Targeting VIP and PACAP Receptor Signalling: New Therapeutic Strategies in Multiple Sclerosis

Tan, Yossan‐Var; Waschek, James A.

doi:10.1042/an20110024

Cited by 42 publications

(36 citation statements)

References 224 publications

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“…PACAP27 binds to a range of receptors at various concentrations and activates a variety of second messengers that are dependent not only on the receptor and G-proteins but also on a repertoire of accessory molecules [82]. We plan to address PACAP signaling pathways in our PGJ2-induced mouse model in future studies, but one of the pathways by which PACAP signals survival is via activation of the G-protein coupled receptor PAC1R (pituitary adenylate cyclase 1 receptor).…”

Section: Discussionmentioning

confidence: 99%

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

Shivers

Nikolopoulou

Machlovi

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Neuroinflammation is a major risk factor in Parkinson disease (PD). Alternative approaches are needed to treat inflammation, as anti-inflammatory drugs such as NSAIDs that inhibit cyclooxygenase-2 (COX-2) can produce devastating side effects, including heart attack and stroke. New therapeutic strategies that target factors downstream of COX-2, such as prostaglandin J2 (PGJ2), hold tremendous promise because they will not alter the homeostatic balance offered by COX-2 derived prostanoids. In the current studies, we report that repeated microinfusion of PGJ2 into the substantia nigra of non-transgenic mice, induces three stages of pathology that mimic the slow-onset cellular and behavioral pathology of PD: mild (one injection) when only motor deficits are detectable, intermediate (two injections) when neuronal and motor deficits as well as microglia activation are detectable, and severe (four injections) when dopaminergic neuronal loss is massive accompanied by microglia activation and motor deficits. Microglia activation was evaluated in vivo by positron emission tomography (PET) with [11C](R)PK11195 to provide a regional estimation of brain inflammation. PACAP27 reduced dopaminergic neuronal loss and motor deficits induced by PGJ2, without preventing microglia activation. The latter could be problematic in that persistent microglia activation can exert long-term deleterious effects on neurons and behavior. In conclusion, this PGJ2-induced mouse model that mimics in part chronic inflammation, exhibits slow-onset PD-like pathology and is optimal for testing diagnostic tools such as PET, as well as therapies designed to target the integrated signaling across neurons and microglia, to fully benefit patients with PD.

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Section: Discussionmentioning

confidence: 99%

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

Shivers

Nikolopoulou

Machlovi

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…These include their roles in inflammatory disorders[10-14]; immune/autoimmune diseases[10, 11]; neurodevelopment/behavior[15-17]; neuroprotection/neurodegenerative disorders[18-23]; pulmonary diseases(asthma, etc. )[24]; sepsis[25]; learning/memory disorders[26]; CNS/neurological disorders[14, 21, 27-29]; diabetes[30, 31]; migraine[32, 33]; stress-responses/disorders[34, 35]; renal injuries[20] and general reviews of their signaling/ pharmacology as well their roles in physiology/pathophysiology[3••, 5, 6, 36, 37]. In this review the roles of VIP/PACAP in neoplastic processes, which has generally not been dealt with recently[38, 39], will be concentrated on.…”

Section: Introductionmentioning

confidence: 99%

Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer

Moody¹,

Nuche-Berenguer

Jensen

2016

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review To summarize the roles of VIP/PACAP and their receptors(VPAC1, VPAC2/PAC1) in human tumors as well as their role in potential novel treatments. Recent findings Considerable progress has been made in understanding of the effects of VIP/PACAP on growth of various tumors as well as in the signaling cascades involved, especially of the role of transactivation of the Epidermal growth factor(EGF) family. The overexpression of VPAC1/2, PAC1 on a number of common neoplasms (breast, lung, prostate, CNS, neuroblastoma) is receiving increased attention both as a means of tumor imaging the location and extent of these tumors, as well as for targeted directed treatment, by coupling cytotoxic agents to VIP/PACAP analogues. Summary VIP/PACAP has prominent growth effects on a number of common neoplasms, which frequently overexpressed the three subtypes of their receptors. The increased understanding of their signaling cascades, effect on tumor growth/differentiation, and the use of the overexpression of these receptors for localization/targeted cytotoxic delivery, are all suggesting possible novel tumor treatments.

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“…VIP promotes anti-inflammatory and tolerogenic effects in several inflammatory and autoimmune disease models [30,[33][34][35][36][37]. Particularly in the NOD mouse model of SS, a local gene therapy with an adenoviral construct encoding VIP restored salivary secretion and reduced autoimmune markers [38].…”

Section: Introductionmentioning

confidence: 99%

Monocytes from Sjögren's syndrome patients display increased vasoactive intestinal peptide receptor 2 expression and impaired apoptotic cell phagocytosis

Hauk

Fraccaroli

Grasso

et al. 2014

Clinical and Experimental Immunology

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SummarySjögren's syndrome (SS) is a chronic autoimmune disease characterized by salivary and lacrimal gland dysfunction. Clinical observations and results from animal models of SS support the role of aberrant epithelial cell apoptosis and immune homeostasis loss in the glands as triggering factors for the autoimmune response. Vasoactive intestinal peptide (VIP) promotes potent anti-inflammatory effects in several inflammatory and autoimmune disease models, including the non-obese diabetic (NOD) mouse model of SS. With the knowledge that VIP modulates monocyte function through vasoactive intestinal peptide receptors (VPAC) and that immune homeostasis maintenance depends strongly upon a rapid and immunosuppressant apoptotic cell clearance by monocytes/macrophages, in this study we explored VPAC expression on monocytes from primary SS (pSS) patients and the ability of VIP to modulate apoptotic cell phagocytic function and cytokine profile. Monocytes isolated from individual pSS patients showed an increased expression of VPAC2 subtype of VIP receptors, absent in monocytes from control subjects, with no changes in VPAC1 expression. VPAC2 receptor expression could be induced further with lipopolysaccharide (LPS) in pSS monocytes and VIP inhibited the effect. Moreover, monocytes from pSS patients showed an impaired phagocytosis of apoptotic epithelial cells, as evidenced by reduced engulfment ability and the failure to promote an immunosuppressant cytokine profile. However, VIP neither modulated monocyte/macrophage phagocytic function nor did it reverse their inflammatory profile. We conclude that monocytes from pSS patients express high levels of VPAC2 and display a deficient clearance of apoptotic cells that is not modulated by VIP.

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Targeting VIP and PACAP Receptor Signalling: New Therapeutic Strategies in Multiple Sclerosis

Cited by 42 publications

References 224 publications

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer

Monocytes from Sjögren's syndrome patients display increased vasoactive intestinal peptide receptor 2 expression and impaired apoptotic cell phagocytosis

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