Abad C, Waschek JA.Immunomodulatory roles of VIP and PACAP in models of multiple sclerosis. Curr Pharm Des 17:1025-35

The Semel Institute for Neuroscience and Human and Department of Psychiatry, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Current pharmaceutical design (Impact Factor: 3.45). 04/2011; 17(10):1025-35. DOI: 10.2174/138161211795589364
Source: PubMed


Multiple sclerosis (MS) is a progressive neurodegenerative disease affecting myelin and axons, which is perpetuated by autoreactive lymphocytes and other inflammatory cell types. Because of the multifactorial nature of this disease, therapies targeting a single process may not be sufficient to halt its progression. VIP and PACAP are two neuropeptides shown to regulate multiple aspects of innate and adaptive immunity, and can also act independently on neural cells to promote their survival and regeneration. Animal studies have proven the efficacy of these peptides for the treatment of several models of neural inflammatory disorders, including those which, like MS, have major Th1/Th17 components. In this review, the immunomodulatory actions of VIP and PACAP will be discussed, with particular emphasis on their potential significance in MS.

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    • "Numerous reports have focused on the effects of VIP treatment. Thus, administration of VIP has demonstrated therapeutic effects in several murine models of inflammatory/autoimmune diseases [10]–[14]. In a murine model of collagen-induced arthritis, administration of VIP reduced joint inflammation and destruction, thus decreasing the inflammatory response and inducing a shift in the Th1/Th2 balance [10], [15]. "
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    ABSTRACT: Suitable biomarkers are essential for the design of therapeutic strategies in personalized medicine. Vasoactive intestinal peptide (VIP) has demonstrated immunomodulatory properties in autoimmune murine and ex vivo human models. Our aim was to study serum levels of VIP during the follow-up of an early arthritis (EA) cohort and to analyze its value as a biomarker predicting severity and therapeutic requirements. Data from 91 patients on an EA register were analyzed (76% rheumatoid arthritis (RA), 24% undifferentiated arthritis, 73% women, and median age 54 years; median disease duration at entry, 5.4 months). We collected per protocol sociodemographic, clinical, and therapeutic data. VIP levels were determined by enzyme immunoassay in sera harvested from the 91 patients (353 visits; 3.9 visit/patient) and from 100 healthy controls. VIP values below the 25(th) percentile of those assessed in healthy population were considered low. To determine the effect of independent variables on VIP levels, we performed a longitudinal multivariate analysis nested by patient and visit. A multivariate ordered logistic regression was modeled to determine the effect of low VIP serum levels on disease activity at the end of follow-up. VIP concentrations varied considerably across EA patients. Those fulfilling the criteria for RA had the lowest values in the whole sample, although no significant differences were observed compared with healthy donors. Disease activity, which was assessed using DAS28, inversely correlated with VIP levels. After a two-year follow-up, those patients with low baseline levels of VIP displayed higher disease activity and received more intensive treatment. Patients who are unable to up-regulate VIP seem to have a worse clinical course despite receiving more intense treatment. Therefore, measurement of VIP levels may be suitable as a prognostic biomarker.
    PLoS ONE 01/2014; 9(1):e85248. DOI:10.1371/journal.pone.0085248 · 3.23 Impact Factor
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    • "Moreover, they can induce production of the anti-inflammatory cytokine IL-10 [12], [14]. Due to their immunomodulatory properties, both neuropeptides have been considered as promising therapeutic agents for a range of pathologies [15]–[17]. "
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    ABSTRACT: It is well established that host factors can modulate HIV-1 replication in macrophages, critical cells in the pathogenesis of HIV-1 infection due to their ability to continuously produce virus. The neuropeptides VIP and PACAP induce well-characterized effects on macrophages through binding to the G protein-coupled receptors VPAC1, VPAC2 and PAC1, but their influence on HIV-1 production by these cells has not been established. Here, we describe that VIP and PACAP reduce macrophage production of HIV-1, acting in a synergistic or additive manner to decrease viral growth. Using receptor antagonists, we detected that the HIV-1 inhibition promoted by VIP is dependent on its ligation to VPAC1/2, whereas PACAP decreases HIV-1 growth via activation of the VPAC1/2 and PAC1 receptors. Specific agonists of VPAC2 or PAC1 decrease macrophage production of HIV-1, whereas sole activation of VPAC1 enhances viral growth. However, the combination of specific agonists mimicking the receptor preference of the natural neuropeptides reproduces the ability of VIP and PACAP to increase macrophage resistance to HIV-1 replication. VIP and PACAP up-regulated macrophage secretion of the β-chemokines CCL3 and CCL5 and the cytokine IL-10, whose neutralization reversed the neuropeptide-induced inhibition of HIV-1 replication. Our results suggest that VIP and PACAP and the receptors VPAC2 and PAC1 could be used as targets for developing alternative therapeutic strategies for HIV-1 infection.
    PLoS ONE 06/2013; 8(6):e67701. DOI:10.1371/journal.pone.0067701 · 3.23 Impact Factor
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    • "Regulatory T cells were reduced in lymph nodes and spinal cord, suggesting a regulatory function for PACAP in regulatory T cells' abundance after inflammation. Altogether, these results clearly show that PACAP is an endogenous protective peptide in a model of multiple sclerosis, providing immunological , pathological, and clinical protection (Tan et al. 2009; Abad and Waschek 2011). "
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    ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widespread neuropeptide with a diverse array of biological functions. Not surprisingly, the lack of endogenous PACAP therefore results in a variety of abnormalities. One of the important effects of PACAP is its neuroprotective and general cytoprotective role. PACAP protects neurons and other tissues against ischemic, toxic, and traumatic lesions. Data obtained from PACAP-deficient mice provide evidence that endogenous PACAP also has protective functions. Mice lacking PACAP are more vulnerable to different in vitro and in vivo insults. The present review summarizes data on the increased sensitivity of PACAP-deficient mice against harmful stimuli. Mice lacking PACAP respond with a higher degree of injury in cerebral ischemia, autoimmune encephalomyelitis, and axonal lesion. Retinal ischemic and excitotoxic injuries also produce increased cell loss in PACAP-deficient mice. In peripheral organs, kidney cell cultures from PACAP-deficient mice are more sensitive to oxidative stress and in vitro hypoxia. In vivo, PACAP-deficient mice have a negative histological outcome and altered cytokine response in kidney and small intestine ischemia/reperfusion injury. Large intestinal inflammation, toxic lesion of the pancreas, and doxorubicin-induced cardiomyopathy are also more severe with a lack of endogenous PACAP. Finally, an increased inflammatory response has been described in subacute endotoxin-induced airway inflammation and in an oxazolone-induced allergic contact dermatitis model. In summary, lack of endogenous PACAP leads to higher vulnerability in a number of injuries in the nervous system and peripheral organs, supporting the hypothesis that PACAP is part of the endogenous cytoprotective machinery.
    Journal of Molecular Neuroscience 04/2012; 48(3):482-92. DOI:10.1007/s12031-012-9762-0 · 2.34 Impact Factor
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