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

Goursaud, Stéphanie;Focant, Marylène;Berger, Julie V.;Nizet, Yannick;Hermans, Emmanuel;et.al.
(2011) The FASEB Journal — Vol. 25, n° 10, p. 3674-3686 (2011)

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Authors
  • Goursaud, StéphanieUCLouvain
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  • Focant, MarylèneUCLouvain
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  • Berger, Julie V.UCLouvain
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  • Nizet, YannickUCLouvain
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  • Maloteaux, Jean-MarieUCLouvain
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  • Hermans, Emmanuelorcid-logoUCLouvain
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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.
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Goursaud, S., Focant, M., Berger, J. V., Nizet, Y., Maloteaux, J.-M., & Hermans, E. (2011). 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. The FASEB Journal, 25(10), 3674-3686. https://doi.org/10.1096/fj.11-182337 (Original work published 2011)