Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease

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.

Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson’s Disease

“…As activated JNK3 can aggravate apoptotic signaling by phosphorylating apoptosis-related proteins, including c-Jun, Bax, and caspase-3, , we then examined the phosphorylation levels of JNK1/2/3 and their downstream substrate c-Jun and upstream MKK7 by Western blotting (Figure A). The result indicated that compared to the control group, MPP + significantly upregulated phosphorylated JNKs and c-Jun in SH-SY5Y cells without affecting their total protein expressions, which was consistent with previous findings. ,, Interestingly, MPP + did not significantly induce the upregulation of p-JNK1/2 alone, which was inconsistent with a previous study, probably due to different concentrations and treatment time points of MPP + . Maybe, it also conferred that JNK3 is the main active JNK isoform in dopaminergic neurons after MPP + induction.…”

“…A growing number of studies have indicated that apoptosis is a major pathological characteristic of PD, and MPP + induces neuronal cell death by activating cell apoptosis. , To test the potential mechanism of the neuroprotective activity of 25c , we examined the apoptotic level and expression levels of apoptosis-related proteins in MPP + -induced SH-SY5Y cells with or without 25c treatment. Flow cytometry analysis revealed that 25c alleviated MPP + -induced cell apoptosis in a concentration-dependent manner (Figure C).…”

IAVPGEVA: Orally Available DPP4-Targeting Soy Glycinin Derived Octapeptide with Therapeutic Potential in Nonalcoholic Steatohepatitis

“…This study has shown that SGP8, as a competitive inhibitor of DPP4, may be used to treat NASH by targeting DPP4 to increase GLP-1 levels in the body and to block the JNK/c-Jun pathway in hepatocytes (Figure H). Similarly, DPP4 Inhibitor Vildagliptin reversed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced phosphorylation of JNK in SH-SY5Y cells . Furthermore, DPP4 enhanced JNK/c-Jun signaling induced by the epidermal growth factor, inducing AP-1 activity and epithelial cell transformation .…”

“…Similarly, DPP4 Inhibitor Vildagliptin reversed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced phosphorylation of JNK in SH-SY5Y cells. 28 Furthermore, DPP4 enhanced JNK/c-Jun signaling induced by the epidermal growth factor, inducing AP-1 activity and epithelial cell transformation. 29 As the first oral GLP-1 receptor agonist to be approved for the treatment of GLP-1 in the world, Semaglutide Tablets were approved by the FDA in September 2019.…”

Extra-Glycemic Effects of Anti-Diabetic Medications: Two Birds with One Stone?

“…However, a recent meta-analysis failed to show any correlation between metformin therapy and PD development [119]. Although there have not yet been any clinical trials, incretin therapies, such as GLP-1RAs and DPP-4 inhibitors, have shown protective effects against PD in animal studies [120][121][122]. These effects should be confirmed in human studies.…”