Neuroprotective properties of VIP derivatives and clinical relevance

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Despite the neuroprotective properties of VIP, its use as a drug is limited by its susceptibility to endopeptidases and its poor passage across biological membranes. Several recently described VIP analogues exhibit more promising properties in terms of resistance to endopeptidases and lipophilic status. They include cyclic molecules, such as RO-25-1553, and fatty molecules, such as stearyl-norleucine-VIP. The biochemical designs of stearyl-norleucine-VIP and RO-25-1553, although aimed at achieving similar properties (i.e., resistance to endopeptidases and/or better diffusion through biological membranes), are basically different. RO-25-1553 is a long-acting cyclic VIP analogue [40]. Stearyl-norleucine-VIP is derived from VIP by means of two chemical modifications, namely addition of an N-terminal long-chain fatty acid (stearyl group) and substitution of norleucine for the methionine in position 17. These two compounds have been characterized, albeit to different extents, in terms of binding affinities, receptor coupling, and biological properties. RO-25-1553 is a selective agonist for the VPAC₂ receptor subtypes with low affinity for VPAC₁ receptor subtypes [41]. It stimulates the production of cAMP in transfected cells expressing VPAC₂ receptors [41]. Its effects on cAMP-independent pathways have not been directly studied. RO-25-1553 has been shown to have biological effects including an ability to induce muscle relaxation in isolated trachea [40] and to stimulate in vivo neocortical astrocytogenesis [42]. Stearyl-norleucine-VIP binds with high affinity to both VPAC₁ and VPAC₂ receptors but is a partial agonist for recombinant VIP receptors [43]. Stearyl-norleucine-VIP promotes survival of cultured neurons through cAMP-independent mechanisms [44] and prevents in vivo neuronal degeneration associated with beta-amyloid toxicity [45].        

RO-25-1553 and stearyl-norleucine-VIP administered intracerebrally or intraperitoneally exhibited a potent dose-dependent protective effect against ibotenate-induced lesions of the developing white matter [27, 30]. Furthermore, significant protection against excitotoxic white matter damage was observed when RO-25-1553 or stearyl-norleucine-VIP were injected up to 12 or 8 hours, respectively, after ibotenate administration. These data showed that systemically-injected VIP analogues effectively protect the developing white matter against excitotoxic lesions in a mouse model mimicking brain damage frequently observed in human preterm infants. This protective effect occurred even when the VIP analogues were given several hours after the excitotoxic insult.

Activity-dependent neuroprotective protein (ADNP) has been shown to be induced by VIP and to be essential for embryogenesis and brain development while NAP, an active motif of ADNP, is neuroprotective in a broad range of neurodegenerative disorders [46-49]. Interestingly, NAP was shown to have potent neuroprotective effects against ibotenate-induced excitotoxic damage in the cortical plate and the white matter of P5 mice [50] as well as in a model of neonatal hypoxic-ischemic insult [51]. NAP (generic name davunetide) has been used in clinical trials in patients suffering from amnestic mild cognitive impairment, a precursor to Alzheimer’s disease, without significant side effect [52].