NAALADase inhibition protects motor neurons against chronic glutamate toxicity.
Glutamate toxicity is implicated in the pathogenesis of amyotrophic lateral sclerosis. The neuropeptide N-acetyl-aspartyl glutamate (NAAG) appears to function both as a storage form for glutamate and as a neuromodulator at glutamatergic synapses. N-acetylated-alpha-linked acidic dipeptidase (NAALADase; also termed glutamate carboxypeptidase II) yields N-acetyl aspartate (NAA) and glutamate. Prior studies have demonstrated NAALADase upregulation in motor cortex and increased NAAG, NAA and glutamate in cerebrospinal fluid from amyotrophic lateral sclerosis patients. The potent NAALADase inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), was tested in an in vitro model of chronic glutamate-mediated motor neuron degeneration. Neuroprotection was determined (1) biochemically, by measuring choline acetyltransferase activity, (2) immunohistochemically, by counting neurofilament-H-positive motor neurons and (3) morphologically, with phase contrast microscopy. 2-PMPA (10 microM) had significant neuroprotective effects on motor neurons as evidenced by increased choline acetyltransferase activity, decreased motor neuron loss and improved gross morphology. Results suggest that NAALADase inhibitors protect against chronic glutamate-mediated motor neuron degeneration and may prove therapeutic towards amyotrophic lateral sclerosis.
Thomas
Ajit G
AG
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 21224, USA.
Corse
Andrea M
AM
Coccia
Carol F
CF
Bilak
Masako M
MM
Rothstein
Jeffrey D
JD
Slusher
Barbara S
BS
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009924:Organ Culture Techniques; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
C402107:2-(phosphonomethyl)pentanedioic acid; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D018698:Glutamic Acid; D043425:Glutamate Carboxypeptidase II