Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice
Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuronal loss in the substantia nigra pars compacta (SNpc), resulting from α-synuclein (αSyn) toxicity. We previously reported that αSyn oligomerization and toxicity are regulated by the fatty-acid binding protein 3 (FABP3), an...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Journal of Pharmacological Sciences |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861323000051 |
| _version_ | 1797847678519869440 |
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| author | Haoyang Wang Kohji Fukunaga An Cheng Yifei Wang Nariko Arimura Hiroshi Yoshino Takuya Sasaki Ichiro Kawahata |
| author_facet | Haoyang Wang Kohji Fukunaga An Cheng Yifei Wang Nariko Arimura Hiroshi Yoshino Takuya Sasaki Ichiro Kawahata |
| author_sort | Haoyang Wang |
| collection | DOAJ |
| description | Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuronal loss in the substantia nigra pars compacta (SNpc), resulting from α-synuclein (αSyn) toxicity. We previously reported that αSyn oligomerization and toxicity are regulated by the fatty-acid binding protein 3 (FABP3), and the therapeutic effects of the FABP3 ligand, MF1, was successfully demonstrated in PD models. Here, we developed a novel and potent ligand, HY-11-9, which has a higher affinity for FABP3 (Kd = 11.7 ± 8.8) than MF1 (Kd = 302.8 ± 130.3). We also investigated whether the FABP3 ligand can ameliorate neuropathological deterioration after the onset of disease in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Motor deficits were observed two weeks after MPTP treatment. Notably, oral administration of HY-11-9 (0.03 mg/kg) improved motor deficits in both beam-walking and rotarod tasks, whereas MF1 failed to improve the motor deficits in both tasks. Consistent with the behavioral tasks, HY-11-9 recovered dopamine neurons from MPTP toxicity in the substantia nigra and ventral tegmental areas. Furthermore, HY-11-9 reduced the accumulation of phosphorylated-serine129-α-synuclein (pS129-αSyn) and colocalization with FABP3 in tyrosine hydroxylase (TH)-positive DA neurons in the PD mouse model. Overall, HY-11-9 significantly improved MPTP-induced behavioral and neuropathological deterioration, suggesting that it may be a potential candidate for PD therapy. |
| first_indexed | 2024-04-09T18:16:20Z |
| format | Article |
| id | doaj.art-19411d539a8a429293d3a7b0b301ebdc |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-04-09T18:16:20Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-19411d539a8a429293d3a7b0b301ebdc2023-04-13T04:26:26ZengElsevierJournal of Pharmacological Sciences1347-86132023-05-0115213038Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in miceHaoyang Wang0Kohji Fukunaga1An Cheng2Yifei Wang3Nariko Arimura4Hiroshi Yoshino5Takuya Sasaki6Ichiro Kawahata7Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, JapanDepartment of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; BRI Pharma Inc., Sendai, Japan; Corresponding author. Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, JapanShiratori Pharmaceutical Co., Ltd. Chiba, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; Corresponding author.Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; Corresponding author.Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuronal loss in the substantia nigra pars compacta (SNpc), resulting from α-synuclein (αSyn) toxicity. We previously reported that αSyn oligomerization and toxicity are regulated by the fatty-acid binding protein 3 (FABP3), and the therapeutic effects of the FABP3 ligand, MF1, was successfully demonstrated in PD models. Here, we developed a novel and potent ligand, HY-11-9, which has a higher affinity for FABP3 (Kd = 11.7 ± 8.8) than MF1 (Kd = 302.8 ± 130.3). We also investigated whether the FABP3 ligand can ameliorate neuropathological deterioration after the onset of disease in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Motor deficits were observed two weeks after MPTP treatment. Notably, oral administration of HY-11-9 (0.03 mg/kg) improved motor deficits in both beam-walking and rotarod tasks, whereas MF1 failed to improve the motor deficits in both tasks. Consistent with the behavioral tasks, HY-11-9 recovered dopamine neurons from MPTP toxicity in the substantia nigra and ventral tegmental areas. Furthermore, HY-11-9 reduced the accumulation of phosphorylated-serine129-α-synuclein (pS129-αSyn) and colocalization with FABP3 in tyrosine hydroxylase (TH)-positive DA neurons in the PD mouse model. Overall, HY-11-9 significantly improved MPTP-induced behavioral and neuropathological deterioration, suggesting that it may be a potential candidate for PD therapy.http://www.sciencedirect.com/science/article/pii/S1347861323000051HY-11-9Fatty acid-binding protein 3α-SynucleinDopaminergic neuronParkinson's disease |
| spellingShingle | Haoyang Wang Kohji Fukunaga An Cheng Yifei Wang Nariko Arimura Hiroshi Yoshino Takuya Sasaki Ichiro Kawahata Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice Journal of Pharmacological Sciences HY-11-9 Fatty acid-binding protein 3 α-Synuclein Dopaminergic neuron Parkinson's disease |
| title | Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice |
| title_full | Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice |
| title_fullStr | Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice |
| title_full_unstemmed | Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice |
| title_short | Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice |
| title_sort | novel fabp3 ligand hy 11 9 ameliorates neuropathological deficits in mptp induced parkinsonism in mice |
| topic | HY-11-9 Fatty acid-binding protein 3 α-Synuclein Dopaminergic neuron Parkinson's disease |
| url | http://www.sciencedirect.com/science/article/pii/S1347861323000051 |
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