title: Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice.
abstract: Vasoactive intestinal peptide (VIP) mediates a broad range of biological responses by activating two related receptors, VIP receptor 1 and 2 (VIPR1 and VIPR2). Although the use of native VIP facilitates neuroprotection, clinical application of the hormone is limited due to VIP's rapid metabolism and inability to distinguish between VIPR1 and VIPR2 receptors. In addition, activation of both receptors by therapeutics may increase adverse secondary toxicities. Therefore, we developed metabolically stable and receptor-selective agonists for VIPR1 and VIPR2 to improve pharmacokinetic and pharmacodynamic therapeutic end points. Selective agonists were investigated for their abilities to protect mice against MPTP-induced neurodegeneration used to model Parkinson's disease (PD). Survival of tyrosine hydroxylase neurons in the substantia nigra was determined by stereological tests after MPTP intoxication in mice pretreated with either VIPR1 or VIPR2 agonist or after adoptive transfer of splenic cell populations from agonist-treated mice administered to MPTP-intoxicated animals. Treatment with VIPR2 agonist or splenocytes from agonist-treated mice resulted in increased neuronal sparing. Immunohistochemical tests showed that agonist-treated mice displayed reductions in microglial responses, with the most pronounced effects in VIPR2 agonist-treated, MPTP-intoxicated mice. In parallel studies, we observed reductions in proinflammatory cytokine release that included IL-17A, IL-6, and IFN-γ and increases in GM-CSF transcripts in CD4(+) T cells recovered from VIPR2 agonist-treated animals. Moreover, a phenotypic shift of effector to regulatory T cells was observed. These results support the use of VIPR2-selective agonists as neuroprotective agents for PD treatment.
  
  
  CONCLUSIONS
  Vasoactive intestinal peptide receptor 2 can elicit immune transformation in a model of Parkinson's disease (PD). Such immunomodulatory capabilities can lead to neuroprotection by attenuating microglial activation and by slowing degradation of neuronal cell bodies and termini in MPTP-intoxicated mice. The protective mechanism arises from altering a Th1/Th2 immune cytokine response into an anti-inflammatory and neuronal sparing profile. These results are directly applicable for the development of novel PD therapies.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198 and.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Olson
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198 and.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kosloski-Bilek
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198 and.
authors.forename: Kristi M
authors.initials: KM
authors.lastname: Anderson
authors.affiliation: Longevity Biotech, Inc., Philadelphia, Pennsylvania 19104.
authors.forename: Breha J
authors.initials: BJ
authors.lastname: Diggs
authors.affiliation: Longevity Biotech, Inc., Philadelphia, Pennsylvania 19104.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Clark
authors.affiliation: Longevity Biotech, Inc., Philadelphia, Pennsylvania 19104.
authors.forename: John M
authors.initials: JM
authors.lastname: Gledhill
authors.affiliation: Longevity Biotech, Inc., Philadelphia, Pennsylvania 19104.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Shandler
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198 and.
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198 and hegendel@unmc.edu.
authors.forename: Howard E
authors.identifier: http://orcid.org/0000-0002-7831-0370
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000187:drug effects / Q000235:genetics; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000187:drug effects / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016207:Cytokines; C000606754:LBT-3627; D018696:Neuroprotective Agents; D009842:Oligopeptides; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495507:Vipr1 protein, mouse; C495510:Vipr2 protein, mouse; D014446:Tyrosine 3-Monooxygenase
keywords: Parkinson's disease; VIP; VPAC; adaptive immunity; inflammation; neuroprotection