Selective VIP receptor agonists facilitate immune transformation for dopaminergic neuroprotection in MPTP-intoxicated mice

Katherine E. Olson, Lisa M. Kosloski-Bilek, Kristi M. Anderson, Breha J. Diggs, Barbara E. Clark, John M. Gledhill, Scott J. Shandler, R Lee Mosley, Howard Eliot Gendelman

Research output: Contribution to journalArticle

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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-÷ 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.

Original languageEnglish (US)
Pages (from-to)16463-16478
Number of pages16
JournalJournal of Neuroscience
Volume35
Issue number50
DOIs
StatePublished - Dec 16 2015

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Vasoactive Intestinal Peptide Receptors
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Vasoactive Intestinal Peptide
Parkinson Disease
Receptors, Vasoactive Intestinal Peptide, Type II
Receptors, Vasoactive Intestinal Polypeptide, Type I
Interleukin-17
Adoptive Transfer
Tyrosine 3-Monooxygenase
Neuroprotective Agents
Substantia Nigra
Regulatory T-Lymphocytes
Therapeutics
Granulocyte-Macrophage Colony-Stimulating Factor
Neuroprotection
Interleukin-6
Pharmacokinetics
Hormones
Cytokines
T-Lymphocytes

Keywords

  • Adaptive immunity
  • Inflammation
  • Neuroprotection
  • Parkinson’s disease
  • VIP
  • VPAC

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Selective VIP receptor agonists facilitate immune transformation for dopaminergic neuroprotection in MPTP-intoxicated mice. / Olson, Katherine E.; Kosloski-Bilek, Lisa M.; Anderson, Kristi M.; Diggs, Breha J.; Clark, Barbara E.; Gledhill, John M.; Shandler, Scott J.; Mosley, R Lee; Gendelman, Howard Eliot.

In: Journal of Neuroscience, Vol. 35, No. 50, 16.12.2015, p. 16463-16478.

Research output: Contribution to journalArticle

Olson, Katherine E. ; Kosloski-Bilek, Lisa M. ; Anderson, Kristi M. ; Diggs, Breha J. ; Clark, Barbara E. ; Gledhill, John M. ; Shandler, Scott J. ; Mosley, R Lee ; Gendelman, Howard Eliot. / Selective VIP receptor agonists facilitate immune transformation for dopaminergic neuroprotection in MPTP-intoxicated mice. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 50. pp. 16463-16478.
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AU - Olson, Katherine E.

AU - Kosloski-Bilek, Lisa M.

AU - Anderson, Kristi M.

AU - Diggs, Breha J.

AU - Clark, Barbara E.

AU - Gledhill, John M.

AU - Shandler, Scott J.

AU - Mosley, R Lee

AU - Gendelman, Howard Eliot

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AB - 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-÷ 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.

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KW - Inflammation

KW - Neuroprotection

KW - Parkinson’s disease

KW - VIP

KW - VPAC

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