Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, Tokyo, Japan.
Neuropharmacology. 2019 May 15;150:164-174. doi: 10.1016/j.neuropharm.2019.03.029. Epub 2019 Mar 28.
Accumulation and aggregation of α-synuclein (αSyn) triggers dopaminergic (DAergic) neuronal loss in Parkinson's disease (PD). This pathological event is partly facilitated by the presence of long-chain polyunsaturated fatty acids (LC-PUFAs), including arachidonic acid. The intracellular transport and metabolism of LC-PUFAs are mediated by fatty acid-binding proteins (FABPs). We previously reported that heart-type FABP (FABP3) interacts with αSyn, thereby promoting αSyn oligomerization in DAergic neurons in the substantia nigra pars compacta (SNpc) following 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. This αSyn oligomerization is prevented in Fabp3 gene knock out mice. We document a novel FABP3 ligand, MF1 (4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy)butanoic acid), that inhibits αSyn accumulation in DA neurons, thereby inhibiting the oligomerization of αSyn, loss of DAergic neurons, and PD-like motor deficits in MPTP-treated mice. Chronic oral administration of MF1 (0.3 or 1.0 mg/kg/day) significantly improved motor impairments and inhibited MPTP-induced accumulation and oligomerization of αSyn in the SNpc, and in turn prevented loss of tyrosine hydroxylase (TH)-positive cells in the SNpc. MF1 administration (0.1, 0.3, or 1.0 mg/kg/day) also restored MPTP-induced cognitive impairments. Although chronic administration of l-DOPA (3,4-dihydroxl-l-phenylalanine; 25 mg/kg/day, i.p.) also improved motor deficits, it failed to improve the cognitive impairments. In addition, l-DOPA failed to inhibit DAergic neuronal loss and αSyn pathologies in the SNpc. In summary, the novel FABP3 ligand MF1 rescues MPTP-induced behavioural and neuropathological features, suggesting that MF1 may be a disease-modifying drug candidate for synucleinopathies.
α-突触核蛋白（αSyn）的积累和聚集引发帕金森病（PD）中多巴胺能（DAergic）神经元的丢失。这种病理事件部分是由长链多不饱和脂肪酸（LC-PUFAs）的存在促进的，包括花生四烯酸。LC-PUFAs 的细胞内运输和代谢由脂肪酸结合蛋白（FABPs）介导。我们之前报道过，心脏型 FABP（FABP3）与 αSyn 相互作用，从而促进 1-甲基-1,2,3,6-四氢吡啶（MPTP）处理后黑质致密部（SNpc）中的 DA 神经元中 αSyn 寡聚化。在 Fabp3 基因敲除小鼠中，这种 αSyn 寡聚化被阻止。我们记录了一种新的 FABP3 配体 MF1（4-（2-（1-（2-氯苯基）-5-苯基-1H-吡唑-3-基）苯氧基）丁酸酸），它抑制 DA 神经元中 αSyn 的积累，从而抑制 αSyn 的寡聚化、DA 能神经元的丢失和 MPTP 处理小鼠的 PD 样运动缺陷。慢性口服 MF1（0.3 或 1.0mg/kg/天）可显著改善运动障碍，并抑制 MPTP 诱导的 SNpc 中 αSyn 的积累和寡聚化，从而防止 SNpc 中酪氨酸羟化酶（TH）阳性细胞的丢失。MF1 给药（0.1、0.3 或 1.0mg/kg/天）也恢复了 MPTP 诱导的认知障碍。虽然慢性给予左旋多巴（3,4-二羟基-L-苯丙氨酸；25mg/kg/天，腹腔注射）也改善了运动缺陷，但未能改善认知障碍。此外，左旋多巴未能抑制 SNpc 中的 DA 能神经元丢失和 αSyn 病理学。总之，新型 FABP3 配体 MF1 挽救了 MPTP 诱导的行为和神经病理学特征，表明 MF1 可能是一种治疗突触核蛋白病的药物候选物。
