Neuroprotection produced by the NAALADase inhibitor 2-PMPA in rat cerebellar neurons.
The present study examined the neuroprotective actions of the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) in four in vitro models of neurotoxicity. Using neuron-enriched primary cultures derived from rat embryo (E15) cerebellum, 2-PMPA afforded 100% neuroprotection from injuries induced by hypoxia (EC(50)=8.4 microM). In contrast, against glutamate or N-methyl-D-aspartate (NMDA) injury, 2-PMPA was less potent and its efficacy limited to a maximum of 46% and 16%, respectively. 2-PMPA was not effective against veratridine-induced injury. Also, the less potent analog of 2-PMPA, 2-[phosphonomethyl]succinic acid (2-PMSA), was ineffective. Unlike 2-PMPA, the endogenous NAALADase substrate and mGlu(3) receptor agonist N-acetyl-aspartyl-glutamate (NAAG) was neuroprotective against all four injury mechanisms and compared to 2-PMPA, exhibited a different "phosphate effect" on neuroprotection. These results confirm the superior efficacy of 2-PMPA to protect against injury caused by cellular anoxia, and are discussed relative to upstream modulation of hyperglutamatergic activity vs. downstream modulation of metabotropic receptors as possible targets for ischemia/stroke therapy.
Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA. frank.tortella@na.amedd.mil
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D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D043425:Glutamate Carboxypeptidase II; D018698:Glutamic Acid / Q000633:toxicity; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014701:Veratridine / Q000633:toxicity
C402107:2-(phosphonomethyl)pentanedioic acid; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D018698:Glutamic Acid; D016202:N-Methylaspartate; D014701:Veratridine; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II