Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease
Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Restoration of nigrostriatal dopamine neurons has been proposed as a potential therapeutic strategy for PD. Because currently used PD therapeutics only help relieve...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/4/2388 |
| _version_ | 1797479242332635136 |
|---|---|
| author | Ramesh Pariyar Tonking Bastola Dae Ho Lee Jungwon Seo |
| author_facet | Ramesh Pariyar Tonking Bastola Dae Ho Lee Jungwon Seo |
| author_sort | Ramesh Pariyar |
| collection | DOAJ |
| description | Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Restoration of nigrostriatal dopamine neurons has been proposed as a potential therapeutic strategy for PD. Because currently used PD therapeutics only help relieve motor symptoms and do not treat the cause of the disease, highly effective drugs are needed. Vildagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, is an anti-diabetic drug with various pharmacological properties including neuroprotective effects. However, the detailed effects of vildagliptin against PD are not fully understood. We investigated the effects of vildagliptin on PD and its underlying molecular mechanisms using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and a 1-methyl-4-phenylpyridium (MPP<sup>+</sup>)-induced cytotoxicity model. Vildagliptin (50 mg/kg) administration significantly attenuated MPTP-induced motor deficits as evidenced by rotarod, pole, and nest building tests. Immunohistochemistry and Western blot analysis revealed that vildagliptin increased tyrosine hydroxylase-positive cells in the SNpc and striatum, which was reduced by MPTP treatment. Furthermore, vildagliptin activated MPTP-decreased PI3k/Akt and mitigated MPTP-increased ERK and JNK signaling pathways in the striatum. Consistent with signaling transduction in the mouse striatum, vildagliptin reversed MPP<sup>+</sup>-induced dephosphorylation of PI3K/Akt and phosphorylation of ERK and JNK in SH-SY5Y cells. Moreover, vildagliptin attenuated MPP<sup>+</sup>-induced conversion of LC3B-II in SH-SY5Y cells, suggesting its role in autophagy inhibition. Taken together, these findings indicate that vildagliptin has protective effects against MPTP-induced motor dysfunction by inhibiting dopaminergic neuronal apoptosis, which is associated with regulation of PI3k/Akt, ERK, and JNK signaling transduction. Our findings suggest vildagliptin as a promising repurposing drug to treat PD. |
| first_indexed | 2024-03-09T21:43:01Z |
| format | Article |
| id | doaj.art-57837971a18e4a00a354964ce6899e61 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:43:01Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-57837971a18e4a00a354964ce6899e612023-11-23T20:24:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234238810.3390/ijms23042388Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s DiseaseRamesh Pariyar0Tonking Bastola1Dae Ho Lee2Jungwon Seo3Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, KoreaInstitute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, KoreaDepartment of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon 21565, KoreaInstitute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, KoreaParkinson’s disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Restoration of nigrostriatal dopamine neurons has been proposed as a potential therapeutic strategy for PD. Because currently used PD therapeutics only help relieve motor symptoms and do not treat the cause of the disease, highly effective drugs are needed. Vildagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, is an anti-diabetic drug with various pharmacological properties including neuroprotective effects. However, the detailed effects of vildagliptin against PD are not fully understood. We investigated the effects of vildagliptin on PD and its underlying molecular mechanisms using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and a 1-methyl-4-phenylpyridium (MPP<sup>+</sup>)-induced cytotoxicity model. Vildagliptin (50 mg/kg) administration significantly attenuated MPTP-induced motor deficits as evidenced by rotarod, pole, and nest building tests. Immunohistochemistry and Western blot analysis revealed that vildagliptin increased tyrosine hydroxylase-positive cells in the SNpc and striatum, which was reduced by MPTP treatment. Furthermore, vildagliptin activated MPTP-decreased PI3k/Akt and mitigated MPTP-increased ERK and JNK signaling pathways in the striatum. Consistent with signaling transduction in the mouse striatum, vildagliptin reversed MPP<sup>+</sup>-induced dephosphorylation of PI3K/Akt and phosphorylation of ERK and JNK in SH-SY5Y cells. Moreover, vildagliptin attenuated MPP<sup>+</sup>-induced conversion of LC3B-II in SH-SY5Y cells, suggesting its role in autophagy inhibition. Taken together, these findings indicate that vildagliptin has protective effects against MPTP-induced motor dysfunction by inhibiting dopaminergic neuronal apoptosis, which is associated with regulation of PI3k/Akt, ERK, and JNK signaling transduction. Our findings suggest vildagliptin as a promising repurposing drug to treat PD.https://www.mdpi.com/1422-0067/23/4/2388vildagliptinMPTPParkinson’s diseaseapoptosisdopaminergic neuronmotor dysfunction |
| spellingShingle | Ramesh Pariyar Tonking Bastola Dae Ho Lee Jungwon Seo Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease International Journal of Molecular Sciences vildagliptin MPTP Parkinson’s disease apoptosis dopaminergic neuron motor dysfunction |
| title | Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease |
| title_full | Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease |
| title_fullStr | Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease |
| title_full_unstemmed | Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease |
| title_short | Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease |
| title_sort | neuroprotective effects of the dpp4 inhibitor vildagliptin in in vivo and in vitro models of parkinson s disease |
| topic | vildagliptin MPTP Parkinson’s disease apoptosis dopaminergic neuron motor dysfunction |
| url | https://www.mdpi.com/1422-0067/23/4/2388 |
| work_keys_str_mv | AT rameshpariyar neuroprotectiveeffectsofthedpp4inhibitorvildagliptinininvivoandinvitromodelsofparkinsonsdisease AT tonkingbastola neuroprotectiveeffectsofthedpp4inhibitorvildagliptinininvivoandinvitromodelsofparkinsonsdisease AT daeholee neuroprotectiveeffectsofthedpp4inhibitorvildagliptinininvivoandinvitromodelsofparkinsonsdisease AT jungwonseo neuroprotectiveeffectsofthedpp4inhibitorvildagliptinininvivoandinvitromodelsofparkinsonsdisease |