Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial
| Autor: | Seema Gulyani, David Tweedie, Maja Mustapić, Yazhou Li, Simon S. Skene, Dimitrios Kapogiannis, Hanuma Kumar Karnati, Sahil Chawla, Dilan Athauda, Kashfia Chowdhury, Nigel H. Greig, Thomas Foltynie |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Insulin Receptor Substrate Proteins MAP Kinase Signaling System medicine.medical_treatment Pharmacology Exosomes Incretins 03 medical and health sciences 0302 clinical medicine Medicine Humans Insulin 030212 general & internal medicine Phosphorylation Protein kinase B Mechanistic target of rapamycin Aged Janus Kinases Mitogen-Activated Protein Kinase 1 Neurons Mitogen-Activated Protein Kinase 3 biology business.industry Akt/PKB signaling pathway TOR Serine-Threonine Kinases Brain Correction Parkinson Disease Middle Aged IRS1 Insulin receptor biology.protein Exenatide Female Neurology (clinical) business Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery medicine.drug Signal Transduction |
| Zdroj: | JAMA neurology. 76(4) |
| ISSN: | 2168-6157 |
| Popis: | Importance: Exenatide, a glucagon-like peptide 1 agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge. Objective: To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways. Design, Setting, and Participants: Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016), which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti–L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017. Main Outcomes and Measures: The main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways. Results: Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU; P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU; P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL; P |
| Databáze: | OpenAIRE |
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