Article

Tan YV, Waschek JA.Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis. ASN Neuro 3:195-212

Division of Adult Psychiatry, University of California, Los Angeles, Los Ángeles, California, United States
ASN Neuro (Impact Factor: 4.02). 09/2011; 3(4). DOI: 10.1042/AN20110024
Source: PubMed

ABSTRACT

MS (multiple sclerosis) is a chronic autoimmune and neurodegenerative pathology of the CNS (central nervous system) affecting approx. 2.5 million people worldwide. Current and emerging DMDs (disease-modifying drugs) predominantly target the immune system. These therapeutic agents slow progression and reduce severity at early stages of MS, but show little activity on the neurodegenerative component of the disease. As the latter determines permanent disability, there is a critical need to pursue alternative modalities. VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating peptide) have potent anti-inflammatory and neuroprotective actions, and have shown significant activity in animal inflammatory disease models including the EAE (experimental autoimmune encephalomyelitis) MS model. Thus, their receptors have become candidate targets for inflammatory diseases. Here, we will discuss the immunomodulatory and neuroprotective actions of VIP and PACAP and their signalling pathways, and then extensively review the structure-activity relationship data and biophysical interaction studies of these peptides with their cognate receptors.

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    • "PACAP could also be potentially produced by the inflammatory immune cells infiltrating the CNS. Finally, PACAP is reported to act as a growth and survival factor for neurons, oligodendrocytes, and other CNS cells, and may function in repair of myelin and/or axonal damage ([33], [34] and reviewed in [3], [35]). "
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    ABSTRACT: We have shown that mice deficient in pituitary adenylate cyclase-activating polypeptide (PACAP, gene name ADCYAP1) manifest enhanced sensitivity to experimental autoimmune encephalomyelitis (EAE), supporting the anti-inflammatory actions described for this neuropeptide. In addition to an increased proinflammatory cytokine response in these mice, a reduction in regulatory T cell (Treg) abundance in the lymph nodes (LN) was observed, suggesting altered Treg kinetics. In the present study, we compared in PACAP deficient (KO) vs. wild type mice the abundances and rates of proliferation FoxP3(+) Tregs in three sites, the LN, central nervous system (CNS) and thymus and the relative proportions of Th1, Th2, and Th17 effector subsets in the LN and CNS. Flow cytometry analyses revealed a decrease in Treg proliferation and an increased T effector/Tregs ratio in the LN and CNS of PACAP KO mice. In the thymus, the primary site of do novo natural Treg production, the total numbers and proliferative rates of FoxP3(+) Tregs were significantly reduced. Moreover, the expression of IL-7, a cytokine implicated in thymic Treg expansion during EAE, failed to increase at the peak of the disease in the thymus and LN of PACAP KO mice. In addition to these Treg alterations, a specific reduction of Th2 cells (about 4-fold) was observed in the lymph nodes in PACAP KO mice, with no effects on Th1 and Th17 subsets, whereas in the CNS, Th1 and Th17 cells were increased and Th2 decreased. Our results suggest that endogenous production of the neuropeptide PACAP protects against EAE by modulating Treg expansion and Th subsets at multiple sites.
    Preview · Article · Apr 2013 · PLoS ONE
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    • "With regard to mechanisms regulating VIP/PACAP receptormediated neuroprotection, PAC-1 has been shown to mediate direct neuronal surviving effects (Ohtaki et al., 2006; Reglodi et al., 2000). In addition, anti-neuroinflammatory properties, indirectly leading to neuroprotection, have been associated with each of the three VIP/PACAP receptors (Delgado et al., 2008; Kim et al., 2000; Nishimoto et al., 2011; Tan and Waschek, 2011), where a potent microglia-deactivating action in the production of proinflammatory factors was reported (Ganea et al., 2003). "
    Dataset: VPAC2

    Full-text · Dataset · Feb 2013
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    • "With regard to mechanisms regulating VIP/PACAP receptormediated neuroprotection, PAC-1 has been shown to mediate direct neuronal surviving effects (Ohtaki et al., 2006; Reglodi et al., 2000). In addition, anti-neuroinflammatory properties, indirectly leading to neuroprotection, have been associated with each of the three VIP/PACAP receptors (Delgado et al., 2008; Kim et al., 2000; Nishimoto et al., 2011; Tan and Waschek, 2011), where a potent microglia-deactivating action in the production of proinflammatory factors was reported (Ganea et al., 2003). "
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    ABSTRACT: VPAC2 receptor is a potential target for the treatment of type 2 diabetes and may also convey neuroprotective effects. The aim of this study was to determine the potential efficacy of the VPAC2 receptor agonist Bay 55-9837 against stroke in type-2 diabetic Goto-Kakizaki (GK) rats. GK rats were treated intravenously once daily for 7days with 0.25 or 0.025nmol/kg Bay 55-9837 or vehicle before inducing stroke by transient middle cerebral artery occlusion. Treatments were then continued for 7 further days. The glycemic effects of Bay 55-9837 were assessed by measuring fasting blood glucose and oral glucose tolerance. The severity of stroke was measured by assessing ischemic volume. The results show that Bay 55-9837 is not effective in lowering fasting glycemia and does not facilitate glucose disposal. The highest dose of Bay 55-9837 (0.25nmol/kg) led to increased mortality and brain hemorrhage when compared to control. The lower dose of Bay 55-9837 (0.025nmol/kg) did not increase mortality rate but caused a threefold increase of the ischemic lesion size with signs of brain hemorrhages as compared to control. In conclusion, Bay 55-9837 did not show antidiabetic or antistroke efficacy in the type 2 diabetic GK rat. Contrarily, Bay 55-9837 treatment led to increased mortality and worsening of the severity of stroke.
    Full-text · Article · Sep 2012 · Neuropeptides
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