Calpain facilitates the neuron death induced by 3-nitropropionic acid and contributes to the necrotic morphology

Zhen Pang, Vimala Bondada, Tomoko Sengoku, Robert Siman, James W. Geddes

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

3-Nitropropionic acid (3NP), an irreversible inhibitor of succinate dehydrogenase, has been used to model features of neurodegenerative disorders including Huntington disease, as well as acute neuronal insults such as cerebral ischemia. 3NP induces rapid necrosis and delayed apoptosis in primary cultures of rat hippocampal neurons. Low levels of extracellular glutamate shift the cell death mechanism to necrosis, whereas antagonism of NMDA receptors results in predominately apoptotic death. In the present study, the involvement of cysteine proteases in the morphologic and biochemical alterations accompanying 3NP-induced neuron death was investigated. Immunoblots of spectrin breakdown products indicated Ca2+-dependent cysteine protease (calpain) activation within the 8 hours of 3NP administration, whereas caspase-3 activation was not evident until 16 to 48 hours after treatment. The NMDA receptor antagonist MK-801 (dizocilpine) decreased 3NP-induced calpain activity, but did not alter caspase-3 activity. Similar to MK-801, calpain inhibitors (Z-Val- Phe.H and Z-Leu-Phe-CONHEt) shifted the cell death morphology towards apoptosis and delayed, but did not prevent, the 3NP-induced cell death. Together, the results indicate that following 3NP administration, increased calpain activity precedes caspase-3 activation, contributes to the necrotic morphology, and facilitates and accelerates the cell death.

Original languageEnglish
Pages (from-to)633-643
Number of pages11
JournalJournal of Neuropathology and Experimental Neurology
Volume62
Issue number6
DOIs
StatePublished - Jun 1 2003

Keywords

  • Apoptosis
  • Excitotoxicity
  • Huntington disease
  • N-methyl-D-aspartate
  • Necrosis
  • Spectrin

ASJC Scopus subject areas

  • General Medicine

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