Neuroprotection produced by the NAALADase inhibitor 2-PMPA in rat cerebellar neurons

Frank C. Tortella, Yu Lin, Haresh Ved, Barbara S. Slusher, Jitendra R. Dave

Research output: Contribution to journalArticlepeer-review

Abstract

The present study examined the neuroprotective actions of the N- acetylated-α-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 (EC50 = 8.4 μM). 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 mGlu3 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. (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)31-37
Number of pages7
JournalEuropean Journal of Pharmacology
Volume402
Issue number1-2
DOIs
StatePublished - Aug 18 2000
Externally publishedYes

Keywords

  • (Rat)
  • NAALADase inhibition (N-acetylated-α-linked-acidic dipeptidase)
  • Neuroprotection
  • Stroke

ASJC Scopus subject areas

  • Pharmacology

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