The main symptom of Parkinson's disease (PD) is motor dysfunction and remarkably approximately 30–40% of PD patients exhibit cognitive impairments. Recently, we have developed MF8, a heart-type fatty acid-binding protein (FABP3)-specific ligand, which can inhibit α-synuclein (α-syn) oligomerization induced by arachidonic acid in FABP3 overexpressing neuro2A cells. The present study aimed to determine whether MF8 attenuates dopaminergic neuronal death and motor and cognitive impairments in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. MF8 can penetrate the blood-brain barrier and its peak brain concentration (21.5 ± 2.1 nM) was achieved 6 h after the oral administration (1.0 mg/kg). We also compared its effects and pharmacological action with those of L-DOPA (3,4-dihydroxy-l-phenylalanine). PD model mice were developed by administering MPTP (25 mg/kg, i.p.) once a day for five consecutive days. Twenty-four hours after the final MPTP injection, mice were administered MF8 (0.3, 1.0 mg/kg, p.o.) or L-DOPA (25 mg/kg, i.p.) once a day for 28 consecutive days and subjected to behavioral and histochemical studies. MF8 (1.0 mg/kg, p.o.), but not L-DOPA, inhibited the dopaminergic neuronal death in the ventral tegmental area and the substantia nigra pars compacta region of the MPTP-treated mice. MF8 also improved both, motor and cognitive functions, while L-DOPA ameliorated only motor dysfunction. Taken together, our results showed that MF8 attenuated the MPTP-induced dopaminergic neuronal death associated with PD pathology. We present MF8 as a novel disease-modifying therapeutic molecule for PD, which acts via a mechanism different from that of L-DOPA.

帕金森氏病（PD）的主要症状是运动功能障碍，大约30％至40％的PD患者表现出认知障碍。最近，我们开发了一种心脏型脂肪酸结合蛋白（FABP3）特异性配体MF8，它可以抑制花生四烯酸在过表达的Neuro2A细胞中诱导的α-突触核蛋白（α-syn）寡聚。本研究旨在确定MF8是否能减轻1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中的多巴胺能神经元死亡以及运动和认知障碍。MF8可以穿透血脑屏障，并且口服后6 h（1.0 mg / kg）达到峰值脑浓度（21.5±2.1 nM）。我们还比较了其与L-DOPA（3,4-dihydroxy- l-苯丙氨酸）。通过每天一次连续五天施用MPTP（25 mg / kg，ip）来开发PD模型小鼠。在最后一次MPTP注射后二十四小时，每天连续28天每天给小鼠施用MF8（0.3，1.0 mg / kg，口服）或L-DOPA（25 mg / kg，ip），并进行行为和组织化学研究。MF8（1.0 mg / kg，po），但不抑制L-DOPA，抑制MPTP处理小鼠腹侧被盖区和黑质致密部区域的多巴胺能神经元死亡。MF8还改善了运动功能和认知功能，而L-DOPA仅改善了运动功能障碍。两者合计，我们的结果表明MF8减轻了MPTP诱发的与PD病理相关的多巴胺能神经元死亡。我们提出MF8作为PD的新型疾病缓解治疗分子，