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Inhibition of the interleukin-1β converting enzyme family rescues neurons from apoptotic death

Abstract

The interleukin-1β converting enzyme (ICE) family of cysteine proteases has been implicated in apoptosis. This study tested the effects of a novel pan-ICE family inhibitor, boc-aspartyl(OMe)-fluoromethylketone (boc-Asp-CH2F), against low potassium-induced apoptosis of cultured rat cerebellar granule neurons (CGN). A single application of this cell-permeant compound (20 μM) inhibited apoptotic cell death up to 48 h. Classical apoptotic changes were monitored by fluorescence microscopy, DNA fragmentation and scanning electron microscopy (SEM). A control peptidic fluoromethylketone (boc-Thr-CH2F), and inhibitors to calpain (Ac-Leu-Leu-norleucinal), cathepsin B (Z-Phe-Ala-CH2F), and CPP32-like proteases (Z-DEVD-CH2F), failed to prevent apoptotic death. An 35S-methionine incorporation assay verified that, unlike cycloheximide, boc-Asp-CH2F did not inhibit protein synthesis, hence excluding this as a rescuing mechanism. Although ICE was not detected by northern blot analysis, both CPP32 and Nedd2 expression were found to increase during apoptosis. Kinetic assays with cell extracts from boc-Asp-CH2F-treated neurons measured reduced rates of cleavage for DEVD-pNA and LEVD-pNA. At present, ICE-like proteases remain viable candidates for mediating neuronal death.

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Lynch, T., Vasilakos, J., Raser, K. et al. Inhibition of the interleukin-1β converting enzyme family rescues neurons from apoptotic death. Mol Psychiatry 2, 227–238 (1997). https://doi.org/10.1038/sj.mp.4000242

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  • DOI: https://doi.org/10.1038/sj.mp.4000242

Keywords

  • apoptosis
  • potassium
  • cerebellar granule neurons
  • cysteine proteases
  • ICE homologs

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