The VPAC ₂ agonist peptide histidine isoleucine (PHI) up‐regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1 ^G93A ) 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.

The Concise Guide toPHARMACOLOGY2013/14: Transporters

“…68; 98), or prevent its down-regulation ( e.g. 56). A thermodynamically uncoupled Cl - flux, activated by Na + and glutamate 59,64,73 (Na + and aspartate in the case of GltPh 82), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability 88,92.…”

Differential Regulation of Glutamate Transporter Subtypes by Pro-Inflammatory Cytokine TNF-α in Cortical Astrocytes from a Rat Model of Amyotrophic Lateral Sclerosis

“…The subsequent identification of splice variants of this transporter was followed by the demonstration of distinct regulatory profiles for the most abundant isoforms, namely GLT-1a and GLT-1b [7], [8]. Differences in the regulation of these splice variants could indeed explain their altered expression ratio in pathological contexts, including ALS [9]–[11]. It is, however, noteworthy that so far, the majority of biochemical studies failed to distinguish between these two isoforms or essentially focused on GLT-1a because the distinctive roles of each of these isoforms and their physiological relevance remain poorly understood.…”

PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis

“…Recently a VPAC2 agonist, peptide histidine isoleucine, was found to up-regulate beneficial glutamate transporter activity in the corpus callosum of SOD1 rats (Goursaud et al, 2011). Our results further indicate that the VIP/PACAP receptor family plays distinct and significant roles in ALS.…”