期刊
NEUROPHARMACOLOGY
卷 150, 期 -, 页码 164-174出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2019.03.029
关键词
1-methyl-1,2,3,6-tetrahydropyridine; Fatty acid-binding protein; Parkinson's disease; Pyrazole derivative; alpha-synuclein
资金
- Ministry of Education, Science, Sports and Culture of Japan [18J20651]
- Project of Translational and Clinical Research Core Centers from Japan Agency for Medical Research and Development (AMED) [JP17dm0107071, JP18dm0107071]
- Grants-in-Aid for Scientific Research [18J20651] Funding Source: KAKEN
Accumulation and aggregation of alpha-synuclein (alpha Syn) 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 alpha Syn, thereby promoting alpha Syn oligomerization in DAergic neurons in the substantia nigra pars compacta (SNpc) following 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. This alpha Syn 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 alpha Syn accumulation in DA neurons, thereby inhibiting the oligomerization of alpha Syn, 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 alpha Syn 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 alpha Syn 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.
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