期刊
EXPERIMENTAL NEUROLOGY
卷 263, 期 -, 页码 91-101出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2014.09.022
关键词
Amyotrophic lateral sclerosis; SOD1; NF kappa-B; VIP; Glutamate transporters
资金
- National Fund for Scientific Research (FNRS, Belgium) [3.4560.07, 1.5.085.10, 1.A198.08]
- DIANE research program of the Belgian Walloon Region Ministry (DGTRE)
- Association beige pour les maladies neuromusculaires (ABMM)
- Ministry of Scientific Policy (Belgium, ARC [10/15-026]
- Televie and a Marie-Curie Fellowship [EURON MEST-CT-2005-020589]
- FSR Incoming Post-doctoral Fellowship of the Academie universitaire 'Louvain'
- Marie Curie Actions of the European Commission
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 steatyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hS0D1(G93A)). When administered by systemic eveiy-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-a and repressed the production of the pro-inflammatory mediators interleukin-1 beta, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-alpha 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 slc1 a2). 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. (C) 2014 Elsevier Inc. All rights reserved.
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