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Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2015 Dec 16; Vol. 35 (50), pp. 16463-78. - Publication Year :
- 2015
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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.<br />Significance Statement: 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.<br /> (Copyright © 2015 the authors 0270-6474/15/3516463-16$15.00/0.)
- Subjects :
- Animals
CD4-Positive T-Lymphocytes metabolism
CHO Cells
Cell Line
Cricetinae
Cricetulus
Cytokines metabolism
Humans
Immunohistochemistry
MPTP Poisoning physiopathology
Mice
Mice, Inbred C57BL
Microglia drug effects
Microglia immunology
Oligopeptides pharmacokinetics
Receptors, Vasoactive Intestinal Peptide, Type II drug effects
Receptors, Vasoactive Intestinal Peptide, Type II genetics
Receptors, Vasoactive Intestinal Polypeptide, Type I drug effects
Receptors, Vasoactive Intestinal Polypeptide, Type I genetics
Spleen cytology
Spleen drug effects
Substantia Nigra enzymology
Substantia Nigra pathology
Tyrosine 3-Monooxygenase metabolism
Dopaminergic Neurons drug effects
Dopaminergic Neurons immunology
MPTP Poisoning drug therapy
MPTP Poisoning immunology
Neuroprotective Agents therapeutic use
Oligopeptides pharmacology
Receptors, Vasoactive Intestinal Peptide agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 35
- Issue :
- 50
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 26674871
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.2131-15.2015