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Sitagliptin attenuates L-dopa-induced dyskinesia by regulating mitochondrial function and neuronal activity in 6-OHDA-induced mouse model of Parkinson’s disease

ABSTRACT: L-dopa-induced dyskinesia (LID) is an incapacitating complication of long-term administration of L-dopa therapy that commonly affects patients with Parkinson’s disease (PD) due to the widespread use of the causative drug. Herein, we investigated the therapeutic potential of sitagliptin, a drug used to treat type 2 diabetes mellitus, to treat LID. 6-hydroxydopamine (6-OHDA) was unilaterally injected into the left side of the substantia nigra pas compacta to induce a mouse model of PD. After four weeks of 6-OHDA induction, L-dopa was administered with or without sitagliptin for 11 consecutive days. LID was monitored using abnormal involuntary movement (AIM) scoring, conducted on days 5 and 10 of L-dopa treatment. Comparative proteomic analysis was performed on the 6-OHDA-lesioned striatum by comparing groups treated with vehicle + L-dopa and sitagliptin + L-dopa. Changes in the expression of Ndufb2 and Arc, which showed the greatest increase or decrease, were validated using western blotting and RT-PCR analysis. Sitagliptin combined with L-dopa significantly attenuated AIM scores in 6-OHDA-lesioned mice. The protein level of Ndufb2 was increased by the co-administration of sitagliptin and L-dopa in both unlesioned and 6-OHDA-lesioned striata compared with the administration of L-dopa alone. The expression levels of FosB and c-Fos, and Arc were suppressed by the co-administration of sitagliptin and L-dopa in the 6-OHDA-lesioned striatum. These findings suggest that sitagliptin may have therapeutic potential for incapacitating complications of long-term L-dopa use in patients with PD.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Ga Seul Lee

LAB HEAD: Kyoung-Shim Kim

PROVIDER: PXD057346 | Pride | 2026-05-20

REPOSITORIES: Pride

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			Action	DRS
	TMT_PD_Sitagliptin_FAIMS_1st_fraction01.raw	Raw
	TMT_PD_Sitagliptin_FAIMS_1st_fraction02.raw	Raw
	TMT_PD_Sitagliptin_FAIMS_1st_fraction03.raw	Raw
	TMT_PD_Sitagliptin_FAIMS_1st_fraction04.raw	Raw
	TMT_PD_Sitagliptin_FAIMS_1st_fraction05.raw	Raw

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Project description:The therapeutic benefits of L–3,4–dihydroxyphenylalanine (L-DOPA) in Parkinson’s disease (PD) patients severely diminishes with the onset of L-DOPA-induced dyskinesia (LID), a debilitating motor side effect. LID is mainly due to altered dopaminergic signaling in the striatum, a brain region that controls motor and cognitive functions. However, the molecular mechanisms that promote LID remain unclear. Here, we have reported that increased striatal RasGRP1 (also known as CalDAG-GEF-II) is instrumentally linked to the development of LID in a 6-hydroxydopamine (6-OHDA) lesioned mouse model of PD. L-DOPA treatment rapidly upregulated RasGRP1 in the dopamine-1 receptor positive neurons in the dorsal striatum. RasGRP1 deleted mice (RasGRP1–/–) had drastically diminished LID, and RasGRP1–/– mice did not interfere with the therapeutic benefits of L-DOPA. In terms of its mechanism, RasGRP1 mediated L-DOPA-induced extracellular regulated kinase (ERK), the mammalian target of rapamycin kinase (mTOR) and the cAMP/PKA pathway. RasGRP1 bind directly with and acts 2 as a guanine nucleotide exchange (GEF) for Ras-homolog-enriched in the brain (Rheb), a potent activator of mTOR, both in vitro and in the intact striatum. High-resolution tandem mass tag mass spectrometry analysis of striatal tissue revealed significant targets, such as phosphodiesterase 10a (Pde10a), Pde2a, catechol-o-methyltransferase (Comt), and glutamate decarboxylase 1 and 2 (Gad1 and Gad2), as downstream regulators of RasGRP1 that are linked to LID vulnerability. Moreover, we found that RASGRP1 protein is also upregulated predominantly in the striatum of MPTP-lesioned macaque treated with L-DOPA, emphasizing the translational potential of this protein. Collectively, the findings of this study demonstrated that RasGRP1 is a major regulator of LID in the dorsal striatum. Pharmacological or gene-depletion strategies targeting RasGRP1 may offer novel therapeutic opportunities for preventing LID in PD patients.

Project description:Levodopa-induced dyskinesia (LID) is a persistent behavioral sensitization that develops after repeated levodopa (L-DOPA) exposure in Parkinson disease (PD) patients. we used reduced representation bisulfite sequencing to determine the methylation status of cytosines genome wide at base pair resolution following a parkinsonian-like lesion and LID development. Due to the enrichment of RRBS, we focused our analysis to cytosines in a CpG context and observed extensive locus-specific changes in DNA methylation, including a preponderance of demethylation, in the dorsal striatum following the development of dyskinetic behaviors in our animal model system. Changes in DNA methylation were concentrated in putative regulatory regions of many genes known to be aberrantly transcribed following L-DOPA exposure and enriched for genes relevant to mechanisms of synaptic plasticity. In the areas of the genome exhibiting the highest levels of effect, the magnitudes of change to methylation were strongly correlated with dyskinetic behaviors. Rats were given a unilateral dopaminergic lesion to the left medial forebrain bundle with 6-OHDA to destroy at least 90% of TH positive axons. Animals were allowed to recover for 3 weeks and then given daily injections of L-DOPA (6 mg/kg) for seven days to establish stable dyskinesia. Animals were sacked 3 hrs following the final L-DOPA injection and the dorsal striatum was immediately dissected and flash frozen. Striatal tissue samples were processed for nucleic acid isolation using the AllPrep DNA/RNA Mini Kit (Qiagen) following the manufacturer's instructions. One Î¼g of gDNA sample was used for library construction. Bisulfite converted DNA libraries were produced and adaptor ligated, and single-end reads were sequenced on an Illumina HiSeq-2500 following library QC. Bisulfite conversion efficiency was greater that 98% for all of the samples and we obtained an average of 68 million reads per library. Quality control on raw reads was performed with FastQC (version 0.10.1, http://www.bioinformatics.bbsrc.ac.uk/projects/fastqc), and adaptor trimming and removal of trimmed reads shorter than 20 bp was performed with Trim Galore (version 0.3.7, http://www.bioinformatics.babraham.ac.uk/projects/trim_galore). Trimmed reads were mapped to the UCSC Rattus norvegicus rn5 genome with the methylation-aware mapper bismark (version 0.13.0). Samtools (version 0.1.19â??96b5f2294a) was used to sort SAM files produced by bismark and de-duplicate reads. SAM files were analyzed using MethylKit (version 0.9.2) in R (Akalin et al., 2012). Reads were filtered based on coverage, with a cutoff of at least ten reads per site, and normalized for each samples coverage before analysis. The genome was tiled at 250 bp and regions were counted if they contained at least 2 identified CpGs per tile. Differential methylation was defined as a sliding linear model correct p-value of <0.01 and, for highly dynamic regions, included at least a 5% change.

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Sitagliptin attenuates L-dopa-induced dyskinesia by regulating mitochondrial function and neuronal activity in 6-OHDA-induced mouse model of Parkinson’s disease

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