title: The anti-inflammatory peptide stearyl-norleucine-VIP delays disease onset and extends survival in a rat model of inherited amyotrophic lateral sclerosis.
abstract: Vasoactive intestinal peptide (VIP) has potent immune modulatory actions that may influence the course of neurodegenerative disorders associated with chronic inflammation. Here, we show the therapeutic benefits of a modified peptide agonist stearyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hSOD1(G93A)). When administered by systemic every-other-day intraperitoneal injections during a period of 80 days before disease, SNV delayed the onset of motor dysfunction by no less than three weeks, while survival was extended by nearly two months. SNV-treated rats showed reduced astro- and microgliosis in the lumbar ventral spinal cord and a significant degree of motor neuron preservation. Throughout the treatment, SNV promoted the expression of the anti-inflammatory cytokine interleukin-10 as well as neurotrophic factors commonly considered as beneficial in amyotrophic lateral sclerosis management (glial derived neuroptrophic factor, insulin like growth factor, brain derived neurotrophic factor). The peptide nearly totally suppressed the expression of tumor necrosis factor-α and repressed the production of the pro-inflammatory mediators interleukin-1β, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-α likely accounted for the observed down-regulation of nuclear factor kappa B that modulates the transcription of genes specifically involved in amyotrophic lateral sclerosis (sod1 and the glutamate transporter slc1a2). In line with this, levels of human superoxide dismutase 1 mRNA and protein were decreased by SNV treatment, while the expression and activity of the glutamate transporter-1 was promoted. Considering the large diversity of influences of this peptide on both clinical features of the disease and associated biochemical markers, we propose that SNV or related peptides may constitute promising candidates for amyotrophic lateral sclerosis treatment.
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Goursaud
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schäfer
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Amélie O
authors.initials: AO
authors.lastname: Dumont
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Maxime
authors.initials: M
authors.lastname: Vergouts
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gallo
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Desmet
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Ronald
authors.initials: R
authors.lastname: Deumens
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium. Electronic address: emmanuel.hermans@uclouvain.be.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Hermans
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; C000606290:SOD1 protein, human; C086770:stearyl-norleucine(17)-vasoactive intestinal peptide; D014660:Vasoactive Intestinal Peptide; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Glutamate transporters; NFκ-B; SOD1; VIP