@article{7410a070dce54ebeac2bd10b4d1562f9,
title = "A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson{\textquoteright}s Disease",
abstract = "A paradigm shift has emerged in Parkinson{\textquoteright}s disease (PD) highlighting the prominent role of CD4+ Tregs in pathogenesis and treatment. Bench to bedside research, conducted by others and our own laboratories, advanced a neuroprotective role for Tregs making pharmacologic transformation of immediate need. Herein, a vasoactive intestinal peptide receptor-2 (VIPR2) peptide agonist, LBT-3627, was developed as a neuroprotectant for PD-associated dopaminergic neurodegeneration. Employing both 6-hydroxydopamine (6-OHDA) and α-synuclein (α-Syn) overexpression models in rats, the sequential administration of LBT-3627 increased Treg activity without altering cell numbers both in na{\"i}ve animals and during progressive nigrostriatal degeneration. LBT-3627 administration was linked to reductions of inflammatory microglia, increased survival of dopaminergic neurons, and improved striatal densities. While α-Syn overexpression resulted in reduced Treg activity, LBT-3627 rescued these functional deficits. This occurred in a dose-dependent manner closely mimicking neuroprotection. Taken together, these data provide the basis for the use of VIPR2 agonists as potent therapeutic immune modulating agents to restore Treg activity, attenuate neuroinflammation, and interdict dopaminergic neurodegeneration in PD. The data underscore an important role of immunity in PD pathogenesis.",
keywords = "6-hydroxydopamine, Parkinson{\textquoteright}s disease, agonist, alpha-synuclein, microglia, neurodegeneration, regulatory T cells, vasoactive intestinal peptide",
author = "Mosley, {R. Lee} and Yaman Lu and Olson, {Katherine E.} and Jatin Machhi and Wenhui Yan and Namminga, {Krista L.} and Smith, {Jenell R.} and Shandler, {Scott J.} and Gendelman, {Howard E.}",
note = "Funding Information: The authors would like to thank Dr. Uma Sinha for her help in editing the manuscript and specifically for her guidance in reviewing the cardiovascular (CV) results, John M. Gledhill Jr. for aiding in the CV study design, and Ms. Breha J. Diggs MS and Ms. Barbara E. Clark for the production of LBT-3627. The authors would also like to thank Dr. David G. Standaert for providing permission to utilize the AAV2/1 constructs used in these studies and the UNMC Cell Analysis Facility for excellent flow cytometric analyses. Funding. This work was supported in part by the University of Nebraska Foundation, which includes donations from the Carol Swarts, M.D., Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, and the Frances and Louie Blumkin and Harriet Singer Research Foundations, the Vice Chancellor?s Office of the University of Nebraska Medical Center for Core Facility Developments, the Michael J. Fox Foundation, and National Institutes of Health grants P01 DA028555, R01 NS36126, P01 NS31492, P01 MH64570, P01 NS43985, P30 MH062261, and R01 AG043540 (HG), and 2R01 NS034239 (HG and RM). Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2019 Mosley, Lu, Olson, Machhi, Yan, Namminga, Smith, Shandler and Gendelman.",
year = "2019",
month = sep,
day = "18",
doi = "10.3389/fncel.2019.00421",
language = "English (US)",
volume = "13",
journal = "Frontiers in Cellular Neuroscience",
issn = "1662-5102",
publisher = "Frontiers Research Foundation",
}