神经元的影响。通过在C57bl/6J小鼠中连续5天进行亚急性MPTP治疗（20mg/kg/天，腹腔注射）建立MPTP模型。本研究包括三组：对照组（仅用生理盐水治疗）、接受KM-819治疗（20mg/kg/天，口服）6天的MPTP模型组和未接受KM-819治疗的MPTP模型组。在MPTP治疗前后，对相同动物进行[F]FE-PE2I PET研究，无论是否使用KM-819治疗，以监测纹状体多巴胺转运体活性的变化，该变化由[F]FE-PE2I的不可置换结合电位（BP）表示，并在KM-819治疗前后使用免疫组织化学评估酪氨酸羟化酶的表达水平。注射MPTP后，与对照组相比，MPTP模型组纹状体BP降低。接受KM-819治疗的MPTP模型组纹状体BP升高，但未接受KM-819治疗的MPTP模型组纹状体BP未升高。与对照组相比，接受KM-819治疗的MPTP模型组酪氨酸羟化酶表达水平也显著升高。本研究表明，KM-819抑制Fas介导的细胞死亡途径对MPTP模型中的纹状体多巴胺神经元具有神经修复作用。需要进一步研究以调查KM-819作为PD治疗药物的潜力。
