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Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson's Disease.
Int J Mol Sci. 2022 Feb 21; 23(4)IJ

Abstract

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+)-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+-induced dephosphorylation of PI3K/Akt and phosphorylation of ERK and JNK in SH-SY5Y cells. Moreover, vildagliptin attenuated MPP+-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.

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Authors+Show Affiliations

Pariyar R
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea. Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX 77555-0625, USA.
Bastola T
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea.
Lee DH
Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea.
Seo J
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea.

MeSH

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineAnimalsCell Line, TumorCorpus StriatumDipeptidyl-Peptidase IV InhibitorsDisease Models, AnimalDopamineDopaminergic NeuronsHumansMAP Kinase Signaling SystemMaleMiceMice, Inbred C57BLNeuroprotective AgentsParkinson DiseasePars CompactaPhosphatidylinositol 3-KinasesSignal TransductionSubstantia NigraTyrosine 3-MonooxygenaseVildagliptin

Pub Type(s)

Journal Article

Language

eng

PubMed ID

35216503

Citation

Pariyar, Ramesh, et al. "Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in in Vivo and in Vitro Models of Parkinson's Disease." International Journal of Molecular Sciences, vol. 23, no. 4, 2022.
Pariyar R, Bastola T, Lee DH, et al. Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson's Disease. Int J Mol Sci. 2022;23(4).
Pariyar, R., Bastola, T., Lee, D. H., & Seo, J. (2022). Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson's Disease. International Journal of Molecular Sciences, 23(4). https://doi.org/10.3390/ijms23042388
Pariyar R, et al. Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in in Vivo and in Vitro Models of Parkinson's Disease. Int J Mol Sci. 2022 Feb 21;23(4) PubMed PMID: 35216503.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson's Disease. AU - Pariyar,Ramesh, AU - Bastola,Tonking, AU - Lee,Dae Ho, AU - Seo,Jungwon, Y1 - 2022/02/21/ PY - 2022/01/25/received PY - 2022/02/16/revised PY - 2022/02/19/accepted PY - 2022/2/26/entrez PY - 2022/2/27/pubmed PY - 2022/3/22/medline KW - MPTP KW - Parkinson’s disease KW - apoptosis KW - autophagy KW - dopaminergic neuron KW - motor dysfunction KW - vildagliptin JF - International journal of molecular sciences JO - Int J Mol Sci VL - 23 IS - 4 N2 - 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+)-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+-induced dephosphorylation of PI3K/Akt and phosphorylation of ERK and JNK in SH-SY5Y cells. Moreover, vildagliptin attenuated MPP+-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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/35216503/Neuroprotective_Effects_of_the_DPP4_Inhibitor_Vildagliptin_in_In_Vivo_and_In_Vitro_Models_of_Parkinson's_Disease_ DB - PRIME DP - Unbound Medicine ER -