Protection against glucose-induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3.
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)-alpha-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.
Berent-Spillson
Alison
A
University of Michigan Neuroscience Program, Ann Arbor, Michigan 48109-0588, USA.
Robinson
Amanda M
AM
Golovoy
David
D
Slusher
Barbara
B
Rojas
Camilo
C
Russell
James W
JW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003929:Diabetic Neuropathies / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D005947:Glucose / Q000633:toxicity*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism
C402107:2-(phosphonomethyl)pentanedioic acid; D004151:Dipeptides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; C027172:isospaglumic acid; D043425:Glutamate Carboxypeptidase II; D005947:Glucose