Protection against glucose‐induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3

Abstract

Glutamate carboxypeptidase II (GCP II) inhibition has previously been shown to be protective against long-term neuropathy in diabetic animals. In the current study, we have determined that the GCP II inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell death (PCD) and neurite degeneration in dorsal root ganglion (DRG) neurons in a cell culture model of diabetic neuropathy. In this model, inhibition of caspase activation is mediated through the group II metabotropic glutamate receptor, mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist (S)-a-ethylglutamic acid (EGLU). In contrast, group I and III mGluR inhibitors have no effect on 2-PMPA neuroprotection. Furthermore, we show that two mGluR3 agonists, the direct agonist (2R,4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC) and N-acetyl-aspartyl-glutamate (NAAG) provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2-PMPA neuroprotection is mediated by increased NAAG activity. Inhibition of GCP II or mGluR3 may represent a novel mechanism to treat neuronal degeneration under high-glucose conditions.

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

“…at both gene and protein level in DRG and sciatic nerve in the diabetic peripheral nervous system and furthermore that TGF-β . in vitro is able to induce cellular injury both in embryonic DRG and neurites, a structure that mimics changes in the axon in vivo (Berent-Spillson et al, 2004;Russell et al, 2000). In the present study, Using QRT-PCR, TGF-β2 mRNA was primarily increased in DRG tissue of diabetic rats.…”

Neuroprotective effects of mGluR II and III activators against staurosporine- and doxorubicin-induced cellular injury in SH-SY5Y cells: New evidence for a mechanism involving inhibition of AIF translocation

“…To some extent our data on the measured apoptotic parameters are in line with previous studies, which demonstrated the neuroprotective effects of mGluR II agonists on the St-induced DNA fragmentation, although caspase-3 activity was not measured in these studies (Guo et al, 2006;Kingston et al, 1999). Taking into consideration the data where both apoptotic parameters were measured, it has been shown that mGluR II agonist, 1,S,3R-APDC and mGluR7 agonist, AMN082 prevented the high glucose-induced cell death in dorsal root ganglion neurons co-cultured with Schwann cells and the sevofluran-induced cell damage in the rat hippocampus, respectively (Berent-Spillson et al, 2004;Wang et al, 2012). Moreover, the attenuation of caspase-3 activity by the mGluR III agonist, ACPT-I was demonstrated in the kainate-evoked cell death in primary cortical and hippocampal neurons, although the DNA fragmentation was not investigated in this study (Domin et al, 2014).…”

“…mGluR I agonist -DHPG, mGluR II agonist -LY354740, mGluR III agonists: L-AP4, L-SOP), in primary neuronal cell cultures where cell damage was induced by various pro-apoptotic stimuli (e.g. low potassium; β-amyloid, NMDA, NO, high glucose, staurosporine, etoposide) (Allen et al, 1999(Allen et al, , 2000Berent-Spillson et al, 2004;Borodezt and D'Mello, 1998;Copani et al,1995;Kingston et al, 1999;Vincent et al, 1997Vincent et al, , 1999aVincent and Maiese, 2000). Unlike in neuronal cells, the anti-apoptotic action of mGluRs activators was previously described for other cells e.g.…”

Driving Cellular Plasticity and Survival Through the Signal Transduction Pathways of Metabotropic Glutamate Receptors

“…Protection by the mGluR system appears to function at two distinct levels. Activation of the mGluRs directly prevents induction of caspase activity (Berent- Spillson, A et al, 2004, Chong, ZZ et al, 2003d, Kajta, M et al, 2005. In addition, mGluRs employ more upstream mechanisms that preserve mitochondrial membrane potential and prevent the release of cytochrome c (Baskys, A et al, 2005, Blandini, F et al, 2004, Chong, ZZ et al, 2005c, Lin, SH et al, 2001b.…”