A few years ago, VIP was identified as a potential therapeutic agent for various diseases including asthma (Groneberg et al., 2001), sexual impotence (Fahrenkrug et al., 1989), brain strokes (Dogrukol-Ak et al., 2004), chronic inflammation (Delgado et al., 2004), neuro-inflammation (Dejda et al., 2005), septic shock (Delgado et al., 2004) and cancers (Moody and Gozes, 2007). From these important physiopathological processes, anti-inflammatory and neuroprotective actions of VIP represent two major promising therapeutic uses of the peptide.
VIP appears to be a very potent anti-inflammatory peptide in animal models of various chronic inflammatory diseases (Table 3). This effect is mediated by modulation of T-helper balance by suppressing Th1 immune responses (Delgado et al., 2004). VIP inhibits leucocyte activation and migration, decreases NF-κB activation and expression of pro-inflammatory cytokines and chemokines (Gomariz et al., 2001). Although anti-inflammatory properties of VIP have been extensively reported in the literature (Delgado et al., 2004), new data using VIP-KO or VPAC1-KO indicate that VIP can also exert pro-inflammatory actions (Abad et al., 2010; Yadav et al., 2011). A very recent report reveals that VIP-deficient mice are resistant to the development of encephalomyelitis (EAE), indicating that in these conditions VIP plays unexpected permissive and/or pro-inflammatory actions (Abad et al., 2010). In the same way, VPAC1-KO mice are partially protected from DSS-induced colitis (Yadav et al., 2011). Clearly, a short-term administration of VIP ameliorates the clinical symptoms of chronic inflammation in animal models (Delgado et al., 2004), but conversely, it seems that genetic loss of VIP or VPAC1 receptor in mice result in a pro-inflammatory response. These recent results show that targeting specific VPAC receptors with agonist and/or antagonist could be considered in human therapy (Abad et al., 2010; Yadav et al., 2011). In spite of these recent findings, it is usually proposed that short-term administration of VIP and other VPAC receptor agonists may be beneficial in inflammatory disorders characterized by macrophage activation and Th1/Th2 misbalanced response.
A large body of study has associated VIP with neuroprotection. In the mid-eighties, a first report demonstrated that this peptide was able to prevent neuronal death associated with electrical blockade induced by the addition of tetrodotoxin (TTX) to primary spinal cord cultures (Brenneman and Eiden, 1986). Further studies have demonstrated that VIP plays a neuroprotective effects in various neurodegenerative diseases developed in animal models including Alzheimer's disease (Gozes et al., 1996), Parkinson's disease or encephalomyelitis (Gonzalez-Rey et al., 2005; 2006). These neuroprotective actions of VIP were associated with glial cells possessing VPAC receptors. Clearly, VIP induced from glial cells the secretion of various trophic molecules having neuroprotective properties (Dejda et al., 2005) such as IL-1, IL-6, protease nexin-1, the chemokine RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted) and MIP (Macrophage Inflammatory Proteins). Moreover, VIP inhibits the production of pro-inflammatory cytokines such as TNF-α and/or IL-1β secreted by activated microglia, which is involved in neuro-inflammation observed in Parkinson's disease (Delgado and Ganea, 2003). VIP also induces neuroprotective effects by increasing the secretion of ADNF (activity-dependent neurotrophic factor) and/or by increasing the concentration of ADNP mRNA (activity-dependent neurotrophic protein) (Brenneman and Gozes, 1996; Gozes et al., 2000). These two protective proteins that belong to the heat shock protein family are able to prevent the neuronal death (Brenneman and Gozes, 1996) and represent some of most potent neuroprotective agents secreted by astroglia in response to VIP. Although the major neuroprotective effects of VIP can be explained by activation of adenylyl cyclase through VPAC receptors (Brenneman, 2007), some reports indicate that VIP-mediated effects on protection did not involve cAMP but rather a mobilization of intracellular calcium in astrocytes (Brenneman, 2007). Recently, it has been suggested that the VPAC2 receptor could be a potential target for the development of antipsychotic drugs related to duplications of VPAC2 receptor gene in schizophrenia (Vacic et al., 2011). However, a major drawback with the use of VIP in therapy is its high sensitivity to protease degradation. Indeed, removing of the first His1-Ser2 residues by peptidases, such as DPPIV (dipeptidyl peptidase IV), induces a drastic loss of affinity (Gourlet et al., 1997a,b). To circumvent this problem, VIP could be modified to increase its resistance to degradation by N-acylation of the peptide N-terminal end or by substitution of residues involved in proteolytic consensus sequences (dibasic doublets). Recent data indicated that N-terminal modifications of PACAP confer resistance to DPPIV (Bourgault et al., 2008). In the same way, acetylation of N-terminal end of VIP increases its stability in the presence of human serum (personal data). Other strategies have been developed to protect peptide against degradation by insertion of VIP into micelles or nanoparticles (Fernandez-Montesinos et al., 2009; Onyüksel and Mohanty, 2009). A second major obstacle that reduces the therapeutic use of VIP in humans is its ability to interact at high affinity with different receptors such as VPAC1 and VPAC2 subtypes but also, with lower affinity, with other class B GPCRs such as PACAP receptor, secretin receptor and/or GRF receptor (Laburthe et al., 2007). These cross-interactions may be responsible for the existence of strong side effects induced by VIP in humans including hypotension and diarrhoea (Laburthe et al., 2007). In this context, the development of specific ligands for VPAC1 and VPAC2 receptors with no affinity with other class B GPCRs is clearly crucial. It should be noted that only one non-peptide antagonist having low affinity for VPAC2 receptor is yet available (Chu et al., 2010). There is an abundant literature regarding the pharmacology of these receptors (Robberecht and Waelbroeck, 1998); moreover, drastic differences between species of VPAC receptor pharmacology have been described (Laburthe et al., 2002). Analysis of VIP structure–function relationships by a complete alanine scan (Nicole et al., 2000) allowed us to rationally design the most potent and specific peptide agonist for VPAC1 receptor currently available, that is [Ala11,22,28]-VIP (Nicole et al., 2000). This VIP derivative has 1000 times higher affinity for the VPAC1 receptor, which is mainly involved in anti-inflammatory action of VIP (Delgado et al., 2004), than for the VPAC2 receptor (Nicole et al., 2000). A selective high-affinity antagonist of the VPAC1 receptor, that is [Ac-His1,D-Phe2,K15, R16, L27]VIP(3–7)/GRF(8–27) named PG 97–269, was characterized (Gourlet et al., 1997a,b). The amino acid sequence of this antagonist has many similarities and identities with the sequence of VIP. However, one of the major differences is the presence of a d-phenylalanine in position 2 instead of a serine. This substitution probably plays an important role in antagonist properties of PG 97–269. Indeed, the presence of D-Phe, a hydrophobic residue, results in a perturbation in the formation of N-cap motif (Neumann et al., 2008) involving residues 2–6. Regarding the VPAC2 receptor, the cyclic peptide analogue of VIP [Ac-Glu8,OCH3-Tyr10,Lys12,Nle17,Ala19,Asp25,Leu26,Lys27,28-VIP(cyclo 21–25)] or Ro 25–1392 is a potent and selective agonist (Xia et al., 1997). In our opinion, there is still no satisfactory VPAC2 receptor antagonist since PG 99–465, a VIP analogue that antagonizes VIP action on VPAC2 receptor, has significant agonist activity on human VPAC1 receptor (Moreno et al., 2000).