title: The VPAC2 agonist peptide histidine isoleucine (PHI) up-regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1G93A) by inhibiting caspase-3 mediated inactivation of GLT-1a.
abstract: Degeneration of corpus callosum appears in patients with amyotrophic lateral sclerosis (ALS) before clinical signs of upper motor neuron death. Considering the ALS-associated impairment of astrocytic glutamate uptake, we have characterized the expression and activity of the glutamate transporter isoforms GLT-1a and GLT-1b in the corpus callosum of transgenic rats expressing a mutated form of the human superoxide dismutase 1 (hSOD1(G93A)). We have also studied the effect of peptide histidine isoleucine (PHI), a vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 2 (VPAC(2)) agonist on glutamate transporters both in vivo and in callosal astrocytes. Before the onset of motor symptoms, the expression of both transporter isoforms was correlated with a constitutive activity of caspase-3. This enzyme participates in the down-regulation of GLT-1 in ALS, and here we demonstrated its involvement in the selective degradation of GLT-1a in the white matter. A single stereotactic injection of PHI into the corpus callosum of symptomatic rats decreased caspase-3 activity and promoted GLT-1a expression and uptake activity. Together, with evidence for a reduced expression of prepro-VIP/PHI mRNA in the corpus callosum of transgenic animals, these data shed light on the modulatory role of the VIP/PHI system on the glutamatergic transmission in ALS.
authors: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, 54.10, Av. Hippocrate 54, 1200 Brussels, Belgium.
authors: Stéphanie
authors: S
authors: Goursaud
authors: Marylène C
authors: MC
authors: Focant
authors: Julie V
authors: JV
authors: Berger
authors: Yannick
authors: Y
authors: Nizet
authors: Jean-Marie
authors: JM
authors: Maloteaux
authors: Emmanuel
authors: E
authors: Hermans
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001692:Biological Transport; D053148:Caspase 3 / Q000378:metabolism*; D003337:Corpus Callosum / Q000187:drug effects* / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D010451:Peptide PHI / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014660:Vasoactive Intestinal Peptide
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D005971:Glutamates; C571326:MOG protein, human; C571328:Mog protein, rat; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010451:Peptide PHI; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C000606290:SOD1 protein, human; D014660:Vasoactive Intestinal Peptide; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D053148:Caspase 3