{
  "abstract": "Background Dipeptidyl peptidase-4 inhibitors (DPP-4is) have been reported to exhibit therapeutic effects in Parkinson’s disease (PD), increasing their potential for drug repurposing. One aspect of PD pathogenesis is thought to be associated with the gut-brain axis, where α-synuclein from the gut is transmitted to the brain via the vagus nerve (VN).Objective We explored whether sitagliptin, a DPP-4i, exhibits a protective effect in a low-dose rotenone-treated gut-brain axis-associated PD model.Design To explore the effect of sitagliptin, we used the oral rotenone-treated mouse model, which showed spreading of pathological α-synuclein from the intestine in a stereotypic manner via the VN into the midbrain with motor deficits.Results Sitagliptin mitigated rotenone-induced gut inflammation and toll-like receptor 2 (TLR2) expression, reduced α-synuclein accumulation in the gut, VN and brain and lessened neuronal loss in the medulla and midbrain with recovery of motor performance. In addition, sitagliptin suppressed inflammation in response to a TLR2 agonist and rotenone in macrophages, enteric glial cells and enteroendocrine cell lines in vitro. In secretin tumour cell 1, an enteroendocrine cell line, sitagliptin also decreased rotenone-induced endogenous α-synuclein levels. The beneficial effects of sitagliptin were maintained even under glucagon-like peptide-1 receptor blockade. Notably, sitagliptin significantly altered the gut microbiome, shifting towards a profile that may counteract PD pathology.Conclusion These findings demonstrated that sitagliptin alleviated α-synuclein deposition in the gut and brain through modulation of TLR2-mediated inflammation and altered the gut microbiome composition towards a more favourable profile, which indicates that DPP-4is can offer a novel therapeutic avenue for managing PD.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin-si, The Republic of Korea",
        "Department of Neurology, Yonsei University College of Medicine, Seoul, The Republic of Korea"
      ],
      "name": "Seong Ho Jeong"
    },
    {
      "affiliations": [
        "Department of Neurology, Yonsei University College of Medicine, Seoul, The Republic of Korea",
        "Severance Biomedical Science Institute, Yonsei University, Seoul, The Republic of Korea"
      ],
      "name": "Yeon Ju Kim"
    },
    {
      "affiliations": [
        "Department of Neurology, Yonsei University College of Medicine, Seoul, The Republic of Korea",
        "Severance Biomedical Science Institute, Yonsei University, Seoul, The Republic of Korea"
      ],
      "name": "Jin Young Shin"
    },
    {
      "affiliations": [
        "Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, The Republic of Korea"
      ],
      "name": "Kyu Won Oh"
    },
    {
      "affiliations": [
        "Catholic Kwandong University College of Medicine Department of Medical Science, Gangneung-si, The Republic of Korea"
      ],
      "name": "Jung Wook Lee"
    },
    {
      "affiliations": [
        "Department of Neurology, Yonsei University College of Medicine, Seoul, The Republic of Korea",
        "Severance Biomedical Science Institute, Yonsei University, Seoul, The Republic of Korea"
      ],
      "name": "Phil Hyu Lee"
    }
  ],
  "title": "DPP-4 inhibitor alleviates gut-brain axis pathology in Parkinson’s disease",
  "uid": "e7908d98-b36c-54c6-a20a-d16c0ba28a05"
}